Usage
Mitomycin is an antineoplastic/antibiotic medication primarily used in palliative chemotherapy for various advanced or metastatic cancers. These include:
- Advanced metastatic gastric carcinoma
- Advanced and/or metastatic breast cancer
- Non-small cell bronchial carcinoma
- Advanced pancreatic carcinoma
It is also administered intravesically for relapse prevention in superficial urinary bladder carcinoma after transurethral resection. Additionally, it is used as an adjunct in ophthalmic surgery, specifically glaucoma filtration surgery. The pharmacological classification of mitomycin is an alkylating agent antibiotic.
Mitomycin’s mechanism of action involves bioreductive activation within cells, leading to the formation of alkylating metabolites. These metabolites cross-link DNA strands, inhibiting DNA synthesis and function, and ultimately leading to cell death. This activity is particularly pronounced in hypoxic tumor environments.
Alternate Names
Mitomycin-C, Mutamycin (brand name), Jelmyto (brand name, for intravesical use in upper tract urothelial cancer) and Mitosol (ophthalmic).
How It Works
Pharmacodynamics: Mitomycin exerts its cytotoxic effects primarily through DNA crosslinking. This disrupts cellular processes, including DNA replication and transcription, ultimately leading to cell death. This effect is more pronounced in hypoxic conditions often found in solid tumors.
Pharmacokinetics: Mitomycin is rapidly distributed throughout the body after intravenous administration. It is metabolized primarily in the liver, with minor contributions from other tissues, including the kidneys. Renal excretion is the primary route of elimination for mitomycin and its metabolites. Metabolism involves reduction by various enzymes to active metabolites, while hepatic pathways involving CYP enzymes may also contribute.
Mode of Action: Mitomycin undergoes enzymatic reduction within cells to become activated. These reduced metabolites form covalent bonds with DNA, primarily at guanine residues. This cross-linking hinders DNA replication and transcription, triggering cell cycle arrest and apoptosis (programmed cell death).
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Mitomycin’s primary action is through direct DNA damage and doesn’t typically involve receptor binding, specific enzyme inhibition, or neurotransmitter modulation.
Dosage
Standard Dosage
Adults:
Intravenous: 10-20 mg/m² body surface area every 6-8 weeks, 8-12 mg/m² every 3-4 weeks, or 5-10 mg/m² every 1-6 weeks depending on the regimen. The maximum cumulative dose is 60 mg/m². Doses greater than 20 mg/m² are associated with increased toxicity without added therapeutic benefit. Combination therapy uses lower doses. Mitomycin is administered as an intravenous bolus injection or infusion.
Intravesical (Bladder): 20-40 mg in 20-40 ml of phosphate buffer (pH 7.4) or sodium chloride 0.9% solution instilled weekly into the bladder for 8-12 weeks. Alternative regimens include 4-10 mg (0.06-0.15 mg/kg) instilled once or three times per week. The solution should be retained for 1-2 hours. For prophylaxis, 20mg every two weeks or 40 mg every month or every three months.
Intravesical (Upper Tract Urothelial Cancer): 4 mg/mL, with a maximum of 60 mg mitomycin, administered once weekly for six instillations. Maintenance therapy may be given monthly for up to 11 months in responding patients. Sodium Bicarbonate should be given to patients the day before, day of, and 30 minutes before instillation.
Ophthalmic: 0.2 mg/mL applied topically during glaucoma filtration surgery for two minutes using saturated sponges.
Children:
The safety and efficacy of mitomycin in children have not been established.
Special Cases:
- Elderly Patients: Dose reduction might be necessary due to potential age-related decline in organ function.
- Patients with Renal Impairment: Dose adjustments are required, and use is generally avoided in severe renal dysfunction (serum creatinine > 1.7 mg/dL or creatinine clearance < 30 mL/min).
- Patients with Hepatic Dysfunction: Caution is advised, although specific dose adjustments are not well-defined.
- Patients with Comorbid Conditions: Careful consideration and dose modification may be necessary based on the specific comorbidity, especially in patients with pre-existing myelosuppression.
Clinical Use Cases
Mitomycin is not indicated for intubation, general surgical procedures, mechanical ventilation, ICU use, or general emergency situations like cardiac arrest or status epilepticus. Its use is specifically restricted to cancer treatment as indicated above and as an adjunct in glaucoma filtration surgery.
Dosage Adjustments
Dose adjustments are based primarily on hematological parameters (leukocyte and platelet counts), renal function, prior chemotherapy regimens, and the presence of other toxicities. Dosage should be reduced or withheld if myelosuppression occurs, or if other significant organ toxicities are observed. Specific guidelines for dose reductions based on blood counts and renal function are available (See source data).
Side Effects
Common Side Effects
Nausea, vomiting, anorexia (loss of appetite), fever, fatigue, myelosuppression (decreased blood cell counts), alopecia (hair loss), stomatitis (mouth sores), skin reactions.
Rare but Serious Side Effects
Pulmonary toxicity (pneumonitis, interstitial lung disease), hemolytic uremic syndrome, renal toxicity, microangiopathic hemolytic anemia, thrombocytopenia, interstitial nephritis.
Long-Term Effects
Cumulative myelosuppression, secondary malignancies, pulmonary fibrosis, renal insufficiency.
Adverse Drug Reactions (ADR)
Hemolytic uremic syndrome (HUS), acute respiratory distress syndrome (ARDS), severe myelosuppression requiring transfusions, extravasation injury (tissue necrosis at injection site if administered outside the vein).
Contraindications
Absolute contraindications include hypersensitivity to mitomycin, severe myelosuppression (pancytopenia, leukopenia, thrombocytopenia), hemorrhagic diathesis (bleeding disorders), and active infections. Relative contraindications include impaired renal function, pre-existing lung disease, and recent or concurrent radiotherapy. Perforation of the bladder wall is an absolute contraindication for intravesical use, and cystitis is a relative contraindication. Pregnancy is a contraindication for mitomycin except in life-threatening situations.
Drug Interactions
Mitomycin interacts with numerous medications, including other myelosuppressive agents (additive bone marrow toxicity), vinca alkaloids (increased risk of pulmonary toxicity), and vaccines (reduced efficacy). It can also interact with drugs metabolized by CYP450 enzymes, potentially affecting their clearance. Consult drug interaction resources for a comprehensive list. Concomitant use of other nephrotoxic drugs is not recommended.
Pregnancy and Breastfeeding
Mitomycin is contraindicated during pregnancy (Pregnancy Category X) due to its teratogenic, mutagenic, and carcinogenic potential. It should also be avoided during breastfeeding due to the risk of transmission to the infant through breast milk.
Drug Profile Summary
- Mechanism of Action: DNA cross-linking agent, leading to inhibition of DNA synthesis and cell death.
- Side Effects: Myelosuppression, nausea, vomiting, anorexia, pulmonary toxicity, renal toxicity.
- Contraindications: Pregnancy, severe myelosuppression, bleeding disorders, active infections.
- Drug Interactions: Numerous drug interactions, consult drug interaction resources.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Variable, depending on route of administration, indication and patient condition. Refer to the detailed dosage section above.
- Monitoring Parameters: Complete blood counts (CBC), renal function tests (creatinine, creatinine clearance), liver function tests (LFTs), pulmonary function tests (PFTs) if indicated.
Popular Combinations
Mitomycin is frequently used in combination regimens for various cancers, such as with 5-fluorouracil and other chemotherapeutic agents. Specific combinations depend on the cancer type and treatment protocol.
Precautions
- General Precautions: Monitor closely for myelosuppression, renal and pulmonary toxicity. Pre-screening for pre-existing conditions is crucial. Avoid extravasation during administration.
- Specific Populations: Dose adjustment required for renal impairment and elderly patients. Contraindicated in pregnancy and breastfeeding. Not recommended in children unless absolutely necessary.
- Lifestyle Considerations: Advise patients to maintain adequate hydration, and report any signs of infection promptly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Mitomycin?
A: Dosage varies depending on the indication and route of administration. For intravenous use in adults, standard dosages range from 5-20 mg/m² every 1-8 weeks, depending on the regimen. Intravesical dosages for bladder cancer are 20-40 mg weekly for 8-12 weeks. Ophthalmic dose is 0.2 mg/mL.
Q2: What are the most serious side effects of Mitomycin?
A: Serious side effects include myelosuppression, hemolytic uremic syndrome (HUS), pulmonary toxicity (pneumonitis, fibrosis), and renal impairment.
Q3: Can Mitomycin be used during pregnancy?
A: No, Mitomycin is contraindicated in pregnancy due to its teratogenic effects.
A: Mitomycin is primarily metabolized in the liver and other tissues through reductive pathways.
Q5: What are the key monitoring parameters for patients on Mitomycin?
A: Complete blood counts (CBCs), renal function tests, liver function tests, and pulmonary function tests if pulmonary toxicity is suspected.
Q6: What is the mechanism of action of Mitomycin?
A: Mitomycin acts as an alkylating agent, cross-linking DNA strands and inhibiting DNA synthesis, which ultimately leads to cell death.
Q7: Is Mitomycin used as a single agent or in combination therapy?
A: Mitomycin can be used as a single agent or in combination with other chemotherapeutic agents, depending on the type of cancer and treatment protocol.
Q8: How is Mitomycin administered for bladder cancer?
A: Mitomycin is administered intravesically, meaning it is instilled directly into the bladder via a catheter.
Q9: Can mitomycin be used in patients with kidney problems?
A: Mitomycin should be used with caution in patients with impaired renal function, and dose adjustments may be necessary. It’s generally avoided in patients with a serum creatinine above 1.7 mg/dL.
Q10: What are the signs of extravasation with mitomycin, and what should be done if it occurs?
A: Extravasation is a serious complication that can occur if mitomycin leaks out of the vein and into surrounding tissues. Signs of extravasation include pain, burning, swelling, redness, and blistering at or near the injection site. If extravasation is suspected, immediately stop the infusion and consult extravasation guidelines for appropriate management which may include local injection of an antidote and application of cold compresses.
