PRODUCT MONOGRAPH

Pr
MESNA for Injection

100 mg / mL

Uroprotector

Fresenius Kabi Canada Ltd. Date of Revision:

165 Galaxy Blvd, Suite 100 December 21, 2017
Toronto, ON M9W 0C8

Submission Control No.: 198273

 Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION .............................................................3

SUMMARY PRODUCT INFORMATION .................................................................................. 3
INDICATIONS AND CLINICAL USE ........................................................................................ 3
CONTRAINDICATIONS ............................................................................................................. 3
WARNINGS AND PRECAUTIONS ............................................................................................ 3
ADVERSE REACTIONS.............................................................................................................. 7
DRUG INTERACTIONS ............................................................................................................ 13
DOSAGE AND ADMINISTRATION ........................................................................................ 14
OVERDOSAGE .......................................................................................................................... 15
ACTION AND CLINICAL PHARMACOLOGY ...................................................................... 15
STORAGE AND STABILITY .................................................................................................... 15
SPECIAL HANDLING INSTRUCTIONS ................................................................................. 16
DOSAGE FORMS, COMPOSITION AND PACKAGING ....................................................... 16

PART II : SCIENTIFIC INFORMATION ..................................................................................17

PHARMACEUTICAL INFORMATION.................................................................................... 17
DETAILED PHARMACOLOGY ............................................................................................... 17
TOXICOLOGY ........................................................................................................................... 18
REFERENCES ............................................................................................................................ 20

PART III: CONSUMER INFORMATION.................................................................................22

Mesna for Injection – Product Monograph Page 2 of 23

 Pr
MESNA for Injection

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Strength Clinically Relevant Nonmedicinal

Administration Ingredients
Intravenous Solution for infusion / Benzyl alcohol, Edetate Disodium,
100 mg / mL in 10 mL Water for Injection and Sodium
multiple-dose vials. Hydroxide.

INDICATIONS AND CLINICAL USE

Mesna for Injection is indicated for the reduction and prevention of urinary tract toxicity
(hemorrhagic cystitis) of oxazaphosphorines. (See ADVERSE REACTIONS sections of the
Procytox (cyclophosphamide) and Ifex (ifosfamide) Product Monographs.)

Geriatrics:
No specific information is available.

Pediatrics (<16 years of age):

Safety and effectiveness of Mesna for Injection in pediatric patients (<16 years of age) have not
been established.

CONTRAINDICATIONS

Mesna is contraindicated in individuals with a known hypersensitivity to mesna or other thiol

compounds, or to any of the excipients, including benzyl alcohol present in the multi-dose vials.
For a complete listing, see the Dosage Forms, Composition and Packaging section of the product
monograph.

WARNINGS AND PRECAUTIONS

The multi dose vials contain benzyl alcohol, which may be fatal in neonates and infants. (See
Special Populations, Pediatrics.)

Mesna for Injection – Product Monograph Page 3 of 23

General
The protective effect of mesna applies only to the urotoxic effects of oxazaphosphorines.
Additional prophylactic or accompanying measures recommended during treatment with
oxazaphosphorines are thus not affected and should not be discontinued.

Mesna is incompatible in vitro with cisplatin, carboplatin and nitrogen mustard.

The combination of an oxazaphosphorine cytostatic agent with mesna and cisplatin, carboplatin,
or nitrogen mustard in the same infusion solution is not stable and is not to be used.

Mixing mesna and epirubicin leads to inactivation of epirubicin and should be avoided.

Benzyl alcohol contained in the mesna injection multi-dose vials can reduce the stability of
cyclophosphamide and ifosfamide.

Patients undergoing treatment with mesna may experience syncope, lightheadedness,

lethargy/drowsiness, dizziness, and blurred vision which could affect the ability to drive or use
machines (see Drug-Lifestyle Interactions).

Carcinogenesis and Mutagenesis

See Toxicology – Mutagenicity and Carcinogenicity sections.

Genitourinary
Mesna does not prevent hemorrhagic cystitis in all patients. To identify the presence of
erythrocytes in the urine, microscopic evidence of red blood cells should be obtained. Patients
should be monitored accordingly.

Sufficient urinary output should be maintained, as required for oxazaphosphorine treatment.

Sensitivity/Resistance
Hypersensitivity reactions to mesna have been reported following administration of mesna as an
uroprotectant. These include:

• Skin reactions characterized by symptoms such as localized or generalized urticaria or other

forms of exanthema, pruritus, burning, angioedema and/or flushing.

• In addition, cases of severe bullous and ulcerative skin and mucosal reactions were reported.
Some reactions were considered to be consistent with Stevens-Johnson Syndrome, toxic
epidermal necrolysis, or erythema exudativum multiforme.

Other reactions appeared to be consistent with a diagnosis of fixed drug eruption.

Photodistribution of a rash has also been reported.

Mesna for Injection – Product Monograph Page 4 of 23

In some cases, skin reactions were accompanied by one or more other symptoms, such as
• fever,
• cardiovascular symptoms (hypotension, in some cases reported as fluid refractory,
tachycardia, ECG signs consistent with perimyocarditis, hypertension; see Post-Market
Adverse Drug Reactions)
• signs consistent with acute renal impairment,
• pulmonary symptoms (hypoxia, respiratory distress, bronchospasm, tachypnea, cough,
bloody sputum; see Post-Market Adverse Drug Reactions)
• prolonged prothrombin time (PT) and partial thromboplastin time (PTT), laboratory signs of
disseminated intravascular coagulopathy (DIC)
• hematological abnormalities (leukopenia, eosinophilia, lymphopenia, thrombocytopenia,
pancytopenia; see Post-Market Adverse Drug Reactions)
• increased liver enzymes,
• nausea, vomiting,
• pain in the extremities, arthralgia, myalgia, malaise,
• stomatitis, and
• conjunctivitis.

Some reactions have presented as anaphylaxis.

Fever accompanied by, e.g., hypotension but no skin manifestations has also been reported.

Allergic reactions to mesna ranging from mild hypersensitivity to systemic anaphylactic

reactions have been reported with the use of mesna in regimens to treat both severe systemic
autoimmune disorders and malignancy. Patients with autoimmune disorders who were treated
with cyclophosphamide and mesna appeared to have a higher incidence of allergic reactions.

In most cases, reactions occurred during or after a first treatment occasion or after several weeks
of mesna exposure. In other cases, the initial reaction was observed only after several months of
exposure.

In many cases, symptoms appeared on the day of exposure, with a tendency to shorter intervals
following subsequent exposures.

In some patients, the occurrence and/or severity of reaction appeared to vary with the dose
administered.

Recurrence of reactions, in some cases with increasing severity, has been reported with re-
exposure. However, in some cases, a reaction did not recur with re-exposure.

Some patients with a history of a reaction have shown positive delayed-type skin test results.
However, a negative delayed reaction does not exclude hypersensitivity to mesna. Positive
immediate-type skin test reactions have occurred in patients regardless of previous mesna
exposure or history of hypersensitivity reactions, and may be related to the concentration of the
mesna solution used for testing.
Mesna for Injection – Product Monograph Page 5 of 23
Prescribers should
- be aware of the potential for such reactions and that reactions may worsen with re-exposure
and may in some cases be life-threatening,
- be aware that hypersensitivity reactions to mesna were interpreted to resemble the clinical
picture of sepsis and, in patients with autoimmune disorders, resemble an exacerbation of the
underlying disease.

Thiol Compounds:
Mesna is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Thiol
compounds show some similarities in their adverse reaction profile, including a potential to elicit
severe skin reactions. Examples of drugs that are thiol compounds include amifostine,
penicillamine, and captopril.

It is not clear whether patients who experienced an adverse reaction to such a drug are at
increased risk for any reactions, or similar reactions, to another thiol compound. However, when
considering subsequent use of another thiol compound in such patients, the possibility of an
increased risk should be taken into account (see CONTRAINDICATIONS).

Multi-dose vials:
Parenteral benzyl alcohol administration has been associated with systemic hypersensitivity
reactions (see CONTRAINDICATIONS).

Special Populations

Pregnant Women:
There are no adequate and well-controlled studies using mesna in pregnant women. Animal
studies have not revealed any embryotoxic or mutagenic effects (see TOXICOLOGY).
However, in view of the fact that oxazaphosphorines are not recommended during pregnancy,
this would eliminate the need for mesna. Mesna should be given to pregnant woman only if the
benefits clearly outweigh any possible risks.

Nursing Women:
It is unknown whether mesna or dimesna are excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for adverse reactions in nursing infants, a
decision should be made whether to discontinue breast-feeding or discontinue the drug, taking
into account the importance of the drug to the mother.

Pediatrics (<16 years of age):

The safety and efficacy of mesna in pediatric patients have not been established.

Mesna in multi-dose vials contains 10.4 mg benzyl alcohol per milliliter. The benzyl alcohol
used in the multi-dose vials could be life-threatening or fatal in neonates or infants. Because of
the risk of severe toxicities (including gasping syndrome), the multi-dose vials should not be
used in neonates or infants and should be used with caution in older children.

Mesna for Injection – Product Monograph Page 6 of 23

Geriatrics (≥65 years of age)
No specific information on the use of mesna in the elderly is available. Clinical studies of mesna
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. However, the ratio of ifosfamide to mesna should
remain unchanged.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most frequently occurring adverse reactions (> 10%) associated with use of mesna, per subject
are: headache (36.05%), infusion site reactions (25.32%), abdominal pain/colic (22.09%),
lightheadedness (16.28%), lethargy/drowsiness (12.79%), pyrexia (12.79%), rash (12.79%),
diarrhea (11.63%), nausea (11.63%), flushing (10.47%), and influenza-like illness (10.47%).

The most frequently occurring adverse reactions (> 1%) associated with use of mesna, per
administration are: infusion site reactions (15.35%), headache (5.24%), abdominal pain/colic
(4.39%), nausea (1.72%), diarrhea (1.53%), rash (1.72%), flushing (1.33%), lightheadedness
(1.33%), lethargy/drowsiness (1.33%), and pyrexia (1.14%).

The most severe adverse reactions associated with use of mesna are: toxic epidermal necrolysis,
Stevens-Johnson Syndrome, anaphylaxis, and drug rash with eosinophilia and systemic symptoms
(DRESS).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction
rates observed in the clinical trials may not reflect the rates observed in practice and should
not be compared to the rates in the clinical trials of another drug. Adverse drug reaction
information from clinical trials is useful for identifying drug-related adverse events and for
approximating rates.

The following mesna adverse reaction data are available from pharmacokinetic studies in healthy
volunteers who received no concomitant medications.

The adverse reactions from clinical trials were identified from 6 mesna pharmacokinetic studies in
healthy volunteers, who were administered mesna without concurrent chemotherapy. In these
studies, a total of 86 subjects received oral doses of mesna. Of these 86 subjects, 79 subjects also
received intravenously administered mesna. A total of 1049 mesna doses were administered.

Four studies administered single oral doses (tablets or solution) of 600 mg to 2400 mg; with three
of these studies also administering single intravenous doses of 600 mg to 1200 mg. Two studies
were multiple-dose studies that administered mesna three times daily for 5 days. In these studies,
total daily doses of mesna tablets ranged from 1200 mg to 2400 mg, and total daily doses of

Mesna for Injection – Product Monograph Page 7 of 23

intravenous mesna infusions ranged from 334 mg to 1800 mg.

Clinical Trial Adverse Drug Reactions to Mesna

Per subject Per administration

N = 86 N = 1049
System Organ Class Adverse Reaction Frequency Frequency Ratio Frequency Frequency Ratio
(SOC) (Percentage) (Percentage)
BLOOD AND Lymphadenopathy Common 3/86 Uncommon 3/1049
LYMPHATIC SYSTEM (3.49%) (0.29%)
DISORDERS
CARDIAC DISORDERS Palpitations Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
EYE DISORDERS Conjunctivitis Common 5/86 Uncommon 5/1049
(5.81%) (0.48%)
Photophobia Common 3/86 Uncommon 5/1049
(3.49%) (0.48%)
Vision blurred Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
GASTROINTESTINAL Abdominal pain/colic Very common 19/86 Common 46/1049
DISORDERS (22.09%) (4.39%)
Nausea Very common 10/86 Common 18/1049
(11.63%) (1.72%)
Diarrhea Very common 10/86 Common 16/1049
(11.63%) (1.53%)
Flatulence Common 8/86 Uncommon 9/1049
(9.30%) (0.86%)
Mucosal irritation1 Common 7/86 Uncommon 7/1049
(8.14%) (0.67%)
Vomiting Common 3/86 Uncommon 6/1049
(3.49%) (0.57%)
Burning pain Common 3/86 Uncommon 4/1049
(substernal / (3.49%) (0.38%)
epigastric)
Constipation Common 2/86 Uncommon 2/1049
(2.33%) (0.19%)
Gingival bleeding Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
GENERAL DISORDERS Infusion site Very common 20/79 Very common 68/443
AND reactions (25.32%) (15.35%)
ADMINISTRATIVE 15/79
SITE CONDITIONS - Infusion site Very common (18.99%) Common 35/443
pruritus 11/79 (7.90%)
(13.92%)
- Infusion site rash Very common 5/79 Common 20/443
(6.33%) (4.51%)
- Infusion site pain Common 3/79 Common 5/443
(3.80%) (1.13%)
- Infusion site Common 2/79 Uncommon 3/443
erythema (2.53%) (0.68%)
1/79
- Infusion site Common (1.27%) Uncommon 3/443

Mesna for Injection – Product Monograph Page 8 of 23

 Per subject Per administration
N = 86 N = 1049
System Organ Class Adverse Reaction Frequency Frequency Ratio Frequency Frequency Ratio
(SOC) (Percentage) (Percentage)
urticaria (0.68%)

- Infusion site Common Uncommon 1/443

swelling (0.23%)
Pyrexia Very common 11/86 Common 12/1049
(12.79%) (1.14%)
Influenza-like Very common 9/86 Unknown Unknown
illness2 (10.47%)
Rigors Common 4/86 Uncommon 5/1049
(4.65%) (0.48%)
Fatigue Common 3/86 Uncommon 3/1049
(3.49%) (0.29%)
Chest pain Common 2/86 Uncommon 2/1049
(2.33%) (0.19%)
Malaise Common 2/86 Uncommon 3/1049
(2.33%) (0.29%)
HEPATOBILIARY Transaminases Common 1/86 Uncommon 1/1049
DISORDERS increased (1.16%) (0.10%)
METABOLISM AND Decreased appetite Common 7/86 Uncommon 7/1049
NUTRITION (8.14%) (0.67%)
DISORDERS Feeling of Common 1/86 Uncommon 1/1049
dehydration (1.16%) (0.10%)
MUSCULOSKELETAL Back pain Common 7/86 Uncommon 9/1049
AND CONNECTIVE (8.14%) (0.86%)
TISSUE DISORDERS Arthralgia Common 6/86 Uncommon 7/1049
(6.98%) (0.67%)
Myalgia Common 6/86 Uncommon 7/1049
(6.98%) (0.67%)
Pain in extremity Common 3/86 Uncommon 3/1049
(3.49%) (0.29%)
Pain in jaw Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
NERVOUS SYSTEM Headache Very common 31/86 Common 55/1049
DISORDERS (36.05%) (5.24%)
Lightheadedness Very common 14/86 Common 14/1049
(16.28%) (1.33%)
Lethargy/ Very common 11/86 Common 14/1049
Drowsiness (12.79%) (1.33%)
Dizziness Common 5/86 Uncommon 5/1049
(5.81%) (0.48%)
Paresthesia Common 4/86 Uncommon 4/1049
(4.65%) (0.38%)
Hyperesthesia Common 2/86 Uncommon 2/1049
(2.33%) (0.19%)
Syncope Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
Hypoesthesia Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)

Mesna for Injection – Product Monograph Page 9 of 23

 Per subject Per administration
N = 86 N = 1049
System Organ Class Adverse Reaction Frequency Frequency Ratio Frequency Frequency Ratio
(SOC) (Percentage) (Percentage)
Disturbance in Common 1/86 Uncommon 1/1049
attention (1.16%) (0.10%)
PSYCHIATRIC Insomnia Common 1/86 Uncommon 1/1049
DISORDERS (1.16%) (0.10%)
Nightmare Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
RENAL AND Dysuria Common 2/86 Uncommon 2/1049
URINARY DISORDERS (2.33%) (0.19%)
RESPIRATORY, Nasal congestion Common 5/86 Uncommon 5/1049
THORACIC, AND (5.81%) (0.48%)
MEDIASTINAL Cough Common 3/86 Uncommon 3/1049
DISORDERS (3.49%) (0.28%)
Pleuritic pain Common 2/86 Uncommon 3/1049
(2.33%) (0.29%)
Dry mouth Common 2/86 Uncommon 2/1049
(2.33%) (0.19%)
Dyspnea Common 2/86 Uncommon 2/1049
(2.33%) (0.19%)
Bronchospasm Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
Laryngeal discomfort Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
Epistaxis Common 1/86 Uncommon 1/1049
(1.16%) (0.10%)
SKIN AND Rash3 Very common 11/86 Common 18/1049
SUBCUTANEOUS (12.79%) (1.72%)
TISSUE DISORDERS Pruritus Common 4/86 Uncommon 6/1049
(4.65%) (0.57%)
Hyperhidrosis Common 2/86 Uncommon 3/1049
(2.33%) (0.29%)
VASCULAR Flushing Very common 9/86 Common 14/1049
DISORDERS (10.47%) (1.33%)
Legend: Adverse Drug Reaction frequency is based upon the following scale: Very Common (≥1/10); Common
(≥1/100 - <1/10), Uncommon (≥1/1,000 - <1/100), Rare (≥1/10 000 - <1/1 000), Very Rare (<1/10 000)
1
Oral, rectal
2
The per administration frequency cannot be determined from the data reviewed.
3
Including nonpruritic, pruritic, erythema/erythematous, eczematous, papular, and/or macular rashes.

Time to onset
In these studies, some subjects experienced their events on first exposure to mesna and others
after the second or third exposure. In general, the complete spectrum of symptoms experienced
by a subject developed over a period of several hours.

Experience with re-exposure

Some subjects experienced no further reactions after their initial event while others
experienced an exacerbation of events upon repeated dosing.

Mesna for Injection – Product Monograph Page 10 of 23

Infusion site reactions
In some subjects experiencing local cutaneous infusion site reactions, subsequent exposure to
mesna resulted in a cutaneous event in other areas.

Cutaneous/mucosal reactions
Cutaneous and mucosal reactions were reported to occur after both intravenous and oral mesna.
These reactions included rashes, pruritus, flushing, mucosal irritation, pleuritic pain, and
conjunctivitis. Approximately one-quarter of subjects with any event experienced
cutaneous/mucosal reactions in conjunction with other adverse symptoms, which included,
dyspnea, fever, headache, gastrointestinal symptoms, drowsiness, malaise, myalgia, and
influenza-like symptoms.

Gastrointestinal reactions
Gastrointestinal reactions reported in healthy subjects included nausea, vomiting, diarrhea,
abdominal pain/colic, epigastric pain/burning, constipation, and flatulence and were reported to
occur after intravenous and oral mesna administration.

Abnormal Hematologic and Clinical Chemistry Findings

Hematologic

Test Effect Clinical Comment

Lymphocyte Decreased In pharmacokinetics studies in healthy volunteers, administration
counts of single doses of mesna was commonly associated with a rapid
(within 24 hours) and in some cases marked decrease in
lymphocyte count, which was generally reversible within 1 week
of administration. Data from studies with repeated dosing over
several days are insufficient to characterize the time course of
lymphocyte count changes under such conditions.

These phenomena should be considered when interpreting

laboratory results.

Clinical Chemistry

Test Effect Clinical Comment

Serum Increased In pharmacokinetics studies in healthy volunteers, administration
phosphorus of mesna on single or multiple days was in some cases associated
levels with moderate transient increases in serum phosphorus
concentration.

These phenomena should be considered when interpreting

laboratory results.

Mesna for Injection – Product Monograph Page 11 of 23

Post-Market Adverse Drug Reactions
Because mesna is used in combination with oxazaphosphorines or oxazaphosphorine-
containing combination chemotherapy, it is often difficult to distinguish adverse reactions that
may be due to mesna from those caused by concomitantly administered cytotoxic agents.

The following adverse reactions have been identified from postmarketing reports of patients
receiving mesna in combination with oxazaphosphorine cytostatics and other medications.

Many of the adverse reactions listed in the following SOCs occurred as part of a syndrome
suggestive of hypersensitivity reactions. (See WARNINGS AND PRECAUTIONS,
Sensitivity/Resistance)

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Pancytopenia, Leukopenia,

Lymphopenia, Thrombocytopenia, Eosinophilia

CARDIAC DISORDERS: Electrocardiogram abnormal (consistent with perimyocarditis),

Tachycardia

EYE DISORDERS: Periorbital edema

GASTROINTESTINAL DISORDERS: Stomatitis, Bad taste

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Face edema,

Edema peripheral, Asthenia, Infusion site reactions (thrombophlebitis, irritation*)

HEPATOBILIARY DISORDERS: Hepatitis, Gamma-glutamyl transferase increased, Blood

alkaline phosphatase increased

IMMUNE SYSTEM DISORDERS: Anaphylaxis, Hypersensitivity

INJURY, POISONING AND PROCEDURAL COMPLICATIONS: Occupational sensitization

to other mesna formulations used for inhalation (manifested as eczema, papulo-vesicular rash,
erythema, pruritus)

INVESTIGATIONS: Laboratory signs of disseminated intravascular coagulation, Prothrombin

time prolonged, Activated partial thromboplastin time prolonged

NERVOUS SYSTEM DISORDERS: Convulsion

RENAL AND URINARY DISORDERS: Acute renal failure

RESPIRATORY, THORACIC, MEDIASTINAL DISORDERS: Respiratory distress, Hypoxia,

Oxygen saturation decreased, Tachypnea, Hemoptysis

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Toxic epidermal necrolysis, Stevens-

Johnson Syndrome, Erythema multiforme, Drug rash with eosinophilia and systemic symptoms,

Mesna for Injection – Product Monograph Page 12 of 23

Ulcerations and/or bullae/blistering (mucocutaneous, mucosal, oral, vulvovaginal, anorectal),
Angioedema, Fixed drug eruption, Rash (vesicular, exfoliative, maculo-papular, morbilliform),
Photodistributed rash, Urticaria, Burning sensation, Erythema

VASCULAR DISORDERS: Hypotension (in some cases fluid refractory), Hypertension

*Venous irritation may be attributed to the physical properties of mesna – (i.e., pH 6, and
hypertonic solution). No venous complications were observed when the solution was given
diluted with Sterile Water for Injection USP (one part mesna solution to three parts water).

DRUG INTERACTIONS

Drug-Drug Interactions
No clinical drug interaction studies have been conducted with mesna.

Drug-Food Interactions
Interactions with food have not been established.

Drug-Herb Interactions
Interactions with herbal products have not been established.

Drug-Lifestyle Interactions
Patients undergoing treatment with mesna may experience syncope, lightheadedness,
lethargy/drowsiness, and blurred vision, which could affect the ability to drive or use machines.
Therefore patients should refrain from driving or operating machinery until they know that
mesna does not affect their ability to drive or use machines.

Drug-Laboratory Test Interactions

Mesna treatment may cause false positive reactions in nitroprusside sodium- based urine tests
(including dipstick tests) for ketone bodies. The colour reaction for ketones observed following
exposure to mesna is reddish purple rather than purple, which is less stable and fades
immediately by adding glacial acetic acid.

Mesna treatment may cause false positive reactions in Tillman’s reagent-based urine screening
tests for ascorbic acid.

In pharmacokinetics studies in healthy volunteers, serum creatine phosphokinase (CPK) values

were lower in samples taken 24 hours after mesna dosing than in pre-dosing samples. While
available data are insufficient to determine the cause of this phenomenon, it might be considered
to represent a significant interference with thiol (e.g., N-acetylcysteine) dependent enzymatic
CPK tests.

Mesna for Injection – Product Monograph Page 13 of 23

DOSAGE AND ADMINISTRATION

Dosing Considerations

Mesna for Injection dosing is dependent on the dose of concomitant oxazaphosphorine drug
that a patient receives.

Mesna for Injection dosing schedule should be repeated each day the oxazaphosphorine drug
is received.

If the oxazaphosphorine drug dose is adjusted, the mesna dose should also be modified to
maintain the mesna-to-oxazaphosphorine drug ratio.

Recommended Dose and Dosage Adjustment

Intravenous Injection
Mesna for Injection should be administered by intravenous bolus injection, usually at 20% of the
respective oxazaphosphorine dose, at times 0 (= administration of the cytostatic agent), 4 and 8
hours. In the case of Ifex (ifosfamide), the usual dose of Mesna for Injection is 10 - 12 mg/kg
intravenous at 0, 4 and 8 hours after the Ifex dose. The total daily dose of Mesna for Injection is
60% of the Ifex dose. (See DOSAGE AND ADMINISTRATION sections of Procytox and Ifex
Product Monographs).

In the treatment of children, and particularly when administering very high doses, such as required
when conditioning patients for bone-marrow transplantations, the Mesna for Injection doses should
be given at 0, 1, 3, 6, 9 and 12 hours or dosage increased to 30% of the respective
oxazaphosphorine dose.

Oral administration of mesna, e.g., in patients with poor veins, is also feasible. Mesna is then
given either at doses of 20% of the oxazaphosphorine dose at time 0 hours by the parenteral route,
followed by oral doses of 40% of the oxazaphosphorine dose after 4 and 8 hours, taken in juice or
cola, or in 3 oral doses of 40% of the oxazaphosphorine dose at times 0, 4 and 8 hours.

Mesna for Injection is available in 100 mg / mL for IV use only. Not for other routes of
administration.

Administration

For intravenous infusion the drug can be diluted by adding the Mesna for Injection solution to
any of the following fluids:
• 5% Dextrose Injection, USP
• 0.9 % Sodium Chloride Injection, USP

For example: One mL of Mesna for Injection multi-dose vial 100 mg / mL may be added to 4 mL
of any of the solutions listed above to create a final concentration of 20 mg / mL.

Mesna for Injection – Product Monograph Page 14 of 23

OVERDOSAGE

Reports of inadvertent overdose and observations from a high-dose tolerability study in healthy
volunteers showed that, in adults, single doses in the range of approximately 4 g to 7 g of mesna
can cause symptoms such as nausea, vomiting, abdominal pain/colic, diarrhea, headache, fatigue,
limb and joint pains, rash, flushing, hypotension, bradycardia, tachycardia, paresthesia, fever, and
bronchospasm.

A markedly increased rate of nausea, vomiting and diarrhea has also been found in
oxazaphosphorine-treated patients receiving ≥ 80 mg mesna per kg per day intravenously
compared with patients receiving lower doses or hydration treatment only.

A specific antidote for mesna is not known. Overdosage should be managed with supportive
measures to sustain the patient through any period of toxicity. Mesna has been administered at
doses from 70 to 100 mg/kg without any toxic effect on hematopoiesis, hepatic and renal function
or the central nervous system.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action
Mesna is rapidly and easily converted by auto-oxidation to its only metabolite disodium 2,2'-
dithio-bis ethane sulfonate (mesna disulfide, dimesna), forming a disulphide link. Following
intravenous injection, only a small portion of the administered dose is detected in the blood as a
reactive thiol compound (mesna). Mesna disulphide remains in the intravascular space and is
rapidly forwarded to the kidney. In the renal tubular epithelium, a considerable proportion of
mesna disulphide is again reduced to a free thiol compound, presumably by mediation of
glutathione reductase. It is then capable of chemically reacting with acrolein or other urotoxic
oxazaphosphorine metabolites in the urine, thereby developing its detoxifying activity.

The first and most important step towards detoxification is the addition of mesna to the double
bond of acrolein, resulting in the formation of a stable thio ether which could be detected in the
urine by chromatography. In the second step, mesna reduces the speed of degradation of the 4-
hydroxy metabolite in the urine. A relatively stable, non-urotoxic condensation product from 4-
hydroxy cyclophosphamide or 4-hydroxy ifosfamide and mesna is formed. By such stabilization,
mesna inhibits the degradation of 4-hydroxy cyclophosphamide or 4-hydroxy ifosfamide and
hence the formation of acrolein. This intermediate deactivated product could also be detected by
chromatographic urinalysis.

STORAGE AND STABILITY

Store the vials between 15 °C and 30 °C. Vials must be discarded 28 days after initial puncture.

Mesna for Injection – Product Monograph Page 15 of 23

Stability of Solution

Storage: Solutions for infusion should be used within 24 hours, if stored below 25 °C, or 48 hours
if stored refrigerated (2 °C to 8 °C), from the time of preparation.

SPECIAL HANDLING INSTRUCTIONS

As with all parenteral drug products, intravenous admixtures should be inspected visually for
clarity, particulate matter, precipitate, discolouration and leakage prior to administration. The
unused portion should be discarded.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition:

Each mL of Mesna for Injection contains: 100 mg Mesna, 10.4 mg Benzyl Alcohol, Edetate
Disodium, Water for Injection, and Sodium Hydroxide for pH adjustment.

AVAILABILITY OF DOSAGE FORMS

Mesna for Injection is available as 100 mg / mL in 10 mL multiple-dose vials as follows:

C730310 10 mL vials in packages of 10 vials.

Mesna for Injection – Product Monograph Page 16 of 23

 PART II : SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Mesna

Chemical Name: Sodium 2-mercaptoethanesulfonate

Structural Formula: Molecular Formula: C 2 H 5 O 3 S 2 Na

Molecular Weight: 164.18 g/mol

Description: Mesna is a white to slightly cream-coloured crystalline or microcrystalline powder

with a characteristic odour. It is freely soluble in water, sparingly soluble in
methanol and practically insoluble in the usual organic solvents.

DETAILED PHARMACOLOGY

Mesna and dimesna are absorbed from the intestine and during absorption, dimesna undergoes
reduction. In the plasma, Mesna is rapidly oxidized by a metal-dependent reaction. Both Mesna
and dimesna pass unchanged through hepatic vasculature, are not taken up in the liver cells and are
not excreted in bile. In the kidney, dimesna is subject to glomerular filtration and subsequently
reabsorbed, whereupon reduction to the pharmacologically active thiol form occurs in the renal
tubular epithelium, and the thiol is then re-excreted into the tubular lumen. Reduction of dimesna
occurs in intestinal and renal epithelial cells by a mechanism involving the enzymes thiol
transferase and glutathione reductase.

Animals
In guinea pigs, the elimination half-life was found to be 1.48 hours following intravenous
administration of 200 mg/kg, and 3.9 hours following oral administration of 200 mg/kg. Similar
rates were determined in rats and dogs.

Blood levels were quantified after oral administration in all 3 species. Serum half-life was found to
be 3.5 hours in the guinea pig, 2.6 hours in the rat, and 2 hours in the dog.

Distribution of Mesna in the tissues was determined in guinea pigs and rats. Following oral
administration of 200 mg/kg, it was observed that Mesna does not permeate all body tissues.

In the rat, placental permeability was investigated after oral administration; in the fetus, the
placental barrier permits fetal blood levels of only 17.6% of the maternal blood level.

In all 3 animal species, irrespective of the route of administration, dimesna is eliminated in the
urine within the first 8 hours at a rate of 38-45% of the administered Mesna dose.

Mesna for Injection – Product Monograph Page 17 of 23

Humans
After intravenous administration of 60 mg/kg Mesna, a half-life of 1.08 hours was established.
Renal elimination starts immediately after administration and is largely completed within 8 hours
after administration. In the first 4 hours, excretion occurs primarily as a free SH-compound,
thereafter occurring almost exclusively in the form of disulphide.

After oral administration of 60 mg/kg, Mesna appears in the blood almost entirely as its disulfide
metabolite with a time-lag of 0.36 hours. Maximum serum levels occur after 1.17 hours. The
elimination half-life is 1.15 hours. The rate of excretion is not different from that seen after
intravenous administration.

Over 60% of the administered oral or intravenous dose (60 mg/kg) is recovered in the urine as
mesna or dimesna.

TOXICOLOGY

Acute Toxicity

Mesna was found to be almost completely non-toxic. The LD 50 values are as follows:

Species Route of Administration LD 50 (mg/kg)

Mice intravenous or intraperitoneal 1800-2050

oral > 6100
Rats intravenous or intraperitoneal 1225-2080
oral > 4330

In dogs, death was observed after intravenous doses of 400 mg/kg and above, but not after oral
doses of up to 2000 mg/kg.

Subacute Toxicity

The low toxicity of Mesna was confirmed in tests for subacute toxicity. In a 6-week study, rats
tolerated daily intravenous doses of up to 316 mg/kg without toxic symptoms. The earliest signs
of toxicity were seen at doses of 1000 mg/kg. These included severe body weight loss, leucopenia
and anemia.

The kidneys showed distended tubules engorged with urine which had a high protein content and
hyaline deposits in the glomerular capillaries.

Dogs tolerated 12 intravenous doses of 200 mg/kg, with vomiting and diarrhea appearing only in
the first days of treatment. In a 6-week study, intravenous doses of up to 316 mg/kg were
tolerated. The only toxic symptoms were vomiting and diarrhea. In the 100 mg/kg group, these

Mesna for Injection – Product Monograph Page 18 of 23

symptoms subsided after about 2 weeks of administration, whereas in the 316 mg/kg group they
occasionally persisted to the end of the experiment. Macroscopic and histologic examinations did
not reveal any drug-related findings.

Chronic Toxicity

In a 6-month chronic toxicity test in rats (oral administration of a 40% solution), daily doses up to
2000 mg/kg were tolerated without drug-related mortality or morbidity.

In a 7-month study in dogs, mesna was administered orally at doses of 31.6, 100 and
316 mg/kg/day. The high dose was subsequently increased to 420 mg/kg/day and further increased
to 560 mg/kg/day. One death occurred at 560 mg/kg/day. Other clinical signs included a dose-
related incidence of semi-solid stools and sporadic emesis, and a decrease in motor activity in all
dogs. There was a slight increase in alkaline phosphatase, a slight decrease in creatinine, and a
slight alteration in the electrolytes in high- and medium-dose dogs.

Mutagenicity

No evidence of mutagenicity of Mesna was found in the Ames tests on strains of Salmonella
typhimurium.

Reproduction and Teratology

There was no evidence of interference with fetal development following oral administration to rats
(doses of up to 2000 mg/kg from day 8 to day 15 of gestation) and to rabbits (doses of up to 2000
mg/kg from day 7 to day 17 of gestation).

Carcinogenicity

Mesna had no carcinogenic effects in rats.

Mesna for Injection – Product Monograph Page 19 of 23

REFERENCES

Clinical
1. Klein HO, Wickramanayake PD, Coerper CL and Christian E: Experimental and clinical
studies on the significance of the urophophylactic sodium 2-mercaptoethane sulfonate
(Uromitexan) in cytostatic therapy with oxazaphosphorines. In: Burkert H, Nagel GA, eds.
Contributions to Oncology. S. Karger, 1980:25-39.

2. Brock N, Pohl J, Stekar J and Scheef W. Studies on the urotoxicity of oxazaphosphorine

cytostatics and its prevention-III. Profile of action of sodium 2-mercaptoethane sulfonate
(mesna). Eur J Cancer Clin Oncol 1982;18:1377-87.

3. Pohl J. The toxicology, pharmacokinetics and interactions of Uromitexan. In: Burkert H,

Nagel GA, eds. Contributions to Oncology. S. Karger, 1980:12-20.

4. Scheulen ME, Niederle N, and Seeber S. Results of a clinical phase II study on the use of
ifosfamide in refractory malignant diseases. Comparison of the uroprotective effect of
Uromitexan and forced diuresis with alkalization of the urine. In: Burkert H, Nagel GA,
eds. Contributions to Oncology. S. Karger, 1980:40-6.

5. Scheulen ME, Niederle N, Bremer K, Schutte J and Seeber S. Efficacy of ifosfamide in

refractory malignant diseases and uroprotection by mesna: results of a clinical phase II-
study with 151 patients. Cancer Treat Rev 1983;10:93-101.

6. Araujo CE and Tessler J. Treatment of ifosfamide-induced urothelial toxicity by oral

administration of sodium 2-mercaptoethane sulphonate (mesna) to patients with inoperable
lung cancer. Eur J Cancer Clin Oncol 1983;19(2):195-201.

7. Falkson G, Van Dyk JJ, Stapelberg R and Falkson HC. Mesna as a protector against kidney
and bladder toxicity with high-dose ifosfamide treatment. Cancer Chemother Pharmacol
1982; 9:81-4.

8. Kaplan S, Malinverni R, Varini M and Cavalli F. Prevention of genito-urinary toxicity of

ifosfamide with Na 2-mercaptoethane sulfonate (mesna). In: Burkert H, Nagel GA, eds.
Contributions to Oncology. S. Karger, 1980:52-6.

9. Scherer HP. Clinical experience with Uromitexan in combination with Holoxan

monotherapy. In: Burkert H, Nagel GA, eds. Contributions to Oncology. S. Karger,
1980:52-62.

10. Klein HO, Wickramanayake P, Coerper CL, Christian E and Pohl J. High-dose ifosfamide
and mesna as continuous infusion over five days - a phase I/II trial. Cancer Treat Rev
1983;10: 167-173.

Mesna for Injection – Product Monograph Page 20 of 23

11. Scheef W, Klein HO, Brock N, Burkert H, Hoefer-Janker H, Gunther U, Mitrenga D,
Schnitker J and Voigtmann R. Controlled clinical studies with an antidote against the
urotoxicity of oxazaphosphorines: Preliminary results. Cancer Treat Rep 1979;63(3):501-5.

12. Bryant BM, Jarman M, Fort HT and Smith IE. Prevention of isophosphamide-induced
urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesna) in patients with
advanced carcinoma. The Lancet 1980; Sept:657-9.

13. Czownicki Z and Utracka-Hutka B. Clinical studies with Uromitexan - An antidote

against urotoxicity of Holoxan. Preliminary results. Nowotwory 1980; 30 : 377-383.

14. Jaeger N, Hartlapp J and Weissbach L. Ifosfamide polychemotherapy with diuresis and
alkalization or Uromitexan in the treatment of metastasizing testicular tumours. In: Burkert
H, Nagel GA, eds. Contributions to Oncology. S. Karger, 1980:88-90.

15. Ritter S. Preliminary results of urinary tract prophylaxis with Uromitexan. In: Burkert H,
Nagel GA, eds. Contributions to Oncology. S. Karger, 1980:60-1.

16. Scheef W and Soemer G. The treatment of solid malignant tumours with Holoxan and
Uromitexan. In: Burkert H, Nagel GA, eds. Contributions to Oncology. S. Karger, 1980:21-
4.

17. Marti C, Steiner R and Viollier AF. High-dose ifosfamide therapy: Systemic application of
Uromitexan to reduce urotoxicity. In: Burkert H, Nagel GA, eds. Contributions to
Oncology. S. Karger, 1980:57-9.

Preclinical
1. Ormstad K, Orrenius S, Lastbom T, Uehara N, Pohl J, Stekar J and Brock N.
Pharmacokinetics and metabolism of sodium 2-mercaptoethane sulfonate. Cancer Res
1983;43:333-338.

2. Brock N, Pohl J and Stekar J. Studies on the urotoxicity of oxazaphosphorine cytostatics

and its prevention. 2. Comparative study on the uroprotective efficacy of thiols and other
sulfur compounds. Eur J Cancer Clin Oncol 1981;17:1155-63.

3. Brock N, Stekar J, Pohl J, Niemeyer U and Scheffler G. Acrolein, the causative of urotoxic
side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Drug Res
1979;29:659-661.

4. Habs MR and Schmahl D. Prevention of urinary bladder tumors in cyclophosphamide-

treated rats by additional medication with uroprotectors sodium 2-mercaptoethane sulfonate
(mesna) and disodium 2,21-dithio-bis-ethane sulfonate (dimesna). Cancer 1983;51:606-9.
General
1. Product Monograph, Uromitexan, Baxter Corporation, August 6, 2013, Control No:
164028.

Mesna for Injection – Product Monograph Page 21 of 23

 IMPORTANT: PLEASE READ

• You are nursing an infant.

PART III: CONSUMER INFORMATION • You plan to drive or operate machinery.
• You have had previous reactions to mesna.

Pr
MESNA FOR INJECTION Mesna for Injection does not prevent hemorrhagic cystitis in
all patients. Contact your doctor or nurse immediately if you
This leaflet is part III of a three-part "Product notice that your urine is pink, red, or bloody.
Monograph" published when Mesna for Injection was
approved for sale in Canada and is designed specifically INTERACTIONS WITH THIS MEDICATION
for Consumers. This leaflet is a summary and will not tell
you everything about Mesna for Injection. Contact your
doctor or pharmacist if you have any questions about the There are no known drug-drug interactions with Mesna for
drug. Injection

ABOUT THIS MEDICATION

PROPER USE OF THIS MEDICATION

What the medication is used for:

Mesna for Injection is used for the reduction and prevention Usual dose:
of bleeding in the bladder (hemorrhagic cystitis) caused by Your doctor will determine what dose of Mesna for Injection
anti- cancer drugs such as cyclophosphamide and ifosfamide. is right for you and how often you should receive it.
Mesna can be taken intravenously or orally.
What it does:
Mesna for Injection helps to protect the lining of the bladder Mesna for Injection is available in 100 mg / mL for IV use
against damage from anti-cancer drugs. The body breaks only. Not for other routes of administration.
down anti-cancer drugs to form products that can harm the
bladder. Mesna for Injection works by making these Overdose:
breakdown products less harmful. A specific antidote for mesna is not known.

When it should not be used: In case of drug overdose, contact a health care
Mesna for Injection should not be used if: practitioner, hospital emergency department or regional
You have a known allergy to mesna, any thiol-containing Poison Control Centre immediately, even if there are no
compound or to any of the nonmedicinal ingredients in symptoms.
particular benzyl alcohol.
Missed Dose:
What the medicinal ingredient is: If you miss your scheduled treatment, contact your doctor or
Mesna nurse as soon as possible to schedule your next treatment.

What the nonmedicinal ingredients are: SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Edetate Disodium, Sodium Hydroxide, Water for Injection,
and Benzyl Alcohol as a preservative.
Because Mesna for Injection is used in combination with other
What dosage forms it comes in: chemotherapy drugs, it is often difficult to distinguish side
Mesna for Injection is available as 100 mg / mL in 10 mL effects that may be caused by mesna from those caused by
multiple-dose vials. other drugs.

If you notice any changes in the way you feel during or after
WARNING AND PRECAUTIONS
the treatment, tell your doctor or another member of your
medical team immediately.
BEFORE you use Mesna for Injection talk to your doctor or
pharmacist if: Like all medicines, mesna can cause side effects although not
• You have any allergies to this drug or other drugs similar everybody gets them.
to mesna, such as amifostine, penicillamine and captopril, The following side effects may happen with this medicine:
or to any of its ingredients. Very common (affects more than 1 in 10 people):
• You are scheduled to undergo urine screening tests. • Headache
• You are pregnant or planning to become pregnant. • Reactions at the application site

Mesna for Injection – Product Monograph Page 22 of 23

 IMPORTANT: PLEASE READ

• Abdominal pain (colic)

• Feeling abnormally sleepy during the day Reporting Side Effects
• Lightheadedness
• Fever You can report any suspected side effects associated with
• Skin rash the use of health products to Health Canada by:
• Diarrhea
• Nausea • Visiting the Web page on Adverse Reaction
• Flushing Reporting (https://www.canada.ca/en/health-
• Flu-like symptoms (e.g., sore throat, fever, canada/services/drugs-health-products/medeffect-
chills, shivering, cough, body aches) canada/adverse-reaction-reporting.html) for
information on how to report online, by mail or
If any of these effects persist or worsen, tell your doctor or by fax; or
nurse promptly. • Calling toll-free at 1-866-234-2345.

Mesna for Injection can cause serious side effects. These NOTE: Contact your health professional if you
include severe skin rash and skin reactions that can cause need information about how to manage your side
death. These problems may occur any time during treatment, effects. The Canada Vigilance Program does not
but more commonly occur during or after a first treatment or provide medical advice.
after several weeks of treatment with Mesna. Sometimes the
first skin reaction occurs only after several months of HOW TO STORE IT
treatment.

Store the vials between 15 °C and 30 oC. Keep out of reach

SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM and sight of children.

Symptom / effect Talk with your doctor or MORE INFORMATION

pharmacist
Only if severe In all cases This document plus the full product monograph, prepared for
health professionals can be obtained by contacting the
Skin rash caused by a reaction sponsor, Fresenius Kabi Canada Ltd., at 1-877-821-7724.
to drugs that includes the
following symptoms: This leaflet was prepared by
- Blisters Fresenius Kabi Canada Ltd.

- Mouth sores 165 Galaxy Blvd, Suite 100
Toronto, ON M9W 0C8
- Swelling of your face
- Cough
Last Revised: December 21, 2017
- Fever

Red or inflamed eyes like

“pink eye” (conjunctivitis) 
Liver problems 

Chest pain, rapid heart beat 

Breathing difficulties 

Feeling unwell or like you have 

the flu.
Tiredness 
Severe dizziness 

This is not a complete list of side effects. For any unexpected

effects while taking Mesna for Injection, contact your doctor
or pharmacist.

Mesna for Injection – Product Monograph Page 23 of 23