ZUSDURI

Mitomycin (also known as mitomycin-C) is an alkylating drug isolated from the broth of Streptomyces . Mitomycin is a blue-violet crystalline powder with a molecular formula of C 15 H 18 N 4 O 5 , and a molecular weight of 334.33. Its chemical name is 7-amino-9α-methoxymitosane, and it has the following structural formula: Mitomycin is heat stable, has a high melting point, and is freely soluble in organic solvents. ZUSDURI is supplied in a kit containing two vials of sterile lyophilized mitomycin for intravesical solution, 40 mg each, and one vial of 60 mL of sterile hydrogel, to be used as a vehicle for reconstitution. Mitomycin for intravesical solution is a sterile, lyophilized, grey to greyish-purple, cake or powder that contains mitomycin 40 mg and mannitol 80 mg in each vial. Hydrogel is a sterile, clear, colorless gel with or without bubbles at room temperature or clear, colorless liquid at 2°C to 8°C (36°F to 46°F), which contains 0.11 g hydroxypropyl methylcellulose, 17.12 g poloxamer, 0.63 g polyethylene glycol, and water for injection in each vial. Once reconstituted, ZUSDURI is a clear, purple, viscous liquid at 2°C to 8°C (36°F to 46°F) or semisolid gel at room temperature, which may contain a few visible particles and have a pH between 6.0 and 8.0. Chemical Structure

ZUSDURI™ is indicated for the treatment of adult patients with recurrent low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC). ZUSDURI is an alkylating drug indicated for the treatment of adult patients with recurrent low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC). ( 1 )

Administer ZUSDURI by intravesical instillation only. Do not administer by pyelocalyceal instillation or by any other route. ( 2.1 ) The recommended dose of ZUSDURI is 75 mg (56 mL) instilled once weekly for six weeks. ( 2.2 ) 2.1 Important Administration Instructions Administer ZUSDURI by intravesical instillation only. Do not administer by pyelocalyceal instillation or by any other route. 2.2 Recommended Dose The recommended dose of ZUSDURI is 75 mg (56 mL) instilled once weekly for six weeks into the bladder via a urinary catheter. [see Dosage and Administration (2.4) ] 2.3 Preparation Instructions See the Instructions for Pharmacy enclosed in the carton for complete information on preparation. ZUSDURI must be reconstituted with sterile hydrogel under chilled conditions. Reconstituted ZUSDURI has reverse thermal properties with a gelation point of approximately 19°C (66°F) and will appear as a viscous liquid under chilled conditions and a semisolid gel at room temperature. Storage Instructions for Reconstituted ZUSDURI: Instill reconstituted ZUSDURI as soon as possible. If not used immediately, store reconstituted ZUSDURI: under refrigeration at 2℃ to 8℃ (36°F to 46°F) for up to 7 days; or under refrigeration at 2℃ to 8℃ (36°F to 46°F) for up to 6 days followed by no more than 24 hours at room temperature, 20°C to 25°C (68°F to 77°F). Discard 7 days after reconstitution. Protect from light. Avoid excessive heat over 40°C (104°F). ZUSDURI is a hazardous drug. Follow applicable special handling and disposal procedures. 1 2.4 Bladder Instillation of ZUSDURI See the Instructions for Administration enclosed in the carton for complete information on bladder instillation. ZUSDURI must be chilled at -3°C to 5°C (27°F to 41°F) to convert to a viscous liquid prior to instillation. When instilling ZUSDURI, each syringe must be emptied within thirty (30) seconds to avoid gelation. Instillation of ZUSDURI requires syringes and a urinary catheter with fixed Luer Lock connectors. Advise patients that ZUSDURI may discolor urine to a violet to blue color following the instillation procedure. Advise patients for at least 24 hours post-instillation to avoid urine contact with skin, to void urine sitting on a toilet, to wash hands and genital area with water and soap after each urination, and to flush the toilet several times after use.

ZUSDURI is contraindicated in patients with: Perforation of the bladder [see Warnings and Precautions (5.1) ], Prior hypersensitivity reactions to mitomycin or any component of the product. Perforation of the bladder, ( 4 ) Prior hypersensitivity reaction to mitomycin or any component of the product. ( 4 )

The most common (≥ 10%) adverse reactions, including laboratory abnormalities, that occurred in patients were increased creatinine, increased potassium, dysuria, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, increased eosinophils, decreased lymphocytes, urinary tract infection, decreased neutrophils, and hematuria. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UroGen Pharma at 1-855-987-6436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. The safety of ZUSDURI was evaluated in ENVISION, a single-arm, multicenter study in 240 patients with recurrent LG-IR-NMIBC [see Clinical Studies (14) ]. Patients received 75 mg ZUSDURI instilled once a week for 6 consecutive weeks. The median number of doses of ZUSDURI administered to patients was 6 (range 1-6) doses and 228 patients (95%) received all six scheduled doses. Serious adverse reactions occurred in 12% of patients who received ZUSDURI, including urinary retention (0.8%) and urethral stenosis (0.4%). A fatal adverse reaction of cardiac failure occurred in 1 patient (0.4%) receiving ZUSDURI. Permanent discontinuation of ZUSDURI due to an adverse reaction occurred in 2.9% of patients, including 1.7% who discontinued due to a renal or urinary disorder. Dosage interruption of ZUSDURI due to adverse reactions occurred in 10% of patients. Adverse reactions (≥ 2%) which required dosage interruption were urinary tract infection (2.5%) and dysuria (2.5%). The most common (≥ 10%) adverse reactions, including laboratory abnormalities, that occurred in patients were increased creatinine, increased potassium, dysuria, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, increased eosinophils, decreased lymphocytes, urinary tract infection, decreased neutrophils, and hematuria. Table 1 summarizes the adverse reactions in ENVISION. Table 1: Adverse Reactions (≥ 10% All Grades Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. ) in Patients Who Received ZUSDURI in ENVISION Adverse Reaction ZUSDURI N = 240 All Grades (%) Grade 3 or 4 Only includes Grade 3 adverse reactions (%) Renal and urinary disorders Dysuria 23 0.4 Hematuria Includes multiple related terms 10 0 Infections and infestations Urinary tract infection 12 0.8 Clinically relevant adverse reactions occurring in < 10% of patients receiving ZUSDURI in ENVISION included increased urinary frequency, fatigue, urinary incontinence, urinary retention, urethral stenosis, genital pain, urinary urgency, genital edema, genital pruritus, genital rash, urethritis, acute kidney injury, balanoposthitis, and nocturia. Table 2 summarizes laboratory abnormalities in ENVISION. Table 2: Laboratory Abnormalities (≥ 10% All Grades Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. ) That Worsened From Baseline in Patients Who Received ZUSDURI in ENVISION Laboratory Abnormality ZUSDURI The denominator used to calculate the rate varied from 227 to 238 based on the number of patients with a baseline value and at least one post-treatment value All Grades (%) Grade 3 or 4 Only includes Grade 3 laboratory abnormalities (%) Hematology Hemoglobin Decreased 17 0.8 Eosinophils Increased 15 0 Lymphocytes Decreased 14 0.4 Neutrophils Decreased 10 0.4 Chemistry Creatinine Increased 29 1.3 Potassium Increased 26 2.2 Aspartate Aminotransferase (AST) Increased 15 0.4 Alanine Aminotransferase (ALT) Increased 15 0.4

Storage and Handling Store ZUSDURI at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Avoid excessive heat over 40°C (104°F). Protect from light. ZUSDURI is a hazardous drug. Follow applicable special handling and disposal procedures . 1