MESNA- mesna injection solution
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1. Patient Information
2. What Is Mesna Injection?
3. Mesna Injection May Cause Serious Side Effects, Including:
4. The Most Common Side Effects Of Mesna Injection When Given With Ifosfamide Include:
5. How Should I Store Mesna Injection?
6. Active Ingredient:
7. Mesna Injection:

Patient Information ⮝

Mesna injection can cause serious allergic reactions and skin reactions.These serious reactions can happen the first time you are treated with mesna injection or after several months of treatment with mesna injection. Stop treatment with mesna injection and go to the nearest hospital emergency room right away if you develop any of the symptoms listed below:

fever swelling of your face, lips, mouth, or tongue trouble breathing or wheezing itching burning skin rash or hives skin redness or swelling

skin blisters or peeling feel lightheaded or faint feel like your heart is racing nausea vomiting joint or muscle aches mouth sores

for more information about side effects.

What Is Mesna Injection? ⮝

Mesna injection is a prescription medicine used to reduce the risk of inflammation and bleeding of the bladder (hemorrhagic cystitis) in people who receive ifosfamide (a medicine used to treat cancer).

Mesna injection is not for use to reduce the risk of blood in the urine (hematuria) due to other medical conditions.

Do not take mesna tablets or receive mesna injection by intravenous (IV) infusion ifyou are allergic to mesna or any of the ingredients in mesna injection.
Mesna is given on the same day that you receive ifosfamide.
Mesna can be given by an intravenous (IV) infusion into a vein or tablets taken by mouth.
You will receive mesna in one of two ways:
o Mesna intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4 and 8 hours after you receive ifosfamide,OR
o Mesna intravenous (IV) infusion into a vein at the time you receive ifosfamide and mesna tablets taken by mouth 2 and 6 hours after you receive ifosfamide.
Take mesna tablets at the exact times and the exact dose your healthcare provider tells you to take it.
During treatment with mesna intravenous (IV) infusion or mesna tablets, you should drink 4 to 8 cups of liquid (1 to 2 liters) each day.
Tell your healthcare provider if you:
o vomit within 2 hours of taking mesna tablets by mouth
o miss a dose of mesna tablets
o have pink or red colored urine

Mesna Injection May Cause Serious Side Effects, Including: ⮝

Mesna injection that is given by intravenous (IV) infusion contains the preservative benzyl alcohol.Benzyl alcohol has been shown to cause serious side effects and death in premature newborns and low-birth weight babies. Avoid use of mesna injection in premature newborns and low birth weight infants. Mesna tablets do not contain benzyl alcohol.

The Most Common Side Effects Of Mesna Injection When Given With Ifosfamide Include: ⮝

nausea vomiting constipation decreased white blood cell count tiredness fever decreased appetite decreased platelet count

decreased red blood cell count diarrhea weakness stomach (abdomen) pain headache hair loss sleepiness

These are not all the possible side effects of mesna injection.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How Should I Store Mesna Injection? ⮝

Store at 20 to 25 C (68 to 77 F).

Keep mesna injection and all medicines out of the reach of children.

General information about the safe and effective use of mesna injection.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use mesna injection for a condition for which it was not prescribed. Do not give mesna injection to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about mesna injection that is written for health professionals.

Active Ingredient: ⮝

mesna

Mesna Injection: ⮝

edetate disodium, sodium hydroxide, and benzyl alcohol as a preservative.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Gland Pharma Limited
D.P.Pally, Dundigal Post
Hyderabad -500043, India

Revised: January 2019

1. Highlights Of Prescribing Information
2. Recent Major Changes
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Use In Specific Populations
10. 1 Indications & Usage
11. 2 Dosage & Administration
12. 3 Dosage Forms & Strengths
13. 4 Contraindications
14. 5 Warnings And Precautions
15. 6 Adverse Reactions
16. 7 Drug Interactions
17. 8 Use In Specific Populations
18. 10 Overdosage
19. 11 Description
20. 12 Clinical Pharmacology
21. 13 Nonclinical Toxicology
22. 14 Clinical Studies
23. 16 How Supplied/storage And Handling
24. Package Label.principal Display Panel

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use MESNA INJECTION safely and effectively. See full prescribing information for MESNA INJECTION .



MESNA injection, for intravenous use

Initial U.S. Approval: 1988

Recent Major Changes ⮝

Warnings and Precautions, Benzyl Alcohol Toxicity (5.3) 12/2018

Indications And Usage ⮝

Mesna Injection is a cytoprotective agent indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1) (1)

Limitation of Use:
Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. (1) (1)

Dosage And Administration ⮝

Mesna injection may be given on a fractionated dosing schedule of three bolus intravenous injections or a single bolus injection followed by two oral administrations of mesna tablets as outlined below. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted, the ratio of mesna to ifosfamide should be maintained. (2)

Intravenous Dosing Schedule: (2)

	0 Hours	4 Hours	8 Hours
Ifosfamide	1.2 g/m2	-	-
Mesna Injection	240 mg/m2	240 mg/m2	240 mg/m2

Intravenous and Oral Dosing Schedule: (2)

	0 Hours	2 Hours	6 Hours
Ifosfamide	1.2 g/m2	-	-
Mesna Injection	240 mg/m2	-	-
Mesna Tablets	-	480 mg/m2	480 mg/m2

Maintain sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. (2.3) (2)

Dosage Forms And Strengths ⮝

Mesna Injection: 1 g (100 mg/mL) Multi-Dose vials. (3) (3)

Contraindications ⮝

Known hypersensitivity to mesna or to any of the excipients in mesna injection, including benzyl alcohol. (4) (4)

Warnings And Precautions ⮝

Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue mesna injection and
provide supportive care. (5.1)
Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also
been seen. Monitor patients. If a reaction occurs, discontinue mesna injection and provide supportive care. (5.2)
Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including mesna injection. Avoid use
in premature neonates and low-birth weight infants. (5.3)
Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4) (5)

Adverse Reactions ⮝

The most common adverse reactions (> 10%) when mesna injection is given with ifosfamide are nausea, vomiting, constipation, leukopenia, fatigue, fever, anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia, abdominal pain, headache, alopecia, and somnolence. (6.1) (6)

To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)

Use In Specific Populations ⮝

Pregnancy: Mesna injection in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to a fetus. (8.1)
Lactation: Do not breastfeed. (8.2)
Females and Males of Reproductive Potential: Advise patients to use effective contraception. Verify pregnancy status prior to initiation of mesna injection in combination with ifosfamide. (8.3)
Pediatric use: In premature neonates and low-birth weight infants, avoid use of benzyl alcohol containing solutions. (8.4)
Geriatric use: Dose selection should be cautious. (8.5) (8)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 3/2019

1 Indications & Usage ⮝

Mesna Injection is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

Limitation of Use:
Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

2 Dosage & Administration ⮝

2.1 Intravenous Dosing

Mesna injection may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.

Table 1. Recommended Intravenous Dosing Schedule

	0 Hours	4 Hours	8 Hours
Ifosfamide	1.2 g/m2	-	-
Mesna Injection1	240 mg/m2	240 mg/m2	240 mg/m2

1 The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.

2.2 Intravenous and Oral Dosing

Mesna injection may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of mesna tablets as outlined below.

Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesna tablets are given orally 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. The recommended dosing schedule is outlined in Table 2.

Table 2. Recommended Intravenous and Oral Dosing Schedule

	0 Hours	2 Hours	6 Hours
Ifosfamide	1.2 g/m2	-	-
Mesna Injection1	240 mg/m2	-	-
Mesna Tablets	-	480 mg/m2	480 mg/m2

1 The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.

The efficacy and safety of this ratio of intravenous and oral mesna has not been established as being effective for daily doses of ifosfamide higher than 2 g/m2.

Patients who vomit within two hours of taking oral mesna should repeat the dose or receive intravenous mesna injection.

2.3 Monitoring for Hematuria

Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

2.4 Preparation for Intravenous Administration and Stability

Preparation
Determine the volume of mesna injection for the intended dose.

Dilute the volume of mesna injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:

5% Dextrose Injection, USP
5% Dextrose and 0.2% Sodium Chloride Injection, USP
5% Dextrose and 0.33% Sodium Chloride Injection, USP
5% Dextrose and 0.45% Sodium Chloride Injection, USP
0.9% Sodium Chloride Injection, USP
Lactated Ringer s Injection, USP

Stability
The mesna injection multidose vials may be stored and used for up to 8 days after initial puncture.

Store diluted solutions at 25 C (77 F). Use diluted solutions within 24 hours.

Do not mix mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.

The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna injection 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 injection 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.

3 Dosage Forms & Strengths ⮝

Mesna Injection: 10 mL Multi-Dose Vial, 1 g/10 mL (100 mg/mL)

4 Contraindications ⮝

Mesna injection is contraindicated in patients known to be hypersensitive to mesna or to any of the excipients [see Warnings and Precautions (5.1)].

5 Warnings And Precautions ⮝

5.1 Hypersensitivity Reactions

Mesna may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue mesna and provide supportive care.

5.2 Dermatologic Toxicity

Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. Mesna may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue mesna and provide supportive care.

5.3 Benzyl Alcohol Toxicity

Serious adverse reactions including fatal reactions and the gasping syndrome occurred in premature neonates and low-birth weight infants who received benzyl alcohol dosages of 99 to 234 mg/kg/day (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Symptoms associated with gasping syndrome and other potential adverse reactions 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 may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Mesna injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of mesna injection in premature neonates and low-birth weight infants. Mesna tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4)].

5.4 Laboratory Test Interferences

False-Positive Urine Tests for Ketone Bodies
A false positive test for urinary ketones may arise in patients treated with mesna injection 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).

False-Negative Tests for Enzymatic CPK Activity
Mesna may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactivation. This may result in a falsely low CPK level.

False-Positive Tests for Ascorbic Acid
Mesna may cause false-positive reactions in Tillman s reagent-based urine screening tests for ascorbic acid.

5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds

Mesna is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to mesna and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to mesna.

6 Adverse Reactions ⮝

The following are discussed in more detail in other sections of the labeling.

Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Dermatological Toxicity [see Warnings and Precautions (5.2)]
Benzyl Alcohol Toxicity [see Warnings and Precautions (5.3)]
Laboratory Test Interferences [see Warnings and Precautions (5.4)]
Use in Patients with a History of Adverse Reactions to Thiol Compounds [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Mesna injection adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600 to 2400 mg of mesna tablets were administered to a total of 82 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of mesna injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received mesna tablets alone or intravenous mesna followed by repeated doses of mesna tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous mesna injection.

Additional adverse reactions in healthy volunteers receiving mesna injection alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, mesna was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.

Because mesna is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to mesna from those caused by the concomitantly administered cytotoxic agents.

Adverse reactions reasonably associated with mesna administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.

T able 3: Adv er se R e a ctions in 5% of P ati ents R eceiving Mesna in c ombin ation with I fo s famid e - cont aining Re gim ens
Mesna R e gim en	Int r av enous - Int ra v enous - Int r av enous1	Int r av enous -O ral -O ral1
N e xpos ed	119 (100.0 %)	119 (100 %)
I n cid en ce of AEs	101 (84.9 %)	106 (89.1 %)
N aus ea	65 (54.6)	64 (53.8)
Vomiting	35 (29.4)	45 (37.8)
Constip ation	28 (23.5)	21 (17.6)
L euko p enia	25 (21.0)	21 (17.6)
Fat i gue	24 (20.2)	24 (20.2)
Fev er	24 (20.2)	18 (15.1)
Ano re xia	21 (17.6)	19 (16.0)
Th rombo c yto p enia	21 (17.6)	16 (13.4)
An emia	20 (16.8)	21 (17.6)
G ranulo c ytop enia	16 (13.4)	15 (12.6)
Asth enia	15 (12.6)	21 (17.6)
Abdomin al P ain	14 (11.8)	18 (15.1)
Alop ecia	12 (10.1)	13 (10.9)
D ysp n ea	11 (9.2)	11 (9.2)
Ch est P ain	10 (8.4)	11 (9.2)
H ypo k al emia	10 (8.4)	11 (9.2)
Di arrh ea	9 (7.6)	17 (14.3)
Di zzin ess	9 (7.6)	5 (4.2)
H ead a che	9 (7.6)	13 (10.9)
P ain	9 (7.6)	10 (8.4)
Sw eating In c r eas ed	9 (7.6)	2 (1.7)
B ack P ain	8 (6.7)	6 (5.0)
H em atu ria	8 (6.7)	7 (5.9)
Inj e ction Site R eaction	8 (6.7)	10 (8.4)
Ed ema	8 (6.7)	9 (7.6)
Ed ema P eriph e r al	8 (6.7)	8 (6.7)
Somnol en ce	8 (6.7)	12 (10.1)
An xi e ty	7 (5.9)	4 (3.4)
Con fusion	7 (5.9)	6 (5.0)
Fa ce Ed ema	6 (5.0)	5 (4.2)
Insomnia	6 (5.0)	11 (9.2)
Cou ghi ng	5 (4.2)	10 (8.4)
D ys p epsia	4 (3.4)	6 (5.0)
H ypot ension	4 (3.4)	6 (5.0)
P allor	4 (3.4)	6 (5.0)
D e h yd ration	3 (2.5)	7 (5.9)
Pn eumonia	2 (1.7)	8 (6.7)
T ac h y c ardia	1 (0.8)	7 (5.9)
Flushing	1 (0.8)	6 (5.0)

1Intravenous dosing of ifosfamide and mesna followed by either intravenous or oral doses of mesna according to the applicable dosage schedule [see Dosage and Administration (2)].

6.2 Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience of patients receiving mesna in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to mesna from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency cannot be made.

Cardiovascular: Hypertension
Gastrointestinal: Dysgeusia
Hepatobiliary: Hepatitis
Nervous System: Convulsion
Respiratory: Hemoptysis

7 Drug Interactions ⮝

No clinical drug interaction studies have been conducted with mesna injection.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary
Mesna injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely
[see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data
Animal Data
Mesna injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm including embryo-fetal lethality. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

In embryo-fetal development studies, oral administration of mesna to pregnant rats (500, 1000, 1500, and 2000 mg/kg) and rabbits (500 and 1000 mg/kg) during the period of organogenesis revealed no adverse developmental outcomes at doses approximately 10 times the maximum recommended total daily human equivalent dose based on body surface area.

8.2 Lactation

Risk Summary
Mesna injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide is excreted in breast milk. Refer to the ifosfamide prescribing information for more information on use during lactation. There are no data on the presence of mesna in human or animal milk, the effect on the breastfed child, or the effect on milk production.

Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for 1 week after the last dose of mesna or ifosfamide.

8.3 Females and Males of Reproductive Potential

Mesna injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.

Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiation of mesna injection in combination with ifosfamide.

Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with mesna injection in combination with ifosfamide and for 6 months after the last dose.

Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with mesna injection in combination with ifosfamide and for 3 months after the last dose.

8.4 Pediatric Use

Mesna injection contains the preservative benzyl alcohol which has been associated with serious adverse reactions and death when administered intravenously to premature neonates and low birth weight infants. Avoid use of mesna injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].

8.5 Geriatric Use

Clinical studies of mesna injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The ratio of ifosfamide to mesna should remain unchanged.

8.6 Use in Patients with Renal Impairment

No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of mesna injection.

8.7 Use in Patients with Hepatic Impairment

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of mesna injection.

10 Overdosage ⮝

There is no known antidote for mesna injection.

In a clinical trial, 11 patients received intravenous mesna injection 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving 80 mg mesna injection per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.

Postmarketing, administration of 4.5 g to 6.9 g of mesna resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

11 Description ⮝

Mesna injection is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:

HS CH2 CH2SO3 Na+

Mesna Injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multi-dose vials for intravenous administration. Mesna Injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection multi-dose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of between 7.5 and 8.5.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.

12.3 Pharmacokinetics

Absorption
Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.

Food does not affect the urinary availability of orally administered mesna.

Distribution
Mean apparent volume of distribution (Vd) for mesna is 0.652 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).

Metabolism
Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration.

Excretion
Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.

Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.

No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies ( 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.

14 Clinical Studies ⮝

14.1 Intravenous Mesna Injection

Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 days, produced hematuria in 31 to 100% of the patients. When mesna injection was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

Table 4: Percent of Mesna Injection Patients Developing Hematuria( 50 RBC/hpf or macrohematuria)

Study	Conventional Uroprophylaxis (number of patients)	Standard Mesna Intravenous Regimen (number of patients)
Uncontrolled Studies*
Study 1	16% (7/44)	-
Study 2	26% (11/43)	-
Study 3	18% (7/38)	0% (0/21)
Study 4	-	0% (0/32)
Controlled Studies
Study 5	31% (14/46)	6% (3/46)
Study 6	100% (7/7)	0% (0/8)
* Ifosfamide dose 1.2 g/m2 d x 5 Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to 5

14.2 Oral Mesna

Clinical studies comparing recommended intravenous and oral mesna dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of mesna in patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 5.

Table 5: Percent of Mesna Patients Developing Grade 3 or 4 Hematuria

	Mesna Dosing Regimen
Study	Standard Intravenous Regimen (number of patients)	Intravenous + Oral Regimen (number of patients)
Study 7	0% (0/30)	3.6% (1/28)
Study 8	3.7% (1/27)	4.3% (1/23)

16 How Supplied/storage And Handling ⮝

Mesna Injection is supplied as follows:

NDC	Mesna Injection (100 mg per mL)	Package Factor
68083-161-01	1 g/10 mL Multi-Dose Vial	1 vial per carton
68083-161-10	1 g/10 mL Multi-Dose Vial	10 vials per carton

Storage Conditions
Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]

If mesna is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.

Sterile, Nonpyrogenic.
The container closure is not made with natural rubber latex.

Package Label.principal Display Panel ⮝

Mesna Injection
1g/10 mL(100 mg/mL)
For Intravenous Use
Vial label

Mesna Injection
1g/10 mL(100 mg/mL)
For Intravenous Use
Mono Carton label-one multi dose vial

Mesna Injection
1 g/10 mL(100 mg/mL)
For Intravenous Use
Outer Carton label-ten multi dose vials

MESNA mesna injection solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68083-161 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MESNA (UNII: NR7O1405Q9) (2-MERCAPTOETHANESULFONIC ACID - UNII:VHD28S0H7F) MESNA 100 mg in 1 mL

Inactive Ingredients Ingredient Name Strength EDETATE DISODIUM (UNII: 7FLD91C86K) 0.25 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) BENZYL ALCOHOL (UNII: LKG8494WBH) 1.04 mg in 1 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68083-161-01 1 in 1 CARTON 12/20/2017 1 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 2 NDC:68083-161-10 10 in 1 CARTON 12/20/2017 2 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA206992 12/20/2017

Labeler - Gland Pharma Limited (918601238)

Establishment
Name	Address	ID/FEI	Business Operations
Gland Pharma Limited		918601238	ANALYSIS(68083-161) , API MANUFACTURE(68083-161) , MANUFACTURE(68083-161) , PACK(68083-161)

Revised: 3/2019 Document Id: 5da38cd8-1b4e-4c1c-9b86-30bf68991552 34391-3 Set id: a7af968c-05cf-4438-94ba-96a2baf9c367 Version: 8 Effective Time: 20190312 Gland Pharma Limited