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mitomycin
mitomycin
SYNONYM(S): mitomycin C; MMC
COMMON TRADE NAME(S): Mutamycin® (generic brand available)
Mitomycin is a purple antibiotic isolated from Streptomyces caespitosus. Mitomycin is activated in vivo to a bifunctional and trifunctional alkylating agent. Binding to DNA leads to cross-linking and inhibition of DNA synthesis and function. RNA synthesis is also inhibited at higher mitomycin concentrations. Mitomycin is cell cycle phase-nonspecific.
Oral absorption: Erratic
Not appreciably absorbed from the bladder
Rapidly cleared from plasma. Highest concentraions found in kidney, followed by muscles, eyes, lungs, intestine and stomach. Found in ascites.
| Cross blood brain barrier? | no |
| PPB | No information found |
Prodrug activated in vivo, primary means of elimination is by hepatic metabolism, also metabolized by enzymes in kidneys, spleen, brain and heart; saturable at relatively low doses.
| Active metabolites | yes |
| Inactive metabolites | yes |
Biphasic elimination. Excreted in urine, detected in bile and feces, biliary level may exceed plasma level.
| Urine | 10% excreted unchanged in urine, increases with increasing doses. |
| Half-life | 17 minutes |
Topical
- Transitional cell bladder cancer (superficial), 1st or 2nd line
Systemic
- Stomach cancer (palliative)
- Colon cancer (palliative)
Other Uses:
- Anal cancer
- Vulvar cancer
Emetogenic Potential:
Extravasation Potential: Vesicant
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (rare, with prior anthracyclines) | E D | |||
| Venous thromboembolism | E | ||||
| Dermatological | Alopecia (frequent) | E | |||
| Radiation recall reaction (rare) | I | ||||
| Rash (10%, generally on extremities) | I E | ||||
| Gastrointestinal | Anorexia | E | |||
| Diarrhea | E | ||||
| Mucositis (4%) | E | ||||
| Nausea, vomiting | I | ||||
| General | Edema | E | |||
| Fatigue | E | ||||
| Pain | E | ||||
| Hematological | Hemolytic uremic syndrome (rare) | D | |||
| Myelosuppression ± infection, bleeding (64%) | E | ||||
| Injection site | Injection site reaction (may be severe) | I | |||
| Metabolic / Endocrine | Hypoglycemia | E | |||
| Nervous System | Ataxia | E | |||
| Renal | Nephrotoxicity (2%) (may be severe) | D | |||
| Reproductive and breast disorders | Irregular menstruation (amenorrhea) | E | |||
| Respiratory | Adult respiratory distress syndrome (ARDS) (or other acute respiratory symptoms; especially with vincas) | E | |||
| Pneumonitis | E D | ||||
| Urinary | Bladder fibrosis (with intravesical use) | I E D | |||
| Cystitis (25%) (with intravesical use) | I E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Cumulative myelosuppression is a major dose-limiting adverse effect. Onset and recovery may be late (2-4 weeks and 10 weeks respectively). .
The tissue necrosis that happens with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected. Soft tissue ulceration distal to the injection site following uneventful injection in a peripheral vein has been reported.
Pulmonary toxicity consisting of dyspnea, non-productive cough or pulmonary infiltrates has been reported infrequently, and may be severe, with both single agent and combination chemotherapy. Threshold dose associated with pulmonary toxicity appears to be 50-60 mg/m2. Steroids may be of some benefit. Acute respiratory distress syndrome may occur with high FIO2 concentrations and combination chemotherapy.
A syndrome of renal failure and microangiopathic hemolytic anemia (hemolytic-uremic syndrome) with hypertension, pulmonary edema and neurological symptoms has been reported in 10% of patients. This syndrome mostly appears after 6 months of therapy/ 60mg of mitomycin, and may be exacerbated with blood transfusions. Patients should be monitored for development of renal failure or hemolysis.
The incidence of cardiotoxicity may be increased in patients receiving mitomycin in combination with doxorubicin or in patients who have had prior exposure to doxorubicin. No studies report cardiotoxicity in patients only receiving mitomycin.
Genitourinary irritation, following intravesical (bladder) administration includes dysuria, cystitis, nocturia, increased micturition and hematuria. Myelosuppression has not been noted with intravesical administration. Bladder fibrosis/contraction or calcification have rarely been reported.
Mitomycin has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the mitomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. Patients should not be retreated until hematological recovery has occurred.
Intravenous:
- On days 1 and 29: 10 mg/m2
- Q6-8W: 20 mg/m2
- q6-8w: 2 mg/m2/day x 5 days, stop x 2 days, repeat x 1 (i.e. day 1-5 and day 8-12)
Intravesical:
- q1w: 20-40 mg in SWI x 8 weeks
Dosage in myelosuppression: Modify according to protocol by which patient is being treated.
|
Lowest Value in Preceding Course |
||
|
ANC (x109/L) |
Platelets (x 109/L) |
% Previous dose* |
|
≥ 1 |
≥ 75 |
100 |
|
0.5 - 0.99 |
25-74.99 |
70 |
|
< 0.5 |
< 25 |
50 or discontinue |
*Do not re-treat until platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L and other toxicities ≤ grade 2.
Other Toxicity:
|
Toxicity
|
Mitomycin dose
|
|
Pneumonitis
|
Hold and investigate if suspected. Discontinue if confirmed. Consider steroids. |
|
Hemolytic uremic syndrome
|
Discontinue
|
|
Grade 3 organ/non-hematologic
|
Hold until ≤ grade 2 and then reduce by 25%
|
|
Grade 4 organ/non-hematologic
|
Discontinue
|
No adjustment required
Do not administer if creatinine > 150 µmol/L, or in patients with moderate to severe renal impairment.
Has not been studied, but caution recommended due to likelihood of organ dysfunction.
Safety and efficacy have not been established.
- Slow push through sidearm of free flowing IV (Normal Saline)
- Doses may be mixed in 50mL minibag (Normal Saline); Infuse through a free-flowing IV over 15-30 minutes
Mitomycin is contraindicated in patients with serious infections, myelosuppression, coagulation disorder, or an increased bleeding tendency due to other causes, with known hypersensitivity or an idiosyncratic reaction to it, or any component of its formulations, even if intended for intravesical use.
High FIO2 concentrations (anesthesia, oxygen therapy) should be avoided especially in patients with pulmonary toxicity.
Mitomycin has been shown to be carcinogenic, fetotoxic, mutagenic, clastogenic and teratogenic in animal studies and should not be used in pregnancy. Adequate contraception must be used by both sexes, during mitomycin treatment and for at least 6 months after the last dose. Breast feeding is not recommended due to the potential secretion into breast milk. Fertility may be affected.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| vinca alkaloids (vincristine, vinblastine, vindesine) | acute bronchospasm occurring within minutes or hours after vinca alkaloid injection | Unknown | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
| CBC | Baseline and regular |
| Renal function tests | Baseline and periodic |
Clinical exam, including pulmonary, neurological, infection, bleeding, thromboembolism, GI effects and local site toxicity |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Liver function tests | Baseline and regular |
| Fluid balance, in patients experiencing pulmonary toxicity |
BCCA Protocol Summary for the Chemotherapy of Pseudomyxoma Peritonei using intraperitoneal Mitomycin and Fluorouracil. Accessed September 10, 2012.
McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1159-61.
Product Monograph: Mitomycin. Hospira Healthcare Corporation. June 13, 2007.
Prescribing Information: Mitozytrex® (mitomycin with glucopyranose polymers). Supergen US, November 2002.
Mitomycin: UpToDate® drug information (v19.2). Accessed September 10, 2012.
October 2017 edited indications
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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