Mitomycin - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Mitomycin is an anti-tumor antibiotic that has been applied in glaucoma (a condition that damages the optic nerve) filtration surgery or trabeculectomy, which is an operation for controlling eye pressure by creating a filter that should not scar over, thus increasing the success rate of the operation. The action of Mitomycin is to inhibit fibroblast proliferation and restrict blood vessels from ingrowing, which in turn brings about the formation of scar tissues, which is likely to lead to surgery failure.

There is information that Mitomycin has reduced the postoperative rate of surgical failure in high-risk and primary trabeculectomy operations, and intraocular pressure has been lower simultaneously. Mitomycin was explicitly licensed for use in glaucoma filtration surgery in the United States; it was approved by the US FDA (United States Food and Drug Administration) on February 7, 2012.

Drug Group

Mitomycin belongs to antineoplastic antibiotics, which can affect cancer cells so that the cancer cells cannot reproduce by directly affecting the cancer cell's DNA (deoxyribonucleic acid).

Indications

Mitomycin is mainly used as a supplementary treatment when performing minimally invasive glaucoma surgery, also known as ab externo glaucoma surgery, because it prevents scarring in the aqueous humor, which increases the effectiveness of the operation.

Contraindications

Mitomycin is not allowed in patients with hypersensitivity (a severe allergic reaction) to Mitomycin.

Dosage Forms and Available Strengths

The vials contain a clear, colorless, sterile, lyophilized liquid containing 0.2 mg (milligrams) of Mitomycin and 0.4 mg Mannitol. After reconstitution with sterile water for injection, the product comprises 0.2 mg/mL (milligrams per milliliter) of Mitomycin.

Warnings and Precautions

• Cell Death: Mitomycin is cytotoxic (a substance that causes cell death). The use of Mitomycin at a concentration greater than 2 mg/mL or an application time of more than two minutes may cause corneal and scleral complications, such as thinning or perforation. Direct contact with corneal endothelium leads to the destruction of the endothelial cell.

• Hypotony: Some studies have highlighted that the application of Mitomycin has some adverse effects, including postoperative hypotony (low intraocular pressure).

• Cataract Development: It has been found that Mitomycin use in phakic (implanting lens into the eye without removing the natural lens) patients is associated with an increase in lenticular change and the formation of cataracts (lens clouding in the eyes).

• Embryo-Fetal Toxicity: Mitomycin can harm a developing fetus. The patient should be informed of this possibility. Mitomycin should be used only after confirming the pregnancy status of females of childbearing potential.

For Patients

How Does Mitomycin Work in Glaucoma Filtration Surgery?

Mitomycin belongs to a class of antitumor antibiotics that has a direct effect on cell DNA. This drug causes DNA cross-linking and cell division arrest, which results in cell death. It is most useful for rapidly dividing cells, such as cancer cells, which divide faster than normal cell division.

Mitomycin works in glaucoma filtration surgery by inhibiting fibroblast proliferation and reducing scar tissue formation at the surgical site. In glaucoma filtration surgery, such as trabeculectomy, a new drainage pathway is created to lower intraocular pressure by allowing excess fluid (aqueous humor) to exit the eye. However, scar tissue can block this new drainage pathway and reduce the surgery's effectiveness.

What Are the Benefits of Mitomycin?

The key benefits of Mitomycin include:

• Cancer Treatment: Mitomycin is used for the treatment of different types of cancers, such as stomach, pancreatic, and bladder cancers. It operates by binding with pathways that cause the cancer cells to cease growing or even die to halt the synthesis of DNA.

• Ophthalmic Use: Mitomycin is used to counteract scar formation in eye surgeries, such as glaucoma filtration surgery. This raises the success of the surgery because it is ascertained that the new drainage routes are not closed.

• Combination Therapy: It is usually administered together with other chemotherapy (a treatment that uses drugs to kill the fast-growing cells in the body) drugs to boost the general efficiency of cancer treatment.

• Topical Application: Mitomycin is used topically for some forms of skin cancer and can be effective without requiring the patient to undergo surgery.

How Is Mitomycin Administered?

Mitomycin is a topical solution used to apply to the surgical site, and it comprises 0.2 mg of Mitomycin and Mannitol, in which the ratio of Mitomycin to Mannitol is 1:2. It is then reconstituted by diluting 1 mL (milliliter) of sterile water for injection, and the contents are mixed by shaking. The sponges in the kit are meant to be saturated with this reconstituted solution, put on the affected area for two minutes, and then thrown away. Such a reconstituted solution is stable at room temperature for one hour on the other end.

Mitomycin is available as a powder dissolved in liquid and administered intravenously (into the vein) in a healthcare center by a physician or a registered nurse. It is normally administered by injection every six to eight weeks. Some side effects may require the doctor to suspend treatment or adjust the dosage. Patients should describe their feelings to the doctor when they are treated with Mitomycin injections.

What Are the Side Effects of Mitomycin?

Inform the doctor if any of the below-mentioned symptoms worsen or do not go away.

Adverse effects associated with Mitomycin include the following:

• Nausea.

• Vomiting.

• Loss of appetite.

• Sore throat and mouth.

• Headache.

• Fainting.

• Blurred vision.

• Hair loss.

• Weaknesses include a decrease in the power and vitality of muscles and bodily energy.

• Rash.

If the patient experiences any of these serious Mitomycin side effects, call the doctor immediately.

• Pain, sensitivity, itching, redness, swelling, blistering, or sores on the skin, particularly the area where a shot has been administered.

• Shortness of breath

• Difficulty breathing

• Rapid, unsteady, or throbbing heartbeat.

What Are the Things to Inform the Doctor Before Taking Mitomycin?

Before receiving Mitomycin,

• Inform the doctor and pharmacist if the patients are allergic to Mitomycin, other medications, or any of the ingredients in Mitomycin injection. It is important to ask the pharmacist for a list of the ingredients of Mitomycin.

• Inform the doctor and the pharmacist about the other prescription and non-prescription drugs, vitamins, nutritional supplements, and herbal preparations that the patients are using or planning to use. Make sure that the patients state that they have ever received Doxorubicin. Inform the doctor if the patient has any blood or bleeding disorder or if they have had frequent episodes of bruising or bleeding. The doctor may not wish patients to take Mitomycin injections.

• Inform the doctor if patients have kidney disease or have ever had it.

• Inform the doctor if patients are pregnant, planning to get pregnant, or breastfeeding. The patients should not breastfeed during the treatment with Mitomycin.

Dietary Considerations

Patients do not require any dietary restrictions and can have regular meals except if the prescribing physician advises them.

Missed Dose

Missing the Mitomycin dose is highly unlikely, as healthcare professionals give it during surgery.

Overdose

Overdosing Mitomycin is also highly unlikely, as healthcare professionals give it during surgery.

Storage and Handling

Mitomycin kits should be stored between 20°C (degrees Celsius) and 25°C or 68°F (degrees Fahrenheit) and 77°F and protected from heat. Mitomycin should be handled with the appropriate precautions in handling and disposal as a cytotoxic drug. The Mitomycin kit for ophthalmic use contains containment and disposal systems.

For Doctors

Pharmacodynamics

Mitomycin belongs to older chemotherapy, an antitumor agent that selectively intersects the zone of DNA synthesis. There is a significant association between the content of guanine and cytosine in Mitomycin and its degree of cross-linking by Mitomycin. Its concentrations reduce RNA (ribonucleic acid) and protein synthesis in cells and, as demonstrated in vitro, inhibit B cell, T cell, and macrophage proliferation, antigen presentation, secretion of interferon-gamma, TNFa (tumor necrosis factor-alpha), and IL-2 (interleukin-2) as well.

Mechanism of Action

Mitomycin's mechanism of action involves it being converted within the body into bifunctional and trifunctional alkylating agents. It forms cross-linking with DNA and also inhibits DNA synthesis and functionality. Like many other antibiotics, Mitomycin is not phase-specifically active in the cell cycle.

Pharmacokinetics

• Absorption: The extent of the systemic exposure to Mitomycin after ocular use of Mitomycin in humans is yet to be determined, but based on a proposed dosage of up to 0.2 mg to intravenous doses used for oncologic treatment, it is believed that the systemic exposures would be multiple orders of magnitude less than those achieved after IV administration.

• Metabolism: In a related study done on humans with the application of Mitomycin in ophthalmic tissue intraoperatively using topical application and irrigation, Mitomycin was cleared from the target tissue mainly by hepatic metabolism. It was found that the clearance rate depends on the serum concentration of the drug; hence, as the serum concentration increases, the clearance rate decreases due to the saturation of the degradative pathway.

• Excretion: It is stated that about 10 percent of one injection dose is eliminated in the human body in the unchanged form in urine, whereas the percentage rises at low doses when the metabolic pathways are saturated.

Drug Interactions

Eye drops with Mitomycin will not be influenced by other oral or injectable medicines.

Clinical Studies

It has been established that Mitomycin can lower the IOP of patients with open-angle glaucoma by 3 mmHg (millimeter of Mercury) in month 12 in placebo-controlled trials and by 5 mmHg in historical control studies if Mitomycin is used as an adjuvant to ab externo glaucoma surgery.

Use in Specific Populations

• Pregnancy: The application of Mitomycin to a pregnant woman may lead to fetal injury, as proved through research done with animals. There is not much data regarding the use of Mitomycin during pregnancy; however, Mitomycin, when administered through the parenteral route, has been proven to possess teratogenic effects. However, the baseline rate of major birth defects and miscarriage for the above-indicated population group is not well defined. In contrast, for the general population of the USA, it ranges between two and four percent for major birth defects and 15 and 20 percent for miscarriages in clinically recognized pregnancies.

• Breastfeeding: No information is known about Mitomycin secretion in human milk, its impact on nursing infants, or the quantity of the milk produced. It is recommended that women who are breastfeeding avoid using Mitomycin because of the possible side effects and effects on the baby and that they not breastfeed for a week after the use of Mitomycin.

• Pediatric Use: It is unknown if Mitomycin is safe and effective for children younger than 18.

• Geriatric Use: Mitomycin's efficacy and safety profile do not differ in elderly patients from those in younger patients.