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MitoMYcin (Systemic)

Pronunciation

(mye toe MYE sin)

Index Terms

  • MITC
  • MITO
  • MITO - C
  • Mitomycin - C
  • Mitomycin - X
  • MMC
  • MTC
  • Mutamycin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Generic: 5 mg (1 ea); 20 mg (1 ea); 40 mg (1 ea)

Pharmacologic Category

  • Antineoplastic Agent, Antibiotic

Pharmacology

Acts like an alkylating agent and produces DNA cross-linking (primarily with guanine and cytosine pairs); cell-cycle nonspecific; inhibits DNA and RNA synthesis; degrades preformed DNA, causes nuclear lysis and formation of giant cells. While not phase-specific per se, mitomycin has its maximum effect against cells in late G and early S phases.

Metabolism

Hepatic

Excretion

Urine (~10% as unchanged drug)

Half-Life Elimination

17-78 minutes; Terminal: 50 minutes

Use: Labeled Indications

Treatment of adenocarcinoma of stomach or pancreas

Use: Unlabeled

Treatment of anal carcinoma (nonmetastatic), bladder cancer, cervical cancer (recurrent or metastatic), esophageal cancer, gastric cancer, non small cell lung cancer (NSCLC)

Contraindications

Hypersensitivity to mitomycin or any component of the formulation; thrombocytopenia; coagulation disorders, or other increased bleeding tendency

Dosing: Adult

Details concerning dosing in combination regimens should also be consulted.

Stomach or pancreas adenocarcinoma (manufacturer’s labeling): IV: 20 mg/m2 every 6-8 weeks

Anal carcinoma (off-label use): IV: 10 mg/m2 as an IV bolus on days 1 and 29 (maximum: 20 mg/dose) in combination with fluorouracil and radiation therapy (Ajani, 2008)

Bladder cancer, nonmuscle invasive (off-label use/route): Intravesicular instillation:

Low risk of recurrence (uncomplicated): 40 mg as a single dose postoperatively; retain in bladder for 2 hours (Hall, 2007)

Increased risk of recurrence: 20 mg weekly for 6 weeks, followed by 20 mg monthly for 3 years; retain in bladder for 1-2 hours (Friedrich, 2007)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

The manufacturer’s labeling states to avoid use in patients with serum creatine >1.7 mg/dL, but no dosage adjustments are provided. The following adjustments have been used by some clinicians (Aronoff, 2007): Adults:

CrCl <10 mL/minute: Administer 75% of dose.

Continuous ambulatory peritoneal dialysis (CAPD): Administer 75% of dose.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Leukocytes 2000 to <3000/mm3: Hold therapy until leukocyte count ≥4000/mm3; reduce to 70% of dose in subsequent cycles

Leukocytes <2000/mm3: Hold therapy until leukocyte count ≥4000/mm3; reduce to 50% of dose in subsequent cycles

Platelets 25,000 to <75,000/mm3: Hold therapy until platelets ≥100,000/mm3; reduce to 70% of dose in subsequent cycles

Platelets <25,000/mm3: Hold therapy until platelets ≥100,000 mm3; reduce to 50% of dose in subsequent cycles

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Dilute powder with SWFI to a concentration of 0.5 mg/mL. May further dilute in NS or sodium lactate to 20-40 mcg/mL.

Administration

IV: Administer slow IV push or by slow (15-30 minute) infusion via a freely-running saline infusion. Consider using a central venous catheter.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate dimethyl sulfate (DMSO) antidote. Apply dry cold compress for 20 minutes 4 times/day for 1-2 days (Pérez Fidalgo, 2012).

DMSO: Apply topically to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo, 2012).

Intravesicular (off-label route): Instill into bladder and retain for up to 2 hours (Friedrich, 2007; Hall, 2007); rotate patient every 15-30 minutes

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in LR, NS.

Y-site administration: Incompatible with aztreonam, cefepime, etoposide phosphate, filgrastim, gemcitabine, piperacillin/tazobactam, sargramostim, topotecan, vinorelbine.

Storage

Store intact vials at controlled room temperature; avoid exposure to temperatures >40°C (104°F). Reconstituted solution is stable for 7 days at room temperature and 14 days when refrigerated. Protect reconstituted solution from light. Solution of 0.5 mg/mL in a syringe is stable for 7 days at room temperature and 28 days when refrigerated and protected from light.

Further dilution to 20-40 mcg/mL:

In normal saline: Stable for 12 hours at room temperature.

In sodium lactate: Stable for 24 hours at room temperature.

Drug Interactions

Antineoplastic Agents (Vinca Alkaloids): May enhance the adverse/toxic effect of MitoMYcin (Systemic). Specifically, the risk of pulmonary toxicity may be increased. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fever (14%)

Gastrointestinal: Nausea, vomiting, and anorexia (14%)

Hematologic: Myelosuppression (64%; onset: 4 weeks; recovery: 8-10 weeks)

Miscellaneous: Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) (≤15%)

1% to 10%:

Dermatologic: Alopecia, mucous membrane toxicity (4%)

Gastrointestinal: Stomatitis (4%)

Renal: Serum creatinine increased (2%)

<1% (Limited to important or life-threatening): Adult respiratory distress syndrome (ARDS), bladder fibrosis/contraction (intravesical administration), dyspnea, extravasation reactions, heart failure, hepatic sinusoidal obstruction syndrome (SOS, veno-occlusive liver disease), interstitial fibrosis, nonproductive cough, pulmonary infiltrates, rash, renal failure (irreversible)

ALERT: U.S. Boxed Warning

Experienced physician:

Mitomycin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Bone marrow suppression:

Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of mitomycin.

Hemolytic uremic syndrome:

Hemolytic uremic syndrome (HUS), a serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure has been reported in patients receiving systemic mitomycin. The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in combination with other cytotoxic drugs; however, most cases occur at doses greater than or equal to 60 mg of mitomycin. Blood product transfusion may exacerbate the symptoms associated with this syndrome. The incidence of the syndrome has not been defined.

Warnings/Precautions

Concerns related to adverse effects:

• Bladder fibrosis/contraction: With intravesical administration (unapproved administration route), bladder fibrosis/contraction has been reported.

• Bone marrow suppression: [U.S. Boxed Warning]: Bone marrow suppression (thrombocytopenia and leukopenia) is common and may be severe and/or contribute to infections. Fatalities due to sepsis have been reported; monitor for infections. Myelosuppression is dose-limiting, delayed in onset, and cumulative; therefore, monitor blood counts closely during and for ≥8 weeks following treatment; treatment delay or dosage adjustment may be required for significant thrombocytopenia (platelets <100,000/mm3) or leukopenia (WBC<4000/mm3) or a progressive decline in either value.

• Extravasation: Mitomycin is a potent vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. May cause necrosis and tissue sloughing; delayed erythema and/or ulceration have been reported,

• Hemolytic-uremic syndrome: [U.S. Boxed Warning]: Hemolytic-uremic syndrome (HUS) has been reported (incidence not defined); condition usually involves microangiopathic hemolytic anemia (hematocrit ≤5%), thrombocytopenia (≤100,000/mm3), and irreversible renal failure (serum creatinine ≥1.6 mg/dL). HUS may occur at any time, is generally associated with single doses ≥60 mg, and HUS symptoms may be exacerbated by blood transfusion. Other less common effects may include pulmonary edema, neurologic abnormalities, and hypertension. High mortality from HUS development has been reported, and is largely the result of renal failure. HUS may also be associated with cumulative doses ≥50 mg/m2.

• Pulmonary toxicity: Cases of acute respiratory distress syndrome (ARDS) have been reported in patients receiving mitomycin in combination with other chemotherapy who were maintained at FIO2 concentrations >50% perioperatively; use caution to provide only enough oxygen to maintain adequate arterial saturation and avoid overhydration. Pulmonary toxicity has also been reported as dyspnea with nonproductive cough and appearance of pulmonary infiltrates on radiograph; discontinue therapy if pulmonary toxicity occurs and other potential etiologies have been ruled out.

Disease-related concerns:

• Renal impairment: Do not administer if serum creatinine is >1.7 mg/dL; monitor for renal toxicity.

Concurrent drug therapy issues:

• Vinca alkaloids: Shortness of breath and bronchospasm have been reported in patients receiving vinca alkaloids in combination with mitomycin or who received mitomycin previously; this acute respiratory distress has occurred within minutes to hours following the vinca alkaloid; may be managed with bronchodilators, steroids and/or oxygen.

Special populations:

• Radiation therapy recipients: Use with caution in patients who have received radiation therapy or in the presence of hepatobiliary dysfunction; reduce dosage in patients who are receiving radiation therapy simultaneously.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

Monitor CBC with differential (repeatedly during therapy and for ≥8 weeks following therapy); serum creatinine; pulmonary function tests; monitor for signs/symptoms of HUS

Pregnancy Considerations

Teratogenic effects have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience mouth sores, lip irritation, hair loss, or lack of appetite. Have patient report immediately to prescriber signs of infection, bruising, bleeding, signs of hemolytic-uremic syndrome (urinary retention; loss of strength and energy; signs of bleeding or bruising; fever; or swelling of the face, hands, feet, or body), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), severe dizziness, passing out, severe nausea, vomiting, severe diarrhea, loss of strength and energy, shortness of breath, excessive weight gain, swelling of arms or legs, bladder irritation, or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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