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MESNA 100 MG/ML SOLUTION FOR INJECTION/INFUSION

Active substance(s): MESNA / MESNA / MESNA

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Mesna 100 mg/ml solution for injection/infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution for injection/ infusion contains 100 mg mesna.
Each 2 ml ampoule contains 200 mg mesna.
Each 4 ml ampoule contains 400 mg mesna.
Excipient(s) with known effect:
Each ml of solution contains 0.610 mmol/ml of sodium.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Solution for injection/infusion.
The solution is a clear colourless, sterile solution for injection, free from visible
particle
Osmolarity: 1000 mOsmol/L to 1500 mOsmol/L.
pH between 6.50 and 7.30

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
For the prevention of urothelial toxicity including haemorrhagic cystitis,
microhaematuria and macrohaematuria in patients treated with oxazaphosphorine
(e.g. ifosfamide, cyclophosphamide and trofosfamid), in doses considered to be
urotoxic, especially in patients considered to be at risk due to prior pelvic irradiation,
cystitis from prior oxazaphosphorine treatment or anamnestic urinary tract diseases.

4.2

Posology and method of administration
Sufficient mesna must be given to adequately protect the patient from the urotoxic
effects of the oxazaphosphorine.
The duration of mesna treatment should equal that of the oxazaphosphorine treatment
plus the time taken for the urinary concentration of oxazaphosphorine metabolites to
fall to nontoxic levels. This usually occurs within 8-12 hours after the end of
oxazaphosphorine treatment but may vary depending on the scheduling of
oxazaphosphorine. Urinary output should be maintained at 100 ml/hr (as required for
oxazaphosphorine treatment) and the urine monitored for haematuria and proteinuria
throughout the treatment period.
Where oxazaphosphorine is used as an iv bolus: Mesna is given by intravenous
injection over15-30 minutes at 20% of the simultaneously administered
oxazaphosphorine on a weight for weight basis (w/w). The same dose of
mesna is repeated after 4 and 8 hours. The total dose of mesna is 60% (w/w) of the
oxazaphosphorine dose. This is repeated on each occasion that the cytotoxic agents
are used.
Example dosages schedule:
Oxazaphosphorine
Mesna 100 mg/ml solution
for injection/infusion

0 HRS
40 mg/kg
8 mg/kg

4 HRS
8 mg/kg

8 HRS
8 mg/kg

If necessary the dose of mesna can be increased to 40% of the oxazaphosphorine dose
given four times at three hourly intervals (0, 3, 6 and 9 hours). (Total dose = 160%
(w/w) of the oxazaphosphorine dose). This larger dose is recommended in children, in
patients whose urothelium may be damaged from previous treatment with
oxazaphosphorine or pelvic irradiation, or in patients who are not adequately
protected by the standard dose of mesna.
Example dosage schedule:
Oxazaphosphorine
Mesna 100 mg/ml solution
for injection/infusion

0
HRS
40
mg/k
16
mg/k
g

3 HRS
16
mg/kg

6
HR
16
mg
/kg

9 HRS
16
mg/kg

Where oxazaphosphorine is used as a 24-hour infusion: Mesna can be used as a
concurrent infusion. An initial 20% (w/w) of the total oxazaphosphorine dose is given
as an i.v. bolus, then an infusion of 100% (w/w) of the oxazaphosphorine over 24
hours, followed by a further 12-hour infusion of up to 50% (w/w) of the
oxazaphosphorine dose. Total mesna dose = <170% of the oxazaphosphorine dose.

Example
schedule:

dosage

0 hrs
Oxazaphosphorine -

0-24 hrs
5 g/m²
infusion

24 hrs
-

28 hrs
-

32 hrs
-

36 hrs
-

Mesna
1 g/m2
100
mg/ml i.v.
solution
for injection

5 g/m2
infusion

3 g/m2 infusion

1 g/m2
i.v.

1 g/m2
i.v.

1 g/m2
i.v.

Where oxazaphosphorine is used as a long-term infusion:
An initial 20% (w/w) of the first 24 hoursoxazaphosphorine dose is given
as an i.v. bolus as the oxazaphosphorine infusion starts. Then each 24 hour
infusion of oxazaphosphorine is given with a concurrent 24 hour infusion
(100% w/w) of mesna. A 12 hour infusion of mesna (60% (w/w) of the
final 24 hour dose ofoxazaphosphorine) should be commenced as
theoxazaphosphorine mesna infusion finishes.
Example dosage schedule:
Day 1
Day 2
Day 3
Day4
0 hrs
0-24
0-24 hrs
0-24 hrs 24 4 hrs 8 hrs 12
hrs
hrs
hrs
Oxazaphosphorine 2 g/m² 2 g/m²
2 g/m² infusion infusion
infusion
Mesna
0.4g/m² 2 g/m² 2 g/m²
2 g/m² 1.2
g/m²
100
mg/ml
infusion infusion
iv
infusion infusion
solution
for
injection

0.4 0.4 0.4
g/m² g/m² g/m²
iv
iv
iv
The final 12-hour infusion of mesna, after long-term or 24 hour infusion of
oxazaphosphorine, may be replaced by boluses at 28, 32 and 36 hours, each
of 20% (w/w) of theoxazaphosphorine dose, or by oral mesna.
Mesna can be mixed in the same infusion bag as the oxazaphosphorine.
Paediatric population:
Children generally urinate more frequently than adults and therefore it
may be necessary to shorten the interval between doses and/or to
increase the number of individual doses. The dose of mesna can be
increased to 40% of the oxazaphosphorine dose given four times at three
hourly intervals (0, 3, 6 and 9 hours) (Total dose = 160% (w/w) of the
oxazaphosphorine dose).
Older people:
No specific information is available. Clinical trials have included patients
over 65 and no adverse reactions specific to this age group have been
reported.

4.3

Contraindications
Known hypersensitivity to the active substance, any thiol-containing compounds or to
any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use
In patients with auto immune disease an increased incidence of pseudo allergic
reactions compared to cancer patients has been reported. Reactions of the skin and
mucous membranes (pruritus, rash, urticaria, exanthema, enanthema), transient
increases in transaminases as well as non-specific general symptoms such as fever,
fatigue, nausea and vomiting were observed. In rare cases, circulatory reactions such
as hypotension and tachycardia occurred. Thus the prevention of urotoxicity with
mesna should only be undertaken after medical guidance and careful consideration of
risks and benefits.
Treatment with mesna may cause false positive reactions in dipstick tests for ketone
bodies, (e.g. Rothera's test, NMultistix reagent strip) and false positive or false
negative reactions in the dipstick tests for erythrocytes in the urine. The colour
reaction for ketones is reddish purple rather than purple, it is less stable, and fades
immediately on the addition of glacial acetic acid. To exactly determine the presence
of erythrocytes in the urine, urinary microscopy is recommended.
Mesna Injection contains 0.610 mmol/ml sodium (1.22 mmol sodium per 2 ampoule
and 2.44 mmol per 4ml ampoule).
This should be taken into consideration by patients on a controlled sodium diet”.

4.5

Interaction with other medicinal products and other forms of interaction
The systemic effects of oxazaphosphorines are not affected by mesna. In clinical
trials it was shown that overdoses of mesna did not diminish the acute toxicity,
subacute toxicity, leucocytic activity, and immunosuppressive efficacy of
oxazaphosphorines. Animal studies with oxazaphosphorine and cyclophosphamide
on a variety of tumours have also demonstrated that mesna does not interfere with
their antineoplastic activity.
Mesna also does not affect the antineoplastic efficacy of other cytostatics (e.g.
adriamycin, BCNU, methotrexate, vincristine), nor the therapeutic effect of other
drugs such as digitalis glucosides.

4.6

Fertility, pregnancy and lactation
Pregnancy

Pregnancy and lactation are contraindications for cytostatic treatment, and
consequently Mesna 100 mg/ml solution for injection/infusion is not likely to be used
under these circumstances.
Should an individual patient be undergoing oxazaphosphorine therapy during
pregnancy then Mesna 100 mg/ml solution for injection/infusion should be
administered to this patient.
Breast-feeding
Mothers should not breast-feed whilst being treated with these drugs.
Fertility
Animal studies have shown no evidence of embryotoxic or teratogenic effects of
mesna.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.
Known adverse reactions of mesna like nausea, vomiting or circulatory reactions can
impair the ability to drive and use machines also at recommended doses.

4.8

Undesirable effects
Hypersensitization reactions have been reported more frequently by immunecompromised patients than by those with cancer. Cases of venous irritation at
site of injection have been reported. During treatment it is difficult to clearly
assess adverse reactions to Uromitexan from those related to other drugs
administered at the same time.
Clinical studies on subjects of age beyond 65 have not shown age-specific
adverse reactions.
Frequency categories are as follows:
Very common: (≥1/10),
Common (≥1/100 to <1/10),
Uncommon (≥1/1,000 to <1/100),
Rare (≥1/10,000 to <1/1,000),
Very rare (<1/10,000).
Very rare (<
Uncommon Rare
System Organ Common
(≥1/10000 and 1/10000
Class (SOC)
(≥1/100
and (≥1/1000
including
<1/10)
and
< < 1/1000)
isolated
1/100)
reporting)
Infections and
Pharyngitis
infestations
Immune system Hypersensitivity
Anaphylactoid

disorders

reactions,
hyperergic
reactions

reactions,
allergic
reactions

Metabolism and
nutrition
disorders
Psychiatric
disorders
Nervous system
disorders
Eye disorders
Cardiac
disorders
Vascular
disorders

Anorexia

Irritability,
depression
Headache
Conjunctivitis
Tachycardia
Hypotension,
hypertension,
flushing,
cardiovascular
reactions

Respiratory,
thoracic
and
mediastinal
disorders
Gastrointestinal
disorders

Tachypnea,
cough

Nausea,
vomiting

Skin
and
subcutaneous
tissue disorders

Itching, rashes,
skin reactions,
enanthem

Musculoskeletal
and connective
tissue disorders
General
disorders and
administration
site conditions

Investigations

Injury,
poisoning

and

Fever

Diarrhea

Urticaria

Ocal tissue
swelling

Back pain

Local
edema,
vein
irritation at
injection
site, chills

Fatigue,
asthenia,
mucocutaneous
reactions,

Increase in the
values
of
various liver
function tests

Flatulence,
constipation,
colic,
abdominal
pain
StevenJohnson
syndrome,
Lyell
syndrome
Arthralgia,
myalgia, joint
pain, articular
pain
Influenza-like
symptoms

Decrease in
platelet
count, pulse
rate>100/min,
ST elevation
Toxic
reactions

procedural
complications
Reporting of suspected adverse reactions
Reporting suspected adverse reactions is an important way to gather more
information to continuously monitor the benefit/risk balance of the medicinal
product. You can also report any side effects directly
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
Healthy volunteers given single bolus doses of 70 mg/kg mesna showed no evidence
of major toxic side-effects.
A specific antidote to mesna is not known.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: detoxifying agent for antineoplastic treatment
ATC Code: VO3AF01.
Mesna is an antidote preventing urotoxic side effevcts associated with cancer
chemotheraphy based on oxazaphosphorine. Pharmacological studies have shown
that mesna has no intrinsic pharmacodynamics activity. The mechanism of action is
based on the stabilisation of the urotoxic hydroxyl metabolities of the
oxazaphosphorines and on the formation of atoxic addition products with acrolein. By
this, a regional detoxification of kidneys and the urinary tract is achieved.

5.2

Pharmacokinetic properties
Absorption
Mesna, a free thiol, is easily and rapidly transformed by auto-oxidation into its only
metabolite mesna-disulphide (dimesna).
Distribution
Dimesna remains in the intravascular compartment and is quickly transported to the
kidneys. In the epithelium of renal tubuli, dimesna is again reduced to the free thiol
compound, which is then able to react chemically in the urine with toxic
oxazaphosphorine metabolites.

Elimination
Elimination (being almost exclusively renal) starts immediately after administration.
Excretion is as the free thiol (mesna) in the first 4 hours after a single dose, and
almost exclusively as the disulphide (dimesna) thereafter. Renal elimination is almost
complete after approximately 8 hours.
Approximately 30% of an intravenous dose is bioavailable as free thiol (mesna) in the
urine.

5.3

Preclinical safety data
Animal studies have shown no evidence of mutagenic, carcinogenic or teratogenic
effects of mesna.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Disodium edetate
Sodium hydroxide
Water for Injections

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6

6.3

Shelf life
30 months.
After opening: The product must be used immediately.
For single use. Any unused solution must be discarded.
Mesna Injection is chemically compatible with Compound Sodium Lactate injection,
0.9 % saline and with 5.0 % dextrose containing diluents for 24 hours.
For microbiological point of view, product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of

the user and would normally not be longer than 24 hours at 250C, unless
reconstitution/dilution has taken place in controlled and validated aspectic conditions.

6.4

Special precautions for storage
Do not store above 30°C. Keep the container in the outer carton to protect from light.

6.5

Nature and contents of container
The solution is a clear colourless, sterile solution for injection, free from visible
particle
2 ml and 4 ml type I clear glass ampoules in packs of 5 or 10 or 25.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
Mesna Injection is chemically compatible with Compound Sodium Lactate injection,
0.9 % saline and with 5.0 % dextrose containing diluents for 24 hours.

7

MARKETING AUTHORISATION HOLDER
Claris Lifesciences UK Limited
Crewe Hall, Crewe, Cheshire CW16UL

8

MARKETING AUTHORISATION NUMBER(S)
PL 20568/0044

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/09/2014

10

DATE OF REVISION OF THE TEXT
25/09/2014

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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