Mutamycin

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Mutamycin

Classes

Other Cytotoxic Antibiotics
Other Surgical Aids

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Low
Administer prn antiemetics as necessary.
Extravasation Risk
Vesicant
Administer drug through a central venous line.

Injectable Administration Intravenous Administration

Mitomycin for injection is administered intravenously. Because the drug is extremely irritating to tissues, it should not be administered intramuscularly or subcutaneously.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Mitomycin IV solutions are a blue-gray color.
Monitor the patient closely for signs and symptoms of extravasation; cellulitis, ulceration, and sloughing may result if extravasation occurs.
 
Reconstitution:
5 mg vial: Add 10 mL Sterile Water for Injection.
20 mg vial: Add 40 mL Sterile Water for Injection.
40 mg vial: Add 80 mL Sterile Water for Injection.
Shake vial to dissolve the powder. If the powder for injection does not dissolve immediately, let stand at room temperature until completely dissolved.
Storage after reconstitution: The reconstituted solution is stable for 7 days at room temperature or 14 days under refrigeration.
 
Dilution
The solution may be further diluted in 0.9% Sodium Chloride for Injection (stable for 12 hours at room temperature) or Sodium Lactate Injection (stable for 24 hours at room temperature) to a final concentration of 20 to 40 mcg/mL.

Ophthalmic Administration

Reconstitution
The non-sterile circulating nurse should open the outer pack of the Mitosol Kit and affect the sterile transfer of all contents to the sterile field.
The sterile scrub technician should handle and open the sterile inner tray, and then assemble and dispense its contents as below.
Remove the vial and vial adapter from the blue foam pouch. Screw the clear plunger rod to the rubber plunger of the pre-filled syringe.
Rock the syringe cap sideways (do not twist) until it breaks free from the syringe collar.
Attach the threaded end of the connector to the syringe, and then firmly attach the smaller threaded end of the vial adapter to the safety connector.
Stand upright on a sturdy, flat surface and push on the vial lid until sealed and secure.
Inject the entire contents of the syringe (1 mL Sterile Water for Injection) into the vial of mitomycin for a final concentration of 0.2 mg/mL; shake to dissolve.
DO NOT force the plunger; the syringe will not operate if the vial adapter and syringe connector are not properly connected. Forcing the plunger may result in syringe leakage and exposure to mitomycin.
If the product does not dissolve immediately, allow it to stand at room temperature until dissolution.
Storage after reconstitution: After reconstitution, mitomycin is stable for 1 hour at room temperature.
 
Preparing Sponges
Invert the mitomycin vial and syringe; draw the full volume of medication into the syringe.
Remove all sponges from the sponge tray, and return to the tray only those sponges to be used.
Unscrew the syringe with the safety connector from the vial and vial adaptor.
DO NOT remove the safety connector from the syringe.
Place the vial and vial adaptor in the chemotherapy waste disposal bag (yellow bag); set the bag aside, within the sterile field, for additional use.
Remove the sponge container from the sterile inner tray.
Screw both syringes into the sponge container: the TB syringe to one end, and the syringe with reconstituted mitomycin to the other.
Inject the medication into the sponge container, fully saturating the sponges with the entire reconstituted contents of the vial.
Leave reconstituted mitomycin undisturbed in the sponge container for 60 seconds. Do not force the syringe plunger. If any excess fluid remains, withdraw the plunger of the TB syringe to draw out excess fluid/air.
 
Administration
NOTE: Mitomycin for solution (for ophthalmic use) is for topical application to the surgical site of glaucoma filtration surgery only; it is not intended for intraocular administration. Intraocular administration may result in cell death leading to corneal infarction, retinal infarction, and ciliary body atrophy.
With both syringes connected, open the sponge container and offer the contents to the surgeon for placement.
The treatment area should approximate 10 mm x 6 mm +/- 2 mm.
Apply fully saturated sponges equally to the treatment area, in a single layer, with the use of surgical forceps.
Keep the sponges on the treatment area for 2 minutes, then remove them and copiously irrigate the surgical site.
Return the used sponges back into the sponge container for disposal. Close the container lid.
With both syringes still connected, remove the entire assembly from the surgical field and place it in the Chemotherapy Waste Bag provided.
The use of mitomycin ophthalmic solution in concentrations higher than 0.2 mg/mL or for use longer than 2 minutes may lead to unintended corneal and/or scleral damage including thinning or perforation. Direct contact with the corneal endothelium will result in cell death.

Other Administration Route(s)

Pyelocalyceal Administration
 
Mitomycin for pyelocalyceal solution is for pyelocalyceal use only. It is NOT for intravenous use, topical use, or oral administration.
Prior to every instillation, the patient should take sodium bicarbonate 1.3 g PO the evening prior to, the morning of, and 30 minutes prior to the instillation procedure (total, 3.9 g). If the patient is to be anesthetized, they should NOT take sodium bicarbonate within 30 minutes prior to treatment.
General anesthesia, local anesthesia, sedation, prophylactic antibiotics, and/or antihistamines may be used at the discretion of the treating urologist.
Consider holding diuretics one day prior to instillation until 4 hours post-instillation.
Intravesical administration of mitomycin may discolor the urine to a violet to blue color following the instillation procedure. Patients should avoid contact with urine for at least 6 hours post-instillation, should void sitting on a toilet, and should flush the toilet several times after use.
Mitomycin for pyelocalyceal solution must be prepared under chilled conditions. Once reconstituted, it will appear as a viscous liquid for instillation. If there is any difficulty pushing or withdrawing the solution during preparation, put the components back in the Chilling Block until it liquifies.
 
Preparation
The day prior to preparation, put the Chilling Block upside down in the freezer at -20 to -12 degrees Celsius (-4 to 10.4 degrees Fahrenheit) overnight.
Remove the Chilling Block from the freezer and disinfect it with 70% Isopropyl alcohol spray or equivalent. Allow the Chilling Block to air dry, and then place it upright inside the hood or isolator.
Wait 20 minutes.
Connect vial adaptors to all 3 vials. Connect a syringe adaptor to one of the 10 mL syringes and to the 20 mL syringe.
Place the 3 vials (2 vials mitomycin, 1 vial sterile hydrogel), the 10 mL syringe, and the 20 mL syringe into the Chilling Block for at least 10 minutes.
During this time, withdraw 2 mL of sterile water into the other 10 mL syringe and set aside for later use.
Slowly fill the chilled 20 mL syringe with 14 mL of sterile hydrogel. Recap the syringe and place it in the Chilling Block.
Slowly fill the chilled 10 mL syringe with 4 mL of sterile hydrogel. Discard the unused portion of sterile hydrogel.
Replace the needle on the 2 mL sterile water syringe with the Luer Lock connector.
Remove the syringe adaptor from the 4 mL sterile hydrogel syringe and connect it to the other side of the Luer Lock connector on the 2 mL sterile water syringe.
Gently mix the sterile water with the sterile hydrogel by pushing the plungers back and forth at least 25 times to create the "pre-wetting solution" (PWS).
Transfer the 6 mL PWS into one of the syringes. Replace the Luer Lock connector with a new syringe adaptor. Place the 6 mL PWS syringe in the Chilling Block.
 
Reconstitution
Remove both mitomycin vials from the Chilling Block; gently tap the bottom of each vial on the table to ensure all powder is at the bottom of the vials.
Remove the chilled 6 mL PWS syringe from the Chilling Block. Inject 3 mL PWS into each vial of mitomycin and discard the empty PWS syringe.
NOTE: To ensure accurate dosing, the contents of each vial must be the same.
Gently swirl each vial of mitomycin upright at least 15 times; ensure all powder and admixture remains at the bottom of the vial. DO NOT invert or shake.
Immediately remove the chilled 14 mL syringe of sterile hydrogel from the Chilling Block and inject 7 mL into each vial of mitomycin.
Gently swirl each vial of mitomycin upright at least 15 times; ensure all powder and admixture remains at the bottom of the vial. DO NOT invert or shake.
Recap and place the 20 mL syringe in the Chilling Block.
Recap and place both vials of mitomycin in the Chilling Block for 5 minutes; then remove the vials and vigorously swirl them upright at least 15 times, ensuring all admixture remains at the bottom of the vials. Return both vials to the Chilling Block. Repeat these steps every 5 minutes for 30 minutes (6 times). DO NOT invert or shake the vials.
Remove 1 vial of mitomycin from the Chilling Block. After vigorously swirling upright at least 15 times, slowly withdraw the entire contents of the vial (7 mL) into the chilled 20 mL syringe. If it is difficult to withdraw the admixture, place the contents back into the Chilling Block until it liquifies again. Inject the contents of this syringe into the remaining chilled vial of mitomycin, so that all the admixture is in 1 vial.
Recap the vial adaptor. Vigorously swirl the vial upright at least 15 minutes.
Reconstituted mitomycin for pyelocalyceal solution has reverse thermal properties with a gelation point of approximately 19 degrees Celsius (66 degrees Fahrenheit).
Storage after reconstitution: Instill mitomycin for pyelocalyceal solution as soon as possible after reconstitution. If immediate instillation is not possible, it may be stored at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit) for up to 8 hours protected from light; it will appear as a semisolid gel when stored under these conditions. The "Discard after" date and time is 8 hours from the completion of the preparation at room temperature; this should be documented on the admixture label and applied to the prepared vial.
 
Administration
Once chilled at -3 to 5 degrees Celsius (27 to 41 degrees Farenheit), mitomycin for pyelocalyceal solution will convert to a viscous liquid for instillation and is stable for up to 1 additional hour.
Reconstituted mitomycin for pyelocalyceal solution must be instilled within 1 hour after it is converted to a viscous liquid.
Instill mitomycin for pyelocalyceal solution as a chilled solution using a Uroject12 Lever, a Luer lock syringe, and a ureteral catheter with molded Luer lock connector.

Adverse Reactions
Severe

urinary tract obstruction / Delayed / 17.0-17.0
hyperuricemia / Delayed / 16.0-16.0
renal failure (unspecified) / Delayed / 0-11.0
wound dehiscence / Delayed / 1.0-10.0
vomiting / Early / 0-4.2
infection / Delayed / 0-4.2
hypertension / Early / 0-4.2
hematuria / Delayed / 2.8-2.8
flank pain / Delayed / 2.8-2.8
hypoalbuminemia / Delayed / 2.8-2.8
nausea / Early / 0-1.4
fatigue / Early / 0-1.4
abdominal pain / Early / 1.4-1.4
fever / Early / 0-1.4
hyperkalemia / Delayed / 1.4-1.4
heart failure / Delayed / 0-1.0
ocular hemorrhage / Delayed / 0-1.0
visual impairment / Early / 0-1.0
endophthalmitis / Delayed / 10.0
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
bronchospasm / Rapid / Incidence not known
pulmonary edema / Early / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
hematemesis / Delayed / Incidence not known
retinal hemorrhage / Delayed / Incidence not known
papilledema / Delayed / Incidence not known
keratitis / Delayed / Incidence not known
macular edema / Delayed / Incidence not known
retinal detachment / Delayed / Incidence not known
tissue necrosis / Early / Incidence not known

Moderate

dysuria / Early / 23.0-33.3
hypocalcemia / Delayed / 17.0-17.0
hypernatremia / Delayed / 11.0-11.0
cataracts / Delayed / 1.0-10.0
stomatitis / Delayed / 10.0
lymphopenia / Delayed / Incidence not known
dyspnea / Early / Incidence not known
hemolysis / Early / Incidence not known
confusion / Early / Incidence not known
hyphema / Delayed / Incidence not known
blurred vision / Early / Incidence not known
iritis / Delayed / Incidence not known
bladder spasm / Early / Incidence not known
edema / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known

Mild

increased urinary frequency / Early / 24.3-24.3
urinary urgency / Early / 21.6-21.6
anorexia / Delayed / 0-14.0
pruritus / Rapid / 13.0-13.0
chills / Rapid / 0-11.0
rash / Early / 0-1.0
ocular hypotonia / Delayed / 10.0
alopecia / Delayed / 10.0
cough / Delayed / Incidence not known
headache / Early / Incidence not known
drowsiness / Early / Incidence not known
syncope / Early / Incidence not known
back pain / Delayed / Incidence not known
malaise / Early / Incidence not known
injection site reaction / Rapid / Incidence not known
diarrhea / Early / Incidence not known

Boxed Warning
Requires an experienced clinician

Mitomycin administration requires an experienced clinician familiar with the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

Bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

Mitomycin for injection is contraindicated in patients with thrombocytopenia. Bone marrow suppression, notably thrombocytopenia and leukopenia, is the most common and severe adverse reaction associated with intravenous administration of mitomycin. Because of cumulative myelosuppression, a complete blood count with differential should be obtained repeatedly during intravenous therapy and for at least 8 weeks following therapy; dose reductions are based on nadir leukocyte and platelet counts of the previous cycle. Subsequent cycles of treatment should not begin until the leukocyte count is at least 4,000 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Thrombocytopenia and neutropenia have also occurred in patients receiving pyelocalyceal mitomycin; there were no signs of gross extravasation via urinary tract perforation or impaired mucosa in these patients. Therefore, a complete blood count with differential should also be obtained prior to each dose. An interruption or discontinuation of therapy may be necessary if thrombocytopenia or neutropenia occur.

Hemolytic-uremic syndrome, renal impairment

Patients with renal impairment (serum creatinine greater than 1.7 mg/dL) should not be treated with systemic mitomycin; monitor patients for evidence of renal toxicity. Hemolytic-uremic syndrome (HUS) has been reported in patients receiving systemic mitomycin therapy, consisting primarily of microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure. Of 83 patients studied, 72 developed HUS at total doses exceeding 60 mg of mitomycin (approximately 87%); closely monitor patients receiving doses higher than 60 mg for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function. Blood product transfusion may exacerbate the symptoms associated with this syndrome.

Common Brand Names

JELMYTO, Mitosol, Mutamycin

Dea Class

Rx

Description

Antitumor antibiotic; alkylating agent
Used systemically for the treatment of stomach and pancreatic cancer; used topically to the surgical site during glaucoma surgery; used for pyelocalyceal administration for the treatment of urothelial cancer
Can be associated neutropenia and thrombocytopenia; an interruption of therapy or discontinuation of therapy may be necessary if myelosuppression occurs

Dosage And Indications
For treatment of gastric cancer. Intravenous dosage Adults

20 mg/m2 IV every 6 to 8 weeks in combination with other chemotherapeutic agents. A commonly used regimen is mitomycin 10 mg/m2 IV on day 1 plus 5-fluorouracil (600 mg/m2/day IV days 1, 8, 29, and 36) and doxorubicin (30 mg/m2/day IV days 1, and 29) (FAM regimen). Other combination regimens include: a) mitomycin 7 mg/m2 (max 14 mg) IV every 6 weeks for 4 doses, cisplatin (60 mg/m2 IV every 3 weeks for 8 doses) and 5-fluorouracil (300 mg/m2/day IV for up to 6 months); b) mitomycin 7 mg/m2 IV on day 2, cisplatin (50 mg/m2 IV on day 1 every 2 weeks), leucovorin (100 mg/m2 IV) then 5-fluorouracil (400 mg/m2 IV bolus then 600 mg/m2 IV over 22-hours on days 1 and 2) every 6 weeks; c) mitomycin 10 mg/m2 IV plus irinotecan (150 mg/m2 IV) every 2 weeks; or d) mitomycin 15 mg/m2 IV on day 1 every 7 weeks plus leucovorin (500 mg/m2 IV) and 5-fluorouracil (2600 mg/m2 IV) on days 1, 8, 15, 22, 29, and 36.

Intravenous dosage (Mitozytrex only) Adults

15 mg/m2 IV every 6 to 8 weeks in combination with other chemotherapy agents. If the disease continues to progress after 2 courses of Mitozytrex, the drug should be stopped since chances of response are minimal.

For the treatment of pancreatic cancer. Intravenous dosage Adults

20 mg/m2 IV every 6 to 8 weeks in combination with other chemotherapy agents. The addition of mitomycin 7 mg/m2 IV every 6 weeks for 4 courses to a protracted 5-fluorouracil (5-FU) regimen (i.e., 300 mg/m2/day IV for up to 24 weeks) resulted in an increased response rate compare to 5-FU alone, but did not translate into a survival advantage.

Intravenous dosage (Mitozytrex only) Adults

15 mg/m2 IV every 6 to 8 weeks in combination with other chemotherapy agents. If the disease continues to progress after 2 courses of Mitozytrex, the drug should be stopped since chances of response are minimal.

For use as an adjunct to ab externo ocular surgery for glaucoma. Topical dosage Adults

Saturate provided sponges with entire reconstituted contents of the vial (see Administration). Apply fully saturated sponges equally to the treatment area, in a single layer, with the use of a surgical forceps. Treat an area of approximately 10 mm x 6 mm +/- 2 mm. Keep the sponges on the treatment area for 2 minutes, then remove and return to the provided tray for defined disposal in the chemotherapy waste bag provided.

For the treatment of urothelial carcinoma.
NOTE: The FDA has designated mitomycin as an orphan drug for this indication.
For the treatment of low-grade upper tract urothelial cancer (LG-UTUC). Ureteral or Nephrostomy Tube dosage Adults

4 mg/mL (maximum, 60 mg mitomycin or 15 mL) via ureteral catheter or a nephrostomy tube over 1 minute once weekly for 6 weeks; the total instillation volume is based on volumetric measurements using pyelography. Mitomycin instillations may continue once monthly for a maximum of 11 additional instillations for patients with a complete response after 3 months. Patients should take sodium bicarbonate 1.3 g PO the evening prior to, the morning of, and 30 minutes prior to each instillation (total, 3.9 g); if the patient will be anesthetized, do not give sodium bicarbonate within 30 minutes prior to the treatment. Consider holding diuretics 1 day prior to instillation and until 4 hours post-instillation. In a multicenter, noncomparative trial (the OLYMPUS trial; n = 71), intravesical administration of mitomycin resulted in a complete response rate of 58% in patients with treatment-naive or recurrent noninvasive low-grade upper tract urothelial cancer (LG-UTUC) with at least one measurable papillary tumor 5 to 15 mm located above the ureteropelvic junction; the median duration of response was not reached (range, up to 18.8+ months). At 12 months, 56% of patients remained in a complete response.

For the treatment of colorectal cancer†. For the treatment of liver metastases from colorectal cancer†. Hepatic Intra-Arterial dosage† Adults

Mitomycin 10 mg in a chemo-emulsion with 5-fluorouracil 1,000 mg and 10 mL of ethiodol in a total volume of 30 mL, administered as an intra-arterial injection into the hepatic artery of the affected lobe. If the disease was present in more than 1 lobe, each lobe was treated on a separate occasion, with an interval of 4 weeks between the 2 procedures.

For the treatment of peritoneal carcinomatosis of colorectal cancer†. Intraperitoneal dosage† Adults

Perfusion was started with a minimum of 3 liters of isotonic dialysis fluid, at 1 to 2 liters/min,and an inflow temperature of 41 degrees C to 42 degrees C. As soon as the temperature in the abdomen was stable above 40 degrees C, MMC was added to the perfusate at a dose of 17.5 mg/m2 followed by 8.8 mg/m2 every 30 minutes. The total dose was limited to 70 mg. If the core temperature exceeded 39 degrees C, the inflow temperature was reduced. After 90 minutes, the perfusion fluid was drained from the abdomen, and bowel continuity was restored.

For the treatment of anal cancer† in combination with fluorouracil and radiation. Intravenous dosage Adults

10 mg/m2 IV bolus on days 1 and 29 in combination with 5-fluorouracil (5-FU) 1,000 mg/m2/day continuous IV for 4 days on days 1 through 4 and 29 through 32 and radiation therapy. A smaller phase III study has also considered mitomycin 15 mg/m2 IV on day 1 in combination with 5-FU 750 mg/m2 IV continuous infusion over 4 days on days 1 through 4 and 29 through 32 and radiotherapy in patients with locally advanced anal cancer.

For the treatment of advanced head and neck cancer† in combination with 5-fluorouracil and radiation therapy. Intravenous dosage Adults

10 mg/m2 IV as a bolus on days 5 and 36 in combination with 5-fluorouracil 600 mg/m2/day CIVI days 1 to 5 plus external beam radiation delivered over 6 weeks.

For the adjuvant treatment of superficial bladder cancer† in patients at high risk for recurrence. Intravesical dosage† Adults

Doses of 20 to 60 mg diluted in sterile water to concentrations of 0.5 to 2 mg/mL weekly for 6 to 8 weeks as induction with or without maintenance for 1 year have been used. In a phase III trial using mitomycin 40 mg in 20 mL of sterile water weekly for 6 weeks, an ultrasound monitor was used to reposition the patient and catheter to reduce the amount of urine that came in contact with the drug. In this trial, patients also received sodium bicarbonate and were instructed to refrain from drinking fluids for 8 hours before and during the procedure.

For the treatment of cervical cancer† in combination with cisplatin. Intravenous dosage Adults

6 mg/m2 IV on day 1 in combination with cisplatin 50 mg/m2 IV on day 1, repeated every 4 weeks.

For the treatment of malignant mesothelioma†. For the treatment of malignant pleural mesothelioma administered locally in the pleural cavity in combination with cisplatin†. Intrapleural dosage† Adults

8 mg/m2 and cisplatin 100 mg/m2 mixed in 100 mL normal saline, instilled into the pleural space via 1 chest tube for 15 minutes. Position was changed every 30 minutes and after 4 hours, the chest tube was put back to suction.

For the treatment of malignant peritoneal mesothelioma in combination with cisplatin†. Intraperitoneal dosage Adults

4 to 6 L of isotonic dialysis fluid was circulated at a flow rate of 500 to 700 mL/min and heated to achieve an intraperitoneal temperature between 42 to 45 degrees C. Intraperitoneal chemotherapy with mitomycin 0.5 mg/kg in combination with cisplatin 0.7 mg/kg was administered over 90 minutes. 5-year overall survival was 28.9% and median overall survival was 35.6 months.

For the treatment of biliary tract cancer†. For the treatment of unresectable intrahepatic cholangiocarcinoma in combination with cisplatin and doxorubicin†. Intra-Arterial dosage Adults

Chemoembolization material consisted of mitomycin 10 mg, doxorubicin 50 mg, and cisplatin 100 mg dissolved in sterile contrast (8.5 mL) and diluted with 1.5 mL of sterile water. This was emulsified in a 1:1 ratio with ethiodol. The emulsion was instilled in 1- to 5-mL aliquots. Intra-arterial 1% lidocaine was administered in 1- to 3-mL boluses interleaved with the aliquots of chemoembolic emulsion. Added to the final aliquot of the emulsion or separately following administration of the emulsion was 0.2 mL of 150- to 250-l polyvinyl alcohol particles. In addition, 0.9% normal saline was administered at 200 to 300 mL/hour until the completion of the procedure, followed by 0.9% normal saline at 150 mL/hour for a total of 3 L. No diuretics were given. Prophylactic antiemetics (ondansetron 24 mg and dexamethasone 10 mg IV) and antibiotics (cefazolin 1 g and metronidazole 500 mg) were given.

For the treatment of unresectable intrahepatic cholangiocarcinoma†. Intra-Arterial dosage Adults

Mitomycin 2 mg and 300 mg degradable starch microspheres (DSM) mixed in 3 mL contrast media were infused within 30 seconds under fluoroscopic guidance via hepatic port. After a 1 minute pause between administrations, the process was repeated until reflux into the gastroduodenal artery or embolization of the hepatic artery was noted. Treatment was repeated weekly without the use of contrast media.

For the treatment of non-small cell lung cancer (NSCLC)†. For the first-line treatment of inoperable stage III or IV NSCLC, in combination with cisplatin and vinblastine (MVP regimen)†. Intravenous dosage Adults

6 or 8 mg/m2 IV on day 1, in combination with cisplatin (50 mg/m2 IV on day 1) and vinblastine (6 mg/m2 IV on day 1), every 3 weeks for 4 cycles has been studied in patients with inoperable stage III or IV non-small cell lung cancer (NSCLC) in randomized clinical studies. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. There was no significant difference in the median overall survival (OS) time (8.7 vs 9.5 months), 1-year OS rate (35% vs 39%), or 2-year OS rate (13% vs 13%) in patients who received MVP or MIC compared with docetaxel plus carboplatin (DC regimen) in a multicenter, randomized, phase 3 trial. Serious toxicity, including grade 3 and 4 neutropenia and leukopenia, was reported significantly less often in the MVP/MIC arm compared with the DC arm (22% vs 41%); additionally, patients in the MVP/MIC arm had significantly less overnight hospital stays due to toxicity and antibiotic use. In another randomized, phase 3 trial, there was no significant difference in the median OS time (248 vs. 236 days), 1-year OS rate (32.5% vs. 33.2%), or 2-year OS rate (11.8% vs. 6.9%) in patients who received MVP or MIC compared with gemcitabine plus carboplatin (GC regimen). Significantly less grade 3 and 4 neutropenia and thrombocytopenia and antibiotic use were reported with MVP/MIC compared with GC; however, emergent overnight hospital stays occurred significantly more often in the MVP/MIC arm.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

CrCl less than 30 mL/min: Avoid the use of mitomycin for pyelocalyceal solution.
SCr greater than 1.7 mg/dL: Do not administer mitomycin for injection.

Drug Interactions

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vinblastine: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. 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 acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.
Vinca alkaloids: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. 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 acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.
Vincristine Liposomal: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. 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 acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.
Vincristine: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. 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 acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.
Vinorelbine: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. 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 acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.

How Supplied

JELMYTO Ureteral Pwd F/Recon: 40mg
Mitomycin/Mutamycin Intravenous Inj Pwd F/Sol: 5mg, 20mg, 40mg
Mitosol Ophthalmic Pwd: 0.2mg
Mitosol Topical Pwd: 0.2mg

Maximum Dosage

The suggested maximum tolerated dose (MTD) for mitomycin is dependent on type of mitomycin injection used, performance status, other chemotherapy agents or radiation given in combination, and disease state. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

Adults

Mitomycin for injection: 20 mg/m2 IV.
Mitomycin for ophthalmic use: topically applied to glaucoma surgery site for no longer than 2 minutes.
Mitomycin for pyelocalyceal solution: 60 mg (15 mL).

Geriatric

Mitomycin for injection: 20 mg/m2 IV.
Mitomycin for ophthalmic use: topically applied to glaucoma surgery site for no longer than 2 minutes.
Mitomycin for pyelocalyceal solution: 60 mg (15 mL).

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Mechanism Of Action

Antineoplastic Activity:
Mitomycin is an alkylating agent that inhibits DNA synthesis; at high concentrations, cellular RNA and protein synthesis are also suppressed. The guanine and cytosine content correlate with the degree of mitomycin-induced cross-linking.
 
Activity in Ocular Surgery:
In glaucoma surgery, mitomycin is applied topically for a short period during the surgery. It inhibits the proliferative phase of the wound-healing pathway through inhibition of fibroblast as well asendothelial cell growth and replication. It is approximately 100-fold more potent than fluorouracil after a single topical intraoperative application. These antifibrotic actions of the drug prevent scarring of the tissue when surgeons create a flap in the eye to relieve the excess fluid buildup, reducing intraocular pressure following the surgery.

Pharmacokinetics

Mitomycin can be administered intravenously, topically, or by pyelocalyceal instillation, depending on the dosage form and indication; one dosage form should not be substituted for another. While systemic clearance is primarily affected by hepatic metabolism, metabolism occurs in other tissue as well. The rate of clearance is inversely proportional to the Cmax due to saturation of the degradative pathways. Approximately 10% of a dose of mitomycin is excreted unchanged in the urine; this percentage increases proportionally with dose due to saturation of metabolic pathways at low doses.
 
Affected cytochrome P450 isoenzymes and drug transporters: None.

Intravenous Route

The Cmax of mitomycin after an intravenous injection of 30 mg was 2.4 mcg/mL; the Cmax after a 20 mg and 10 mg injection was 1.7 mcg/mL and 0.52 mcg/mL, respectively. After intravenous administration, mitomycin is rapidly cleared from the serum, with concentrations reduced by 50% in 17 minutes after a single bolus injection.

Topical Route

Ocular Administration
It is not known if mitomycin is systemically absorbed following topical ocular administration during surgery. The proposed dose of mitomycin used during glaucoma surgery (0.2 mg) is significantly lower than intravenous doses used for oncologic indications (up to 20 mg/m2); therefore, systemic concentrations after topical ocular administration would be expected to be multiple orders of magnitude lower than those achieved by IV administration. Mitomycin is cleared from ophthalmic tissue after intraoperative topical application and irrigation, as metabolism occurs in other affected tissues.

Other Route(s)

Pyelocalyceal Use
Plasma concentrations of mitomycin were variable after instillation of up to 60 mg of mitomycin into the pyelocalyceal system, ranging from 2.43 ng/mL to 12.8 ng/mL over the course of treatment. The mean Cmax of mitomycin was 6.24 ng/mL, which is estimated to be less than 1% of the expected Cmax after intravenous administration. After instillation into the pyelocalyceal system, mitomycin (Jelmyto) forms a semisolid gel which dissolves from normal kidney urine flow, releasing mitomycin for up to 4 to 6 hours; it is eliminated unchanged in the urine.

Pregnancy And Lactation
Pregnancy

Pregnancy should be avoided by females of reproductive potential during mitomycin treatment. The manufacturer of mitomycin for pyelocalyceal administration recommends avoidance of pregnancy during treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, mitomycin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving mitomycin should be apprised of the potential hazard to the fetus. When administered parenterally, mitomycin has been shown to be teratogenic in mice and rats when given at doses equivalent to the usual human intravenous dose. There are no available data on mitomycin for pyelocalyceal administration or ophthalmic administration to inform the drug-associated risk with these dosage forms.

Due to the potential for serious adverse reactions in nursing infants from mitomycin, advise women to discontinue breast-feeding during treatment; the manufacturers of mitomycin for pyelocalyceal administration and mitomycin ophthalmic solution additionally recommend avoidance of breast-feeding for 1 week after the final dose. It is not known whether mitomycin is present in human milk, although many drugs are excreted in human milk.