Indications : התוויות

INDICATIONS AND USAGE

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


DOSAGE AND ADMINISTRATION

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.
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.

Preparation and Handling

See the Instructions for Pharmacy for preparation provided separately.
JELMYTO is a cytotoxic drug. Follow applicable special handling and disposal procedures.

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.
Reconstituted JELMYTO should be instilled as soon as possible after reconstitution. Store reconstituted JELMYTO at room temperature 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, 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.


DOSAGE FORMS AND STRENGTHS

For pyelocalyceal solution: A single-dose carton 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, to be used as a vehicle for reconstitution 

CONTRAINDICATIONS

JELMYTO is contraindicated in patients with:

•   perforation of the bladder or upper urinary tract.

•   Hypersensitivity to the active substance or to any of the excipients listed in section 8.
WARNINGS AND PRECAUTIONS

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.

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.

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 (7.1, 7.3) and Clinical Pharmacology (9)].

Effects on Abillity to Drive and Use Machines

Even when used in accordance with instructions, this medicinal product may cause nausea and vomiting and thereby reduce reaction times to such an extent that the ability to drive a motor vehicle or operate machinery is impaired. This applies even more in connection with alcohol.
       ADVERSE 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)] 
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 (11)]. 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*
(n=71)
Adverse Reaction                           All Grades      Grade 3-4
(%)           (%)
Renal and urinary disorders
Ureteric 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‡                                                                  41             2.8 Hematuria§                                                                                          34                 2.8 Urinary tract infection¶                                                                            34                 4.2 Renal dysfunction#                                                                                  25                 2.8 Dysuria                                                                                             23                  0 Pollakiuria                                                                                         14                  0 Gastrointestinal disorders
Nausea                                                                                              25                 1.4 Abdominal painÞ                                                                                     24                 1.4 Vomiting                                                                                            20                 4.2 General disorders and administration site conditions
Fatigueß                                                                                            24                 1.4 Pyrexia                                                                                             13                 1.4 Chills                                                                                              11                  0 Blood and lymphatic system disorders
Anemia                                                                                              14                 1.4 Skin and subcutaneous tissue disorders
Rashà                                                                                               14                  0 Pruritus                                                                                            13                  0 Metabolism and nutrition disorders
Decreased appetite                                                                                  10                  0 Vascular disorders
Hypertension                                                                                        10                 4.2 *
Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 5.0 (NCI CTCAE v5) † Includes hydronephrosis, obstructive uropathy, pelvi-ureteric obstruction, ureteric obstruction, ureteric stenosis, and urinary  tract obstruction.
‡ Includes flank pain and back pain.
§
Includes hematuria and hemorrhage urinary tract.
¶ Includes urinary tract infection, pyelonephritis, and urinary tract infection fungal.
# Includes renal impairment, acute kidney injury, and renal failure.
Þ
Includes abdominal pain and abdominal pain lower.
ß Includes asthenia, fatigue and malaise.
à Includes rash, dermatitis allergic, rash generalized, genital rash, eczema, rash maculo-papular, and skin exfoliation.

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
JELMYTO
Laboratory Abnormality*
All Grades (%)             Grade ≥ 3 (%)
Hematology
Anemia                                                                           38                              0 Lymphopenia                                                                      21                             2.9 Thrombocytopenia                                                                 21                             2.8 Chemistry
Estimated Glomerular Filtration Rate (eGFR) †                                    38                             11 Creatinine increased                                                             34                              0 Hypoalbuminemia                                                                  28                             2.8 Hypocalcemia                                                                     16                              0 Hyperuricemia                                                                    16                             16 Hyperkalemia                                                                     13                             1.4 Hypernatremia                                                                    11                              0 * 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.
† eGFR calculated per MDRD (Modification of Diet in Renal Disease) equation Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com 

USE IN SPECIFIC POPULATIONS
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 (9)]. 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.

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.

Females and Males of Reproductive Potential

JELMYTO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (7.1)].

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.

Pediatric Use

The safety and efficacy in children and adolescents under the age of 18 years have not yet been established.

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.

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.