Mesna – Uses, Dosage, Side Effects, Interactions

Mechanism of Action

A metabolite called acrolein is produced when ifosfamide and cyclophosphamide are metabolized. This metabolite concentrates in the bladder and causes cell death via the upregulation of reactive oxygen species (ROS), and activates inducible nitric oxide synthase (iNOS) which leads to the production of nitric oxide (NO). Both ROS and NO produce products which are detrimental to lipids, proteins, and DNA strands. Furthermore, ROS stimulates gene expression of pro-inflammatory cytokines such as TNF-α AND IL-1β. Acrolein may also lead to ulceration of the bladder urothelium. Mesna protects against cyclophosphamide and ifosfamide-induced hemorrhagic cystitis by binding to their toxic metabolites. Mesna is metabolized to demesne and excreted by the kidneys. Glutathione dehydrogenase acts on the reabsorbed portion and produces free sulfhydryl groups. These free sulfhydryl groups bind acrolein in the bladder, allowing effective excretion and prevention of toxic effects. In addition, Mesna binds to and detoxifies a urotoxic ifosfamide metabolite called 4-hydroxy-ifosfamide.

Mesna reduces the toxicity of urotoxic compounds that may form after chemotherapy administration. Mesna is a water-soluble compound with antioxidant properties and is given concomitantly with the chemotherapeutic agent’s cyclophosphamide and ifosfamide. Mesna concentrates in the bladder where acrolein accumulates after administration of chemotherapy and through a Michael addition, forms a conjugate with acrolein and other urotoxic metabolites.[rx] This conjugation reaction inactivates the urotoxic compounds to harmless metabolites. The metabolites are then excreted in the urine.[rx]

Indications

Mesna is a neuroprotective agent and is used prophylactically to reduce ifosfamide and cyclophosphamide-induced hemorrhagic cystitis. Mesna is a neuroprotective agent and is used prophylactically to reduce ifosfamide and cyclophosphamide-induced hemorrhagic cystitis.

  • (1) Osteosarcoma of bone and articular cartilage of other specified sites [co-prescribed with V03AF01];
  • (2) Other specified malignant neoplasms of the ovary [co-prescribed with V03AF01];
  • (3) Germ cell tumor of testis [co-prescribed with V03AF01];
  • (4) Ewing sarcoma of bone and articular cartilage of unspecified sites [co-prescribed with V03AF01];
  • (5) Rhabdomyosarcoma primary site [co-prescribed with V03AF01];
  • (6) Unspecified malignant neoplasms of ill-defined or unspecified sites [co-prescribed with V03AF01];
  • (7) Burkitt lymphoma including Burkitt leukemia [co-prescribed with V03AF01]; (8) Malignant neoplasms of the kidney, except renal pelvis [co-prescribed with V03AF01]
  • Hemorrhagic cystitis caused by cyclophosphamide
  • Hemorrhagic cystitis caused by ifosfamide

Use in Cancer

Mesna is approved to prevent:

FDA-approved Indication

  • Mesna is a prophylactic medication to reduce the incidence of ifosfamide-induced hemorrhagic cystitis.
  • It is important to recognize that mesna is not indicated to decrease the risk of hematuria due to thrombocytopenia.

Non-FDA-approved Indications

  • Mesna is also used widely as a prophylactic medicine to reduce the incidence of cyclophosphamide-induced hemorrhagic cystitis.
  • Treatment of chemically-assisted dissection of recurrent and residual cholesteatoma
  • Reduction of the incidence of BK viruria following post-transplantation cyclophosphamide
  • Inhibition of propylene glycol-induced cholesteatoma formation
  • Treatment of pain following failed back surgery syndrome via epidural injection
  • Treatment of chronic cholesteatomatous otitis media in children

Contraindications

  • cancer metastasis to bone
  • dehydration
  • low amount of potassium in the blood
  • Fanconi syndrome, a condition of the kidneys resulting in excessive urination, thirst and vomiting
  • anemia
  • decreased blood platelets
  • low levels of white blood cells
  • confusion
  • generalized disorder of peripheral nerves
  • liver problems
  • renal tubular acidosis
  • decreased kidney function
  • inflammation and bleeding of the bladder due to chemotherapy
  • coma
  • the high amount of bilirubin in the blood
  • abnormal liver function tests
  • impaired wound healing
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • the operation to remove kidney tissue

Dosage

Strengths: 100 mg/mL; 400 mg

American Society of clinical oncology (ASCO) guidelines recommend following protocols for administering mesna.

  • Mesna dosing recommendations with standard-dose ifosfamide: ASCO recommends that the daily dose of mesna be calculated to be equivalent to 60% of the total daily dose of ifosfamide, given as three bolus doses given 15 minutes before and four and eight hours after administration of each dose of ifosfamide when the ifosfamide dose is less than 2.5 g/m/day administered as a short infusion. When mesna is used with continuous ifosfamide infusion, it may be given as a bolus dose equivalent to 20% of the total ifosfamide dose, followed by a constant infusion of mesna equivalent to 40% of the ifosfamide dose, given for 12 to 24 hours after completion of the ifosfamide infusion. 
  • Mesna dosing recommendations with high-dose ifosfamide: The efficacy of mesna for the prevention of urotoxicity with very high-dose ifosfamide (>2.5 g/m/day) has not been established. The half-life of ifosfamide is extended at higher doses. Consequently, prolonged mesna dosage regimens may be required for protection against urotoxicity. A higher concentration of ifosfamide (50 mg/mL) is incompatible with mesna and can decrease the stability of ifosfamide.
  • Mesna dosing recommendations by the oral route: ASCO recommends administering mesna as an IV bolus injection in a dose of 20% of the ifosfamide dose at the time of ifosfamide administration; mesna tablets are administered orally in a dosage equal to 40% of the ifosfamide dose at 2 and 6 hours following each dose of ifosfamide; the total daily dose of mesna is 100% of the ifosfamide dose; patients who vomit within 2 hours of taking oral mesna should repeat the dose or receive IV mesna; the dosing schedule should be repeated on each day that ifosfamide is administered.
  • Mesna recommendations with cyclophosphamide: Mesna plus saline diuresis or forced saline diuresis is advised to reduce the incidence of urotoxicity associated with high-dose cyclophosphamide. It is important to note that mesna injection should not be mixed with cyclophosphamide, cisplatin, carboplatin, and epirubicin. According to KDIGO (kidney disease improving global outcomes) guidelines, mesna should be administered if the cyclophosphamide dosage is considered high.

Studies have also shown mesna administration as a topical agent for chemically assisted dissection of recurrent and residual cholesteatoma, most commonly in pediatric patients. Another study showed that epidural injection of mesna reduced pain following failed back surgery syndrome (FBSS).

Hemorrhagic Cystitis Prophylaxis

  • This drug may be given on a fractionated dosing schedule of either 3 bolus IV injections or a single injection followed by 2 oral doses. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dose of ifosfamide is adjusted, the ratio of mesna to ifosfamide should be maintained.
  • IV: Mesna is given at 20% of the ifosfamide dose once at the time of ifosfamide administration and 20% of the ifosfamide dose 4 and 8 Hours after each dose of ifosfamide (e.g., if ifosfamide were given at 1.2 g/m2 at 0 Hours, the dose of mesna would be 240 mg/m2 given at 0, 4, and 8 Hours after ifosfamide)
  • ORAL (to be given after one dose of IV mesna): Mesna is given at 40% of the ifosfamide dose at 2 and 6 Hours after each dose of ifosfamide (e.g., if ifosfamide were given at 1.2 g/m2 at Hour 0, the IV dose of mesna would be 240 mg/m2 given at the time of ifosfamide administration (0 Hour) and the oral dose of this drug would be 480 mg/m2 given at 2 and 6 Hours after ifosfamide)
  • In order to maintain adequate protection, the recommended dosage regimen should be repeated on each day that ifosfamide is administered.
  • When the dosage of ifosfamide is adjusted (either increased or decreased), the dose of mesna should also be modified accordingly.
  • Adequate hydration and sufficient urinary output should be maintained, as required for ifosfamide treatment, and urine should be monitored for the presence of hematuria. If severe hematuria develops when mesna is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.
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Pediatric Dose for Hemorrhagic Cystitis Prophylaxis

  • Do not give this drug to premature neonates and low-birth-weight infants. This drug may be given on a fractionated dosing schedule of either 3 bolus IV injections or a single injection followed by 2 oral doses. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dose of ifosfamide is adjusted, the ratio of mesna to ifosfamide should be maintained.
  • IV: Mesna is given at 20% of the ifosfamide dose once at the time of ifosfamide administration and 20% of the ifosfamide dose 4 and 8 Hours after each dose of ifosfamide (e.g., if ifosfamide were given at 1.2 g/m2 at 0 Hours, the dose of mesna would be 240 mg/m2 given at 0, 4, and 8 Hours after ifosfamide)
  • ORAL (to be given after one dose of IV mesna): Mesna is given at 40% of the ifosfamide dose at 2 and 6 Hours after each dose of ifosfamide (e.g., if ifosfamide were given at 1.2 g/m2 at Hour 0, the IV dose of mesna would be 240 mg/m2 given at the time of ifosfamide administration (0 Hour) and the oral dose of this drug would be 480 mg/m2 given at 2 and 6 Hours after ifosfamide)
  • In order to maintain adequate protection, the recommended dosage regimen should be repeated on each day that ifosfamide is administered.
  • When the dosage of ifosfamide is adjusted (either increased or decreased), the dose of mesna should also be modified accordingly.
  • Adequate hydration and sufficient urinary output should be maintained, as required for ifosfamide treatment, and urine should be monitored for the presence of hematuria. If severe hematuria develops when mesna is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.
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General:

  • Do not mix this drug with epirubicin, cyclophosphamide, cisplatin, carboplatin, or nitrogen mustard.
  • The benzyl alcohol contained in the injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with mesna and may reduce the stability of ifosfamide.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

PATIENT COUNSELING INFORMATION

  • Advise the patient to discontinue this drug and seek immediate medical attention if they experience a hypersensitivity reaction, including systemic anaphylactic reactions.
  • Advise the patient to take this drug at the exact time and in the exact amount as prescribed.
  • Advise the patient to contact their healthcare provider if they miss a dose or if they vomit within 2 hours of taking the oral formulation.
  • This drug does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide.
  • Advise the patient to report to their healthcare provider if his/her urine turns a pink or red color.
  • Advise the patient to drink 1 to 2 liters of fluid each day during the therapy.
  • Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and bullous and ulcerative skin and mucosal reactions have occurred.

Side Effects

The Most Common

  • nausea
  • Back pain
  • bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • vomiting
  • constipation
  • loss of appetite or weight
  • diarrhea
  • abdominal pain
  • headache
  • tiredness
  • dizziness
  • hair loss
  • pain or redness at the place where the injection was given
  • loss of strength and energy
  • fever
  • sore throat
  • cough
  • flushing
  • pink or red-colored urine or blood in the urine
  • swelling of the face, arms, or legs
  • hives
  • rash
  • itching
  • difficulty breathing or swallowing
  • chest pain
  • fast, irregular, or pounding heartbeat
  • unusual bleeding or bruising

More common

  • Black, tarry stools
  • bleeding gums
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • blood in the urine or stools
  • chest pain
  • chills
  • cough
  • decreased urination
  • dizziness
  • dry mouth
  • fainting
  • fast, pounding, or irregular heartbeat or pulse
  • fever
  • increased thirst
  • lightheadedness
  • loss of appetite
  • mood changes
  • muscle pain or cramps
  • nausea
  • numbness or tingling in the hands, feet, or lips
  • painful or difficult urination
  • pinpoint red spots on the skin
  • rapid breathing
  • rapid weight gain
  • seizures
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • sunken eyes
  • swelling
  • swollen glands
  • tightness in the chest
  • trouble breathing
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
  • wrinkled skin

Rare

  • Blurred vision
  • confusion
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • sweating
  • Coughing or spitting up blood
  • dark urine
  • general tiredness and weakness
  • headache
  • light-colored stools
  • nervousness
  • pounding in the ears
  • slow heartbeat
  • upper right abdominal or stomach pain
  • yellow eyes and skin
  • diarrhea
  • difficulty having a bowel movement
  • hair loss
  • increased sweating
  • lack or loss of strength
  • sleepiness or unusual drowsiness
  • stomach pain
  • trouble sleeping
  • weight loss
  • Belching
  • feeling of warmth
  • heartburn
  • indigestion
  • redness of the face, neck, arms, and occasionally, upper chest
  • stomach discomfort or upset

Drug Interactions

  • anisindione
  • dicumarol
  • warfarin
  • prematurity
  • autoimmune disorders

Pregnancy and Lactation

FDA pregnancy category B

Pregnancy

As per the manufacturer’s labeling information, it is considered the former FDA pregnancy category B medicine. Clinicians should also inform the risk associated with ifosfamide/cyclophosphamide therapy. According to ACOG, in addition to pretreatment fertility conservation counseling, sexually active young women should be informed about the risks of becoming pregnant during cancer treatment. Clinicians should also guide, and women should also receive counseling regarding effective contraception.

Lactation

An essential consideration of mesna administration is the breastfeeding status of females of reproductive age. It is not well understood if mesna is present in breast milk; however, benzyl alcohol is often a component of mesna intravenous formulations. The manufacturer indicated that exposure to the breastfeeding infant is unlikely in part due to maternal metabolism. Nonetheless, benzyl alcohol has been linked to adverse events in infants, and therefore breastfeeding is not recommended for at least one week after the last mesna injection.

Why is this medication prescribed?

Mesna is used to reduce the risk of hemorrhagic cystitis (a condition that causes inflammation of the bladder and can result in serious bleeding) in people who receive ifosfamide (a medication used for the treatment of cancer). Mesna is in a class of medications called cytoprotectants. It works by protecting against some of the harmful effects of certain chemotherapy medications.

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How should this medicine be used?

Mesna comes as a solution (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a medical facility. It is usually given at the same time as you receive your chemotherapy treatment and then 4 and 8 hours after your chemotherapy treatment.

Drink at least 1 quart (4 cups; about 1 liter) of fluid daily while you are receiving mesna injection.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Other uses for this medicine

Mesna is also sometimes used to reduce the risk of hemorrhagic cystitis in people who receive the chemotherapy drug cyclophosphamide. Talk to your doctor about the risks of using this medication for your condition.

What special precautions should I follow?

Before receiving a mesna injection,

  • tell your doctor and pharmacist if you are allergic to mesna, any other medications, or any of the ingredients in mesna injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had an autoimmune disorder (a condition that occurs when your immune system mistakenly attacks healthy body tissue) such as rheumatoid arthritis, systemic lupus erythematosus, or nephritis (a type of kidney problem).
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding.

It is very important that your doctor check your progress closely while receiving this medicine to make sure this medicine is working properly. Blood and urine tests will be needed to check for unwanted effects.

This medicine is used together with ifosfamide. Ifosfamide can harm your unborn baby while you are pregnant. It may also cause birth defects if the father is receiving it when his sexual partner becomes pregnant. Use an effective form of birth control during treatment with this medicine in combination with ifosfamide and for 6 months after the last dose. Male patients with female partners should use an effective form of birth control during treatment and for 3 months after the last dose. If you think you have become pregnant while receiving this medicine, tell your doctor right away.

This medicine may cause serious allergic reactions, including anaphylaxis, which can be life-threatening and require immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, or fainting. Other signs may include changes in facial skin color, very fast but irregular heartbeat or pulse, hive-like swellings on the skin, and puffiness or swellings of the eyelids or around the eyes. If these side effects occur, get emergency help at once.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are receiving this medicine.

This medicine contains benzyl alcohol which may cause serious reactions in premature or low-birth-weight infants. Talk to your doctor if you have concerns about this.

Make sure any doctor or dentist who treats you knows that you are receiving this medicine. It may affect the results of certain medical tests.

References