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) ].

t 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.

ical 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: 0-11). 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, abdominal pain, fatigue, renal dysfunction, nausea, 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 abdominal pain includes abdominal pain and abdominal pain lower. 28 1.4 nausea 25 1.4 vomiting 20 4.2 general disorders and administration site conditions fatigue includes asthenia and fatigue. 27 1.4 pyrexia 13 1.4 chills 11 0 blood and lymphatic system disorders anemia 14 1.4 skin and subcutaneous tissue disorders 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

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.

nto the pyelocalyceal system, jelmyto forms a semisolid gel which dissolves from normal kidney urine flow releasing mitomycin for up to 4 to 6 hours. mitomycin is eliminated unchanged in the urine. systemically absorbed mitomycin is rapidly cleared from the serum and approximately 10% is excreted unchanged in the urine. metabolism mitomycin is metabolized primarily in the liver, but metabolism occurs in other tissues as well. it is believed that the rate of clearance is inversely proportional to the maximal serum concentration because of saturation of the degradative pathways.

f clearance is inversely proportional to the maximal serum concentration because of saturation of the degradative pathways.

ion volume based on individualized volumetric measurements using pyelography with the intent to fill the renal pelvis. patients were treated with 6 instillations once a week. patients who maintained a complete response (cr) after the initial treatment period were allowed to proceed to the follow-up period. during the initial treatment period, 71 patients were treated with jelmyto, of whom 41 were subsequently continued in the follow-up period. during the follow-up period, 29 patients received at least one dose of maintenance therapy. the baseline demographic and disease characteristics for the trial population were: median age 71 years (range: 42-87 years); 68% male; 87% white; 90% eastern cooperative oncology group performance status (ecog ps) 0 or 1 and 10% ecog ps 2. the median number of papillary lesions subsequent to debulking and/or biopsy and prior to treatment was 1 lesion (range: 1, 5), the median diameter of the largest lesion was 8.0 mm (range: 5.0, 15.0), and the median total visible tumor burden was 10.0 mm (range: 5.0, 25.0). twenty-six (37%) patients underwent tumor debulking during the six weeks preceding enrollment. of 71 enrolled patients, 48% had tumors located in regions not amenable to endoscopic resection. general anesthesia was used in 37% of patients for at least one instillation during the treatment period and for 83% of patients for at least one instillation during the follow-up period. the major efficacy outcome measures were cr and durability of cr at 12 months after determination of cr based on ureteroscopic and local pathology assessment. cr was defined as complete absence of tumor lesions in the ipsilateral pyelocalyceal system at 3 months after initiation of jelmyto by urine cytology and ureteroscopy. biopsy was performed if warranted. durability of response in patients with a cr was evaluated at 3, 6, 9 and 12 months following the initial assessment. assessment of durability of cr subsequent to these evaluations was performed per local standards of care. forty-one patients (58%) achieved cr in the study (95% ci: 45%, 69%). of the 41 patients who achieved cr, 23 (56%) of the patients remained at cr at the 12-month time point for assessment of durability, 8 (20%) experienced recurrence of disease, and 10 (24%) were unable to be evaluated (died, discontinued from the study, or were indeterminate for ongoing response). the median duration of response was not reached (range: 0, 18.8 months and ongoing). one patient, who achieved 6 months of durable cr, was diagnosed with metastatic urothelial carcinoma approximately 4.5 months after the last dose of study medication and died from the disease.

precautions (5.3) and use in specific populations (8.1) ] . advise females of reproductive potential to use effective contraception during treatment with jelmyto and for 6 months following the last dose [see use in specific populations (8.3) ] . 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 (8.3) ]. lactation advise women not to breastfeed during treatment with jelmyto and for 1 week following the last dose [see use in specific populations (8.2) ]. important post-treatment instructions [see dosage and administration (2.1) ] advise patients that jelmyto contains mitomycin which is a violet to blue color and may discolor urine following the instillation procedure. advise patients to avoid contact with urine for at least six hours post-instillation. advise patients to void sitting on a toilet, flush the toilet several times after use, and to wash hands, perineum or glans with soap and water after each instillation procedure. advise patients to wash clothing soiled with urine promptly and separately from other clothing.

to become pregnant: your healthcare provider will check to see if you are pregnant before starting treatment with jelmyto. you should use effective birth control (contraception) during treatment with jelmyto and for 6 months after the last dose. talk to your healthcare provider if you have questions about birth control options that are right for you. males being treated with jelmyto: if you have a female partner who is able to become pregnant, you should use effective birth control (contraception) during treatment with jelmyto and for 3 months after the last dose. are breastfeeding or plan to breastfeed. it is not known if jelmyto passes into your breast milk. do not breastfeed during treatment with jelmyto and for 1 week after the last dose. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. know the medicines you take. keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. especially tell your healthcare provider if you take water pills (diuretic). how will i receive jelmyto? your healthcare provider will tell you to take a medicine called sodium bicarbonate before each jelmyto treatment. your healthcare provider will provide instructions about how and when to take sodium bicarbonate. jelmyto will be given to you by your healthcare provider. you will receive jelmyto 1 time a week for 6 weeks. it is important that you receive all 6 doses of jelmyto according to your healthcare provider's instructions. your healthcare provider may recommend up to an additional 11 monthly doses. if you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. jelmyto is given to your kidney through a tube called a catheter. during treatment with jelmyto, your healthcare provider may tell you to take additional medicines or change how you take your current medicines. ask your healthcare provider if you have any questions. after receiving jelmyto: jelmyto may cause your urine color to change to a violet to blue color. avoid contact between your skin and urine for at least 6 hours. to urinate, males and females should sit on a toilet and flush the toilet several times after you use it. after going to the bathroom, wash your hands, your inner thighs, and genital area well with soap and water. clothing that comes in contact with urine should be washed right away and washed separately from other clothing. what are the possible side effects of jelmyto? jelmyto may cause serious side effects, including: swelling and narrowing of the tube that carries urine from the kidney to the bladder (ureteric obstruction). if you develop swelling and narrowing, and to protect your kidney from damage, your healthcare provider may recommend the placement of a small plastic tube (stent) in the ureter to help the kidney drain. tell your healthcare provider right away if you develop side pain or fever during treatment with jelmyto. bone marrow problems. jelmyto can affect your bone marrow and can cause a decrease in your white blood cell, red blood cell, and platelet counts. your healthcare provider will do blood tests prior to each treatment to check your blood cell counts during treatment with jelmyto. your healthcare provider may need to temporarily or permanently stop jelmyto if you develop bone marrow problems during treatment with jelmyto. the most common side effects of jelmyto include: urinary tract infection blood in your urine side pain nausea trouble with urination kidney problems vomiting tiredness stomach (abdomen) pain call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. you can also report side effects to urogen pharma at 1-855-987-6436. general information about jelmyto. medicines are sometimes prescribed for purposes other than those listed in this patient information leaflet. you can ask your pharmacist or healthcare provider for information about jelmyto that is written for healthcare professionals. what are the ingredients of jelmyto? active ingredient: mitomycin inactive ingredients: hydroxypropyl methylcellulose, mannitol, poloxamer, polyethylene glycol, and water for injection distributed by: urogen pharma, inc. princeton, nj 08540 jelmyto ® and urogen ® are registered trademarks of urogen pharma, ltd. u.s. patent nos. 9,040,074 and 9,950,069 copyright© 2022 urogen pharma, inc. all rights reserved. jel-ppi-003 for more information go to www.jelmyto.com or call 1-855-987-6436.