MITOMYCIN: 2,111 Adverse Event Reports & Safety Profile

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. JELMYTO is supplied in a kit containing two vials of sterile lyophilized mitomycin for pyelocalyceal solution, 40 mg each, and one vial of 20 mL of sterile hydrogel, to be used as a vehicle for reconstitution. Mitomycin for pyelocalyceal solution is a sterile, lyophilized, grey to greyish-purple, cake or powder that contains mitomycin 40 mg and mannitol 80 mg in each vial. Sterile 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 0.04 g hydroxypropyl methylcellulose, 5.67 g poloxamer, 0.21 g polyethylene glycol, and water for injection in each vial. Once reconstituted, JELMYTO is a clear, purple, viscous liquid at 2°C to 8°C (36°F to 46°F) or semisolid gel at room temperature with a concentration of 4 mg per mL of mitomycin, which may contain a few visible particles and have a pH between 6.0 and 8.0.

Chemical

Structure

INDICATIONS AND USAGE MUTAMYCIN ® (Mitomycin) for Injection is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed. Mitomycin is not recommended to replace appropriate surgery and/or radiotherapy.

AND ADMINISTRATION JELMYTO is for pyelocalyceal use only and not for intravenous use, topical use, or oral administration. ( 2.1 )

Administer

1.3 g of sodium bicarbonate orally the evening prior to, the morning of, and 30 minutes prior to instillation procedure (total of 3.9 g). ( 2.1 ) The dose of JELMYTO to be instilled is 4 mg per mL via ureteral catheter or nephrostomy tube, with total instillation volume based on volumetric measurements using pyelography, not to exceed 15 mL (60 mg of mitomycin). ( 2.2 ) Instill JELMYTO once weekly for six weeks. For patients with a complete response 3 months after JELMYTO initiation, JELMYTO instillations may be administered once a month for a maximum of 11 additional instillations. ( 2.2 )

2.1 Important Administration Instructions See the Instructions for Administration provided separately. JELMYTO is for pyelocalyceal use only. JELMYTO is not for intravenous use, topical use, or oral administration. Prior to every instillation, instruct the patient to take 1.3 g of sodium bicarbonate orally the evening prior to, the morning of, and 30 minutes prior to the instillation procedure (total of 3.9 g). General anesthesia, local anesthesia, sedation, prophylactic antibiotics and/or antihistamines may be used at the discretion of the treating urologist. If the patient is to be anesthetized, advise the patient not to take sodium bicarbonate within 30 minutes prior to the treatment. Consider withholding diuretics one day prior to instillation until 4 hours post-instillation. When instilling JELMYTO, the entire syringe must be emptied within one minute. Advise patients that JELMYTO may discolor urine to a violet to blue color following the instillation procedure. Advise patients to avoid contact with urine for at least six hours post-instillation, to void urine sitting on a toilet, and to flush the toilet several times after use.

2.2 Recommended Dosage The dose of JELMYTO to be instilled is 4 mg per mL via ureteral catheter or a nephrostomy tube, with total instillation volume based on volumetric measurements using pyelography, not to exceed 15 mL (60 mg of mitomycin). Instill JELMYTO once weekly for six weeks. For patients with a complete response 3 months after JELMYTO initiation, JELMYTO instillations may be administered once a month for a maximum of 11 additional instillations.

2.3 Preparation and Handling See the Instructions for Pharmacy for preparation provided separately. JELMYTO is a hazardous drug. Follow applicable special handling and disposal procedures. 1 JELMYTO must be prepared under chilled conditions. Once reconstituted , the admixture will have a concentration of 4 mg of mitomycin per mL and will appear as a viscous liquid for instillation. Reconstituted JELMYTO has reverse thermal properties with a gelation point of approximately 19°C (66°F). Reconstituted JELMYTO should be instilled as soon as possible after reconstitution. Store reconstituted JELMYTO at 20°C to 25°C (68°F to 77°F) for up to 96 hours (4 days). JELMYTO will appear as a semisolid gel when stored under these conditions. Protect reconstituted JELMYTO from light. JELMYTO must be instilled as a chilled solution using a Uroject12 Lever, a Luer Lock syringe, and a ureteral catheter with molded Luer Lock connector. Once chilled at -3°C to 5°C (27°F to 41°F), JELMYTO will convert to a viscous liquid for instillation and is stable for up to 1 additional hour. Reconstituted JELMYTO must be instilled within 1 hour after it is converted to a viscous liquid.

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 )

REACTIONS 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . 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 &gt; 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 &gt; 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 &gt; 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 &lt; 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

AND PRECAUTIONS 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ]</span>.

PRECAUTIONS Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin. The onset of this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen have produced symptomatic relief. A few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin in combination with other chemotherapy and maintained at FIO 2 concentrations greater than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided. Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route of administration), which in rare cases has required cystectomy.

Nursing

Mothers It is not known if mitomycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mitomycin, it is recommended that nursing be discontinued when receiving mitomycin therapy.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Insufficient data from clinical studies of mitomycin are available for patients 65 years of age and older to determine whether they respond differently than younger patients. Post-marketing surveillance suggests that elderly patients may be more susceptible than younger patients to injection site reactions (see ADVERSE REACTIONS: Integument and Mucous Membrane Toxicity ) and hypersensitivity reactions. In general, caution should be exercised when prescribing to elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.