Mitomycin

Mitomycin is an antineoplastic agent belonging to the pharmacological class of antibiotics.

Mitomycin is also known as mitomycin-C. The FDA approved Mitomycin to treat stomach (gastric) and pancreas cancers and certain bladder cancers.

Mitomycin exhibits minimal systemic absorption topically but rapidly enters systemic circulation after parenteral administration. Widely distributed, it undergoes hepatic metabolism and is primarily excreted via faeces (90%)

The most common side effects of Mitomycin include anaemia (low number of red blood cells), increased bleeding tendency, decreased white blood cell count, loss of appetite, nausea, and vomiting.

Mitomycin is available as tablets and powder for injection.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Mitomycin is an antineoplastic agent belonging to the pharmacological class of antibiotics.

Mitomycin, a derivative of Streptomyces caespitosus, exhibits antitumor action akin to alkylating drugs. Mitomycin promotes nuclear lysis, the development of large cells, and the degradation of preformed DNA, all of which specifically prevent DNA synthesis by inducing cross-linking. Protein synthesis and cellular RNA production may also be inhibited at high dosages. Although it has the most effect in the late G- and early S-phases, mitomycin is not phase-specific throughout the cell cycle.

Mitomycin is available as a powder for injection.

Powder for injection: To be administered parenterally, as applicable.

As prescribed by the physician, take the medication with or without meals.

• Pancreatic cancer
• Stomach cancer
• Breast cancer
• Non-small cell lung cancer
• Off-label Anal Carcinoma
• Head and neck cancer
• Superficial bladder tumours
• Adjunct in ophthalmic surgery

• Pancreatic cancer: The production of the body's endogenous insulin by the pancreas makes it necessary for both blood sugar metabolism and digestion of food. The drug will alleviate the symptoms of pancreatic cancer, including appetite loss and unexplained weight loss, and help manage the disease. Mitomycin can block the actions of specific molecules that promote the growth and spread of pancreatic cancer.
• Stomach cancer: The mucosa or walls of the stomach can develop stomach cancer, also known as gastric cancer. The cancer can take many different forms depending on where it originates, what is affected, and how severe it is. Mitomycin is an important drug that stops the spread of cancer by specifically targeting and killing cancer cells. This effectively stops the cancer cells from growing further.
• Breast cancer: Mitomycin is an effective treatment for breast cancer that can be used either on its own or in conjunction with other medications or therapies, such as chemotherapy. It reduces breast cancer symptoms, including breast lumps, bloody nipple discharge, and changes to the texture or shape of the breast. Mitomycin inhibits the development and proliferation of cancer cells and their death.
• Non-small cell lung cancer: One of the most common types of lung cancer, non-small cell lung cancer, can strike both non-smokers and smokers. Mitomycin is used either alone or in conjunction with other medications to treat non-small cell lung cancer. Consult the doctor about the advantages and hazards associated with this potent and highly toxic drug.
• Adjunct in ophthalmic surgery: Mitomycin is a valuable adjuvant in ocular surgery, especially for trabeculectomy and glaucoma treatments. Mitomycin improves surgical results by preventing excessive scarring and fibrosis by blocking cell division and collagen formation.

• When combined with other approved chemotherapeutic drugs, mitomycin is effective in treating disseminated adenocarcinoma of the stomach or pancreas. It has also been used as a form of palliative therapy after other treatment methods have failed.
• Mitomycin is indicated as an adjunct in ab externo (outside approach) eye surgeries to treat glaucoma.

Parenterally: Administer Mitomycin via slow IV push exclusively through a central line. For injection, dilute it with sterile water to achieve a final concentration of 0.5 mg/mL. Further dilution in 0.9% NaCl or Na lactate to a concentration of 0.02-0.04 mg/mL may be performed. Flush with 5-10 mL of IV solution before and after drug administration. Monitor the IVPB infusion closely to ensure vein patency. Monitor out for any extravasation, as this might result in necrosis. If extravasation develops, promptly consult a plastic surgeon for management.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Mitomycin is available as a powder for injection.

Dose Adjustment in Adult Patients:

Prostate cancer

If blood counts allow, 10–20 mg/m2 doses may be repeated every 6–8 weeks and modified based on the prior haematological response. Alternatively, provide 4–10 mg (0.06-0.15 mg/kg) every 1-6 weeks.

Pancreas cancer

Standard dosage: 10–20 mg/m2 may be repeated every 6–8 weeks if blood counts allow, and dosage may be changed based on prior haematological response. Alternatively, provide 4–10 mg (0.06-0.15 mg/kg) every 1-6 weeks.

Metastatic breast cancer

Standard dosage: 10–20 mg/m2 may be repeated every 6–8 weeks if blood counts allow, and dosage may be changed based on prior haematological response. Alternatively, provide 4–10 mg (0.06-0.15 mg/kg) every 1-6 weeks.

Cancer of the stomach

Usual dosage: 10–20 mg/m2; if blood counts allow, this dose may be repeated every 6–8 weeks, and it may also be modified based on the patient's prior hemolytic reaction. As an alternative, 4–10 mg (0.06-0.15 mg/kg) every one to six weeks.

Head and neck cancer

Usual dosage: 10–20 mg/m2; if blood counts allow, this dose may be repeated every 6–8 weeks, and it may also be modified based on the patient's prior hemolytic reaction. As an alternative, 4–10 mg (0.06-0.15 mg/kg) every one to six weeks.

Non-small cell lung cancer

Usual dosage: 10–20 mg/m2; if blood counts allow, this dose may be repeated every 6–8 weeks, and it may also be modified based on the patient's prior hemolytic reaction. As an alternative, 4–10 mg (0.06-0.15 mg/kg) every one to six weeks.

Superficial bladder tumours

Standard dosage: 20–40 mg administered once or thrice each week for 20 doses. After 15 minutes, rotate dosage contact with every part of the bladder urothelium to keep the solution in the bladder for at least an hour. A substitute would be an injection of 4–10 mg (0.06-0.15 mg/kg) once or thrice a week. You can take 20 mg every two weeks, 40 mg monthly, or 40 mg every three months to prevent recurrence instances.

Ophthalmic

Adjunct in ocular surgery

When 0.2 mg/mL is dissolved, apply it to the surgical site of the glaucoma filtration procedure using soaked sponges. For two minutes, leave the sponges on the treated region.

There are no specific dietary requirements when taking Mitomycin. When taking Mitomycin, avoid smoking and alcohol. The diet includes leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs. Avoid fast, fried, processed meats, refined carbs, and added sugar. Stay hydrated and maintain a balanced diet. Avoid smoking and alcohol consumption.

The dietary restriction should be individualized as per patient requirements.

• In patients who have a history of hypersensitive or idiosyncratic reactions to mitomycin.
• In patients with thrombocytopenia, coagulation disorder, or increased bleeding tendency due to other causes.
• Pregnancy and lactation.

• Bone Marrow Suppression: Mitomycin use is associated with high bone marrow suppression, notably thrombocytopenia and leukopenia. Repeatedly monitor platelet count, white blood cell count, differential, and haemoglobin during therapy and at least eight weeks afterwards. A platelet count below 100,000/mm3, a WBC below 4,000/mm3, or a progressive decline indicates therapy withholding until blood counts recover. Advise patients about potential drug toxicity, emphasizing the risk of bone marrow suppression. Deaths attributed to septicemia from drug-induced leukopenia have been reported.
• Renal Toxicity: Monitor mitomycin recipients for signs of renal toxicity. Mitomycin is contraindicated in patients with a serum creatinine exceeding 1.7 mg per cent.
• Bladder Toxicity: Bladder fibrosis/contraction, reported with intravesical mitomycin (an unapproved route), may necessitate cystectomy. Intravesical Mitozytrex safety is unstudied. Bladder toxicities have occurred with HPβCD excipient parenteral administration in rodents and dogs.
• Pulmonary: Use caution with mitomycin in patients receiving or previously treated with vinca alkaloids. Acute respiratory distress may occur, warranting close observation. Mitomycin-treated patients may develop adult respiratory distress syndrome under high perioperative oxygen concentrations.
• Concurrent use with anthracyclines may increase the risk of heart failure.

Dose Considerations

Use only in combination with more antineoplastics.

If after two courses there is still development, stop.

The adverse reactions related to Mitomycin can be categorized as:

• Common Adverse Effects: Hemolytic uremic syndrome, myelosuppression, nausea, vomiting, and fever.
• Less Common Adverse Effects: Mucous membrane toxicity, stomatitis and increased serum creatinine levels
• Rare Adverse Effects: Bladder fibrosis/contraction with the intravesical route, necrotizing cystitis and acute respiratory distress when combined with vinca alkaloids.

Reports on Postmarketing

Malaise and asthenia

• Drug-Drug Interactions: Mitomycin may interact with several cancer-treatment medications (doxorubicin, for example) and some antibiotics (ciprofloxacin, levofloxacin, for example).

When used together with other chemotherapeutic drugs (such as vinca alkaloids), side effects include lung toxicity and bone marrow suppression may worsen.

• Drug-Food Interactions: Avoid alcohol to prevent uncomfortable side effects.
• Drug-Disease Interactions: Infections, bone marrow suppression, bleeding disorders, and myelosuppression.

The common side effects of Mitomycin include nausea, vomiting, fever, stomatitis, and myelosuppression, leading to reduced blood cell counts, potentially causing anaemia, leukopenia, or thrombocytopenia.

• Pregnancy

ROUTE(S): Parenteral: D; Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

ROUTE(S): Ocular: X; When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

There is no data on the use of treatment in pregnant women to inform the drug-associated risk, despite evidence in animals and the mechanism of action suggesting that it can cause harm to a developing fetus. Inform expectant mothers about the possible risk to a fetus since mitomycin injection caused teratogenicity in studies on animal reproduction.

Before starting therapy, find out whether any females are capable of becoming pregnant.

Contraception

Females: Advise women who might get pregnant to take safe contraception both throughout and for six months after the final dosage of therapy.

Male patients: Advise male patients who have female partners who might get pregnant to use effective contraception during therapy and for three months after the final dosage.

Animal data

Mitomycin has been linked to teratological abnormalities in animals.

• Nursing Mothers

Breastfeeding mothers are advised not to nurse during therapy and for one week after the final dosage due to the possibility of significant adverse reactions in their children. There is no data about the presence of mitomycin in human milk, its effects on breastfed children, or its impact on milk supply.

• Pediatric Use

As per FDA, the safety and effectiveness of mitomycin in pediatric patients have not been established.

• Geriatric Use

There is not enough information from clinical research, including mitomycin for people 65 years of age and above, to ascertain whether their responses differ from those of younger patients. Elderly people may be more vulnerable to injection site responses and hypersensitivity reactions than younger patients, according to postmarketing monitoring. Prescriptions for senior patients should generally be made with prudence due to the higher incidence of concurrent diseases, other pharmacological therapy, and reduced hepatic, renal, or cardiac function.

Dose Adjustment in Kidney Impairment Patients:

Avoid use if serum creatinine is more significant than 1.7 mg/dL.

If CrCl is less than 10 mL/min, reduce the dosage by 25%.

Dose Adjustment in Hepatic Impairment Patients:

Mitomycin should be used with caution in patients with liver disease. A dose adjustment of Mitomycin may be needed.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Mitomycin.

Signs and Symptoms

Overconsumption of Mitomycin could lead to fever, nausea, vomiting, and myelosuppression.

Management

The management of Mitomycin overdose involves supportive measures. There isn't a specific antidote, and the drug is not removed by hemodialysis in case of overdose. Monitor hematologic parameters, liver function, and renal function. If severe adverse reactions occur, consider dose reduction or discontinuation of Mitomycin.

Pharmacodynamic

One of the oldest known chemotherapy medications, mitomycin, has been produced and used for many years. It is an antibiotic with anticancer action demonstrated. Deoxyribonucleic acid (DNA) production is inhibited explicitly by mitomycin. The amount of mitomycin-induced cross-linking is correlated with the concentration of guanine and cytosine. Additionally, the medication suppresses cellular RNA and protein production at high dosages. In vitro studies with mitomycin have demonstrated its ability to impede the proliferation of B cells, T cells, and macrophages and affect antigen presentation and the release of interferon-gamma, TNFa, and IL-2.

Pharmacokinetics

• Absorption: Mitomycin demonstrates limited systemic absorption when applied topically. Conversely, after parenteral administration, it rapidly absorbs, entering the systemic circulation and eliciting therapeutic effects in target tissues. The half-life is approximately 48 minutes.
• Distribution: Mitomycin is widely distributed in the body, with a volume of distribution (Vd) ranging from 16 to 56 L/m².
• Metabolism: The primary site of metabolism for Mitomycin is the liver, where it undergoes metabolic transformations.
• Excretion:Mitomycin is mainly excreted through the faeces, with approximately 10% eliminated unchanged in the urine. The terminal half-life is around 50 minutes, and the clearance ranges from 201 to 810 mL/min/m².

• Tolley DA, Hargreave TB, Smith PH, Williams JL, Grigor KM, Parmar MK, Freedman LS, Uscinska BM. Effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: interim report from the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). Br Med J (Clin Res Ed). 1988 Jun 25;296(6639):1759-61. doi: 10.1136/bmj.296.6639.1759. PMID: 3136828; PMCID: PMC2546235.
• Weissberg JB, Son YH, Papac RJ, Sasaki C, Fischer DB, Lawrence R, Rockwell S, Sartorelli AC, Fischer JJ. Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys. 1989 Jul;17(1):3-9. doi: 10.1016/0360-3016(89)90362-3. PMID: 2501243.
• Inman BA, Stauffer PR, Craciunescu OA, Maccarini PF, Dewhirst MW, Vujaskovic Z. A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer. Int J Hyperthermia. 2014 May;30(3):171-5. doi: 10.3109/02656736.2014.882021. Epub 2014 Feb 3. PMID: 24490762; PMCID: PMC4006292.
• Lee HW, Lee HH, Park EY, Park WS, Kim SH, Joung JY, Chung J, Seo HK. Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study. J Urol. 2023 Jan;209(1):131-139. doi: 10.1097/JU.0000000000003002. Epub 2022 Oct 12. PMID: 36250938.

• https://www.ncbi.nlm.nih.gov/books/NBK562249/
• http://www.bccancer.bc.ca/drug-database-site/Drug Index/Mitomycin_monograph.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Doxil® (doxorubicin HCl)