Mitomycin

JELMYTO ® is indicated for the treatment of adult patients with low-grade Upper Tract Urothelial Cancer (LG-UTUC). JELMYTO is an alkylating drug indicated for the treatment of adult patients with low-grade Upper Tract Urothelial Cancer (LG-UTUC). ( 1 )

For pyelocalyceal solution: A kit containing the following: Two 40 mg (each) single-dose vials of sterile, lyophilized, grey to greyish-purple, cake or powder of mitomycin for pyelocalyceal solution One single-dose vial of 20 mL of 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), to be used as a vehicle for reconstitution For pyelocalyceal solution: A kit containing the following: Two 40 mg (each) single-dose vials of mitomycin for pyelocalyceal solution ( 3 ) One vial of 20 mL sterile hydrogel for reconstitution ( 3 )

JELMYTO is contraindicated in patients with perforation of the bladder or upper urinary tract. Perforation of the bladder or upper urinary tract. ( 4 )

Ureteric Obstruction: Ureteric obstruction may occur. Monitor patients for signs and symptoms of ureteric obstruction. Transient or long-term ureteral stents or alternative procedures may be required. Withhold or permanently discontinue JELMYTO based on the severity of the ureteric obstruction. ( 5.1 ) Bone Marrow Suppression: Thrombocytopenia and neutropenia may occur. Monitor blood counts. Withhold or permanently discontinue JELMYTO based on the severity. ( 5.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 )

5.1 Ureteric Obstruction Ureteric obstruction, including ureteral stenosis and hydronephrosis, occurred in patients receiving JELMYTO. In the Olympus study, ureteric obstruction was reported in 58% (n=41) of patients receiving JELMYTO, including 17% (n=12) of patients who experienced Grade 3 obstruction. The median time to first onset was 72 days (range: 15-462). Interventions in the 41 patients experiencing ureteric obstruction included ureteral stent placement (88%), balloon dilatation (29%), and nephroureterectomy (4.9%). In the 36 patients who required ureteral stent placement, the median duration of indwelling stents was 52 days (range: 1-292). Ureteric obstruction did not resolve or resolved with sequelae in 44% (n=18) of these patients. Of the 41 patients who experienced ureteric obstruction, 17% (n=7) experienced Grades 1-2 increase in serum creatinine. In the 42 patients who only received JELMYTO during the treatment phase (no maintenance therapy), ureteric obstruction was reported in 40% (n=17). Monitor patients for signs and symptoms of ureteric obstruction, including flank pain, and fever, and for changes in renal function. Patients who experience obstruction may require transient or long-term ureteral stents or alternative procedures. Withhold or permanently discontinue JELMYTO based on the severity of ureteric obstruction.

5.2 Bone Marrow Suppression The use of JELMYTO can result in bone marrow suppression, particularly thrombocytopenia and neutropenia. In the Olympus study, Grade 3 thrombocytopenia occurred in three patients, Grade 3 anemia in one patient, and Grade 3 neutropenia in one patient. Gross extravasation of JELMYTO via urinary tract perforation or impaired mucosa was not observed in these patients. The following tests should be obtained prior to each treatment: Platelet count, white blood cell count differential and hemoglobin. Withhold JELMYTO for Grade 2 thrombocytopenia or neutropenia. Permanently discontinue for Grade 3 or greater thrombocytopenia or neutropenia.

5.3 Embryo-Fetal Toxicity Based on findings in animals and mechanism of action, JELMYTO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of mitomycin resulted in teratogenicity. Advise females of reproductive potential to use effective contraception during treatment with JELMYTO and for 6 months following the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with JELMYTO and for 3 months following the last dose [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ].

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Ureteric Obstruction [see Warnings and Precautions (5.1) ] Bone Marrow Suppression [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥ 20%) are ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, nausea, abdominal pain, fatigue, dysuria, and vomiting. ( 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 JELMYTO was evaluated in Olympus, an open-label, single-arm study in 71 patients with LG-UTUC [see Clinical Studies (14) ] . For the 71 patients treated with JELMYTO during the treatment period, the median number of instillations was 6 (range: 3-6). Following initial treatment, 29 patients were treated with up to 11 doses of maintenance instillations, with a median of 6 instillations (range: 1-11). Serious adverse reactions occurred in 39% of patients who received JELMYTO. Serious adverse reactions in > 3% of patients included ureteric obstruction (including ureteric stenosis and hydronephrosis), flank pain, and urosepsis. Two deaths occurred due to cerebrovascular accident and failure to thrive. JELMYTO was permanently discontinued due to an adverse reaction in 17 (24%) patients, including 11 patients who discontinued during the treatment phase and 6 who discontinued during the maintenance phase. Adverse reactions resulting in study drug discontinuation of JELMYTO in > 3% of patients who received JELMYTO included ureteric obstruction. Dosage interruptions due to an adverse reaction occurred in 37% of patients who received JELMYTO. Adverse reactions requiring dosage interruption in > 3% of patients who received JELMYTO included renal dysfunction, ureteric obstruction, urinary tract infection, and flank pain. The most common adverse reactions (≥ 20%) reported were ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, nausea, abdominal pain, fatigue, dysuria, and vomiting. Table 1 summarizes the adverse reactions in Olympus. Table 1: Adverse Reactions (≥ 10% All Grades) in Patients Who Received JELMYTO in Olympus JELMYTO Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 5.0 (NCI CTCAE v5) (n=71) Adverse Reaction All Grades (%) Grade 3-4 (%) Renal and urinary disorders Ureteric Obstruction Includes hydronephrosis, obstructive uropathy, pelvi-ureteric obstruction, ureteric obstruction, ureteric stenosis, and urinary tract obstruction. 58 17 Ureteric stenosis 44 9 Hydronephrosis 18 6 Urinary tract obstruction 7

1.4 Pelvi-ureteric obstruction 6

1.4 Ureteric obstruction 2.8

1.4 Obstructive uropathy 1.4 0 Flank pain Includes flank pain and back pain. 41

2.8 Hematuria Includes hematuria and hemorrhage urinary tract. 34

2.8 Urinary tract infection Includes urinary tract infection, pyelonephritis, and urinary tract infection fungal. 34

4.2 Renal dysfunction Includes renal impairment, acute kidney injury, and renal failure. 25

2.8 Dysuria 23 0 Pollakiuria 14 0 Gastrointestinal disorders Nausea 25

1.4 Abdominal pain Includes abdominal pain and abdominal pain lower. 24

1.4 Vomiting 20

4.2 General disorders and administration site conditions Fatigue Includes asthenia, fatigue, and malaise. 24

1.4 Pyrexia 13

1.4 Chills 11 0 Blood and lymphatic system disorders Anemia 14

1.4 Skin and subcutaneous tissue disorders Rash Includes rash, dermatitis allergic, rash generalized, genital rash, eczema, rash maculo-papular, and skin exfoliation. 14 0 Pruritus 13 0 Metabolism and nutrition disorders Decreased appetite 10 0 Vascular disorders Hypertension 10

4.2 Selected clinically relevant adverse reactions in < 10% and ≥ 2% of patients who received JELMYTO in Olympus include urinary tract inflammation, bladder spasm, urosepsis, hypersensitivity, and instillation site pain. Table 2 summarizes the laboratory abnormalities in Olympus. Table 2: Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients Who Received JELMYTO in Olympus Laboratory Abnormality Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 5.0 (NCI CTCAE v5). Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. JELMYTO All Grades (%) Grade ≥ 3 (%) Hematology Anemia 38 0 Lymphopenia 21

2.9 Thrombocytopenia 21

2.8 Chemistry Estimated Glomerular Filtration Rate (eGFR) eGFR calculated per MDRD (Modification of Diet in Renal Disease) equation 38 11 Creatinine increased 34 0 Hypoalbuminemia 28

2.8 Hypocalcemia 16 0 Hyperuricemia 16 16 Hyperkalemia 13

1.4 Hypernatremia 11 0

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings in animals and mechanism of action, JELMYTO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on JELMYTO use in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of mitomycin resulted in teratogenicity (see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively. Data Animal Data Teratological changes have been noted with mitomycin in animal studies.

8.2 Lactation Risk Summary There are no data on the presence of mitomycin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with JELMYTO and for 1 week following the last dose.

8.3 Females and Males of Reproductive Potential JELMYTO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating JELMYTO. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with JELMYTO and for 6 months following the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with JELMYTO and for 3 months following the last dose.

8.4 Pediatric Use Safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of patients in the Olympus trial, 75% (53 patients) were 65 years of age and over and 37% (26 patients) were 75 years of age and over. Clinical studies of JELMYTO did not include sufficient numbers of younger patients less than 65 years old to determine whether they respond differently from older patients.

8.6 Renal Impairment No data are available in patients with severe renal impairment. Avoid use of JELMYTO in patients with a Glomerular Filtration Rate of < 30 mL/min.

Mitomycin inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.