CLASSES
Cytoprotectant Agents
DESCRIPTION
Chemoprotectant against hemorrhagic cystitis; more effective prophylaxis than fluids, diuretics, forced diuresis, and intravesical administration of other sulfhydryl-compounds; does not interfere with the antitumor activity of ifosfamide or cyclophosphamide.
COMMON BRAND NAMES
Mesnex
HOW SUPPLIED
Mesna/Mesnex Intravenous Inj Sol: 1mL, 100mg
Mesnex Oral Tab: 400mg
DOSAGE & INDICATIONS
For prophylaxis of ifosfamide-induced or cyclophosphamide-induced† hemorrhagic cystitis.
NOTE: Mesna has been designated an orphan drug by the FDA for this indication.
Bolus intravenous dosage
Adults, Adolescents and Children†
Administer mesna IV at a dosage of at least 20% (w/w) of the ifosfamide dosage 15 minutes before ifosfamide administration. Then give the same dose 4 and 8 hours after ifosfamide administration. Total daily mesna dosage is at least 60% of the ifosfamide dosage. For high-dose ifosfamide therapy, a mesna dose of 20% of the ifosfamide dosage IV has been administered 15 minutes before ifosfamide administration and then every 3 hours for 3 to 6 doses. A similar regimen may be used for high-dose cyclophosphamide therapy.
Continuous intravenous infusion+
Adults, Adolescents and Children†
Administer a mesna IV bolus at a dose of 10% (w/w) of the ifosfamide dosage 15 minutes before beginning the continuous IV infusion, then follow with a continuous IV infusion of mesna at a dose of 100% (w/w) of the ifosfamide dosage. Generally, mesna is continued as an IV infusion for 24 hours after the completion of ifosfamide.
Intravenous and Oral dosage (injection followed by use of tablets)
Adults, Adolescents and Children†
At the time of ifosfamide administration, give a single dose of mesna IV at a dose of 20% (w/w) of the ifosfamide dosage, then mesna tablets PO in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose.
Intravenous and Oral dosage (injection followed by the administration of injection by the oral route)
Adults, Adolescents and Children†
Following an initial IV bolus, mesna injection PO is given at a dosage of 40% (w/w) of the ifosfamide dose 4 and 8 hours after ifosfamide administration. It is not recommended to give mesna orally as the initial dose.
MAXIMUM DOSAGE
Specific maximum dosage information is not available. Individualize dosage based on dose of ifosfamide or cyclophosphamide.
DOSING CONSIDERATIONS
Hepatic Impairment
No dosage adjustments are needed.
Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
ADMINISTRATION
Oral Administration
Patients who vomit within 2 hours of oral mesna should repeat the oral dose or receive an intravenous dose.
Oral administration of mesna is only recommended in patients with good compliance and when emesis is controlled.
Oral Solid Formulations
Mesna tablets are given orally without regard to meals or food.
Oral Liquid Formulations
Mesna injection may be diluted 1:1 to 1:10 in carbonated cola drinks or chilled fruit juice such as apple, grape, tomato, or orange juice for oral administration. Plain or chocolate milk has also been used. Due to the sulfur odor (rotten eggs) of the mesna injection, more dilute solutions may be better tolerated.
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Mesna injection should be diluted to obtain a final concentration of 20 mg/ml.
Mesna may be given as a rapid IV infusion/bolus or as a continuous infusion.
Mesna is compatible with cyclophosphamide and ifosfamide in the same infusion fluid and may be admixed for continuous infusion.
Diluted solutions are chemically and physically stable for 24 hours at room temperature, 77 degrees F (25 degrees C). Mesna multidose vials may be stored and used for up to 8 days.
STORAGE
Mesnex:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Store at controlled room temperature (between 68 and 77 degrees F)
- Use within 24 hours from time of preparation
CONTRAINDICATIONS / PRECAUTIONS
General Information
Mesna is contraindicated in patients with hypersensitivity to thiol compounds.
Hematuria
Mesna will prevent oxazaphosphorine chemotherapy-induced hemorrhagic cystitis in the majority of patients; however, up to 6% of patients treated with mesna will develop hematuria (> 50 rbc/hpf or >WHO grade 2). Patients should be counseled to drink at least a quart of liquid a day. A morning specimen of urine should be examined daily for the presence of hematuria. If severe hematuria develops while mesna is being given, dosage reduction or discontinuation of ifosfamide or cyclophosphamide should be considered. Mesna is not effective in reducing the risk of hematuria due to other pathological conditions (e.g., thrombocytopenia). Mesna will not prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide or cyclophosphamide therapy.
Benzyl alcohol hypersensitivity, infants, neonates
Patients with benzyl alcohol hypersensitivity may be at increased risk of allergic reactions during treatment with mesna injection, as this formulation contains 10.4 mg/mL of benzyl alcohol as a preservative. Benzyl alcohol (at doses of 99 to 234 mg/kg/day) has also been associated with fatal reactions and gasping syndrome in premature neonates and low-birth-weight infants; therefore, use of the injectable formulation in these patient populations must be avoided. Symptoms associated with gasping syndrome include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Premature neonates and low-birth-weight infants are more likely to develop these reactions because they are less able to metabolize benzyl alcohol.[57332]
Autoimmune disease, polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus (SLE)
There is an increased incidence of hypersensitivity reactions in patients with autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and polyarteritis nodosa treated with cyclophosphamide and mesna. The majority of these patients received mesna orally. Allergic reactions are rare in oncology patients.
Pregnancy
No adequate and well-controlled studies have been performed in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. Two case reports have described the use of mesna, in combination with chemotherapeutic agents, during pregnancy. In the first report, a 21-year-old woman was treated with three courses of chemotherapy plus mesna (5 gm/m2 three times weekly) during the third trimester. The patient underwent a cesarean section at gestational week 36; no adverse effects were noted in the infant at delivery or during follow up at age 2 years.[49545] The second patient was a 20-year-old who began chemotherapy and mesna treatment at gestational week 23. Prior to treatment, the fetal weight was at the 20th percentile and fetal movement and amniotic fluid volume was normal; however, an ultrasound on week 4 of treatment revealed an absence of amniotic fluid, cessation of fetal growth, and an absence of fetal movement. Two weeks later (gestational week 29), the infant was born via an emergency cesarean section and died at age 7 days. An association with mesna was not able to be established.[49546] The manufacturer recommends use during pregnancy only if needed.[49539]
Breast-feeding
Data are limited regarding use of mesna during breast-feeding and its excretion in human milk is unknown. The drugs low molecular weight (164) suggest its possible distribution into milk; however due to its short half-life (1—8 hours), significant presence in milk is not expected. According to the manufacturer, a decision to discontinue either the drug or breast-feeding should be made. Because the drug is administered in combination with chemotherapeutic agents, ifosfamide or cyclophosphamide, women requiring treatment with mesna should be instructed to avoid breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
Laboratory test interference
Administration of mesna may result in laboratory test interference, specifically urine tests for ketones, urine tests for ascorbic acid, and enzymatic creatinine phosphokinase (CPK) activity tests. A false positive test for urinary ketones may arise in patients treated with mesna when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies). It may also cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid. Additionally, mesna may interfere with enzymatic CPK activity tests that use a thiol compound for CPK reactivation, resulting in a falsely low (false negative) CPK level.
Contraception requirements, pregnancy testing
Mesna is used in combination with ifosfamide and other cytotoxic agents; therefore, it is advised that women of reproductive potential undergo pregnancy testing before receiving treatment. In addition, instruct drug recipients of contraception requirements that include use of an effective contraception for 6 months after the last mesna/ifosfamide dose for women and 3 months after the last dose for men.[49539] [57332]
ADVERSE REACTIONS
Severe
seizures / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
Moderate
constipation / Delayed / 17.6-23.5
leukopenia / Delayed / 17.6-21.0
anemia / Delayed / 16.8-17.6
thrombocytopenia / Delayed / 13.4-17.6
chest pain (unspecified) / Early / 8.4-9.2
hypokalemia / Delayed / 8.4-9.2
dyspnea / Early / 9.2-9.2
edema / Delayed / 6.7-7.6
hematuria / Delayed / 5.9-6.7
peripheral edema / Delayed / 6.7-6.7
sinus tachycardia / Rapid / 0.8-5.9
confusion / Early / 5.0-5.9
dehydration / Delayed / 2.5-5.9
hypotension / Rapid / 3.4-5.0
hypertension / Early / Incidence not known
dysuria / Early / Incidence not known
colic / Delayed / Incidence not known
hyperesthesia / Delayed / Incidence not known
photophobia / Early / Incidence not known
hemoptysis / Delayed / Incidence not known
conjunctivitis / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
hypoxia / Early / Incidence not known
skin ulcer / Delayed / Incidence not known
erythema / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
bullous rash / Early / Incidence not known
hepatitis / Delayed / Incidence not known
Mild
nausea / Early / 53.8-54.6
vomiting / Early / 29.4-37.8
fatigue / Early / 20.2-20.2
fever / Early / 15.1-20.2
anorexia / Delayed / 16.0-17.6
asthenia / Delayed / 12.6-17.6
abdominal pain / Early / 11.8-15.1
diarrhea / Early / 7.6-14.3
headache / Early / 7.6-10.9
alopecia / Delayed / 10.1-10.9
drowsiness / Early / 6.7-10.1
insomnia / Early / 5.0-9.2
injection site reaction / Rapid / 6.7-8.4
cough / Delayed / 4.2-8.4
dizziness / Early / 4.2-7.6
hyperhidrosis / Delayed / 1.7-7.6
back pain / Delayed / 5.0-6.7
anxiety / Delayed / 3.4-5.9
dyspepsia / Early / 3.4-5.0
flushing / Rapid / 0.8-5.0
pallor / Early / 3.4-5.0
flatulence / Early / Incidence not known
xerostomia / Early / Incidence not known
dysgeusia / Early / Incidence not known
malaise / Early / Incidence not known
paresthesias / Delayed / Incidence not known
myalgia / Early / Incidence not known
arthralgia / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
nasal congestion / Early / Incidence not known
rhinitis / Early / Incidence not known
influenza / Delayed / Incidence not known
chills / Rapid / Incidence not known
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
DRUG INTERACTIONS
There are no drug interactions associated with Mesna products.
PREGNANCY AND LACTATION
Pregnancy
No adequate and well-controlled studies have been performed in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. Two case reports have described the use of mesna, in combination with chemotherapeutic agents, during pregnancy. In the first report, a 21-year-old woman was treated with three courses of chemotherapy plus mesna (5 gm/m2 three times weekly) during the third trimester. The patient underwent a cesarean section at gestational week 36; no adverse effects were noted in the infant at delivery or during follow up at age 2 years.[49545] The second patient was a 20-year-old who began chemotherapy and mesna treatment at gestational week 23. Prior to treatment, the fetal weight was at the 20th percentile and fetal movement and amniotic fluid volume was normal; however, an ultrasound on week 4 of treatment revealed an absence of amniotic fluid, cessation of fetal growth, and an absence of fetal movement. Two weeks later (gestational week 29), the infant was born via an emergency cesarean section and died at age 7 days. An association with mesna was not able to be established.[49546] The manufacturer recommends use during pregnancy only if needed.[49539]
Mesna is used in combination with ifosfamide and other cytotoxic agents; therefore, it is advised that women of reproductive potential undergo pregnancy testing before receiving treatment. In addition, instruct drug recipients of contraception requirements that include use of an effective contraception for 6 months after the last mesna/ifosfamide dose for women and 3 months after the last dose for men.[49539] [57332]
MECHANISM OF ACTION
Mechanism of Action: Mesna forms thioether bonds with acrolein, 4-hydroxy-ifosfamide and chloracetaldehyde, which are the urotoxic metabolites of oxazaphosphorine agents. Within the kidney mesna reacts with acrolein. The acrolein-mesna thioether complex is inactive and eliminated in the urine without causing hemorrhagic cystitis. Mesna also blocks or stabilizes the breakdown of 4-hydroxy-ifosfamide in the bladder preventing the formation of more acrolein. Mesna will not prevent non-urologic toxicities.
PHARMACOKINETICS
Mesna is administered intravenously (IV) or orally. Mesna is metabolized to dimesna (2,2'-dithio-bis-ethane sulfonate) by oxidative, metal-catalyzed reactions. Dimesna does not distribute outside the intravascular space and is rapidly excreted by the kidney. There is virtually no hepatic metabolism of mesna. Mesna is filtered by the glomeruli, reabsorbed by the proximal tubule, and then secreted back in the tubule of the kidney. In the renal epithelium, dimesna is reduced to mesna by thiol transferase and glutathione reductase. Following IV administration mesna and dimesna have half-lives of 10.2 minutes and 66 minutes, respectively. The majority of the IV dose is eliminated within 4 hours. The half-life of mesna ranged from 1.2—8.3 hours after administration of IV plus oral doses. Approximately 5% of the mesna dose given as the IV and oral regimen is excreted during the 12—24 hour period as compared to negligible amounts in patients given the IV regimen.
Oral Route
The urinary bioavailability of oral mesna ranged from 45—79% of IV mesna. Food does not affect the urinary bioavailability of oral mesna. Protein binding of mesna is moderate (69—75%). When compared to IV mesna, the IV plus oral regimen increases systemic exposure (150%) and provides more sustained excretion of mesna in the urine over a 24-hour period.
Intravenous Route
When compared to IV mesna, the IV plus oral regimen increases systemic exposure (150%) and provides more sustained excretion of mesna in the urine over a 24-hour period.