Mesna Injection 1g/10ml Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Mesna Injection 200mg/2ml Taj Pharma
Mesna Injection 1g/10ml Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Each vial contains:
Mesna 200mg
Water for Injection 2ml

b) Each vial contains:
Mesna 1g
Water for Injection 10ml

3. PHARMACEUTICAL FORM

Liquid Injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For the prevention of urothelial toxicity including haemorrhagic cystitis, microhaematuria and macrohaematuria in patients treated with ifosfamide and cyclophosphamide, in doses considered to be urotoxic.

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 non-toxic 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

Where ifosfamide or cyclophosphamide is used as an iv bolus: Mesna is given by intravenous injection over 15-30 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 dosage schedule:

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:

Where cyclophosphamide is used orally: The same dose regimen of mesna applies as though cyclophosphamide were used as an i.v. bolus.

Where ifosfamide is used as a 24-hour infusion: Mesna can be used as a concurrent infusion. An initial 20% (w/w) of the total ifosfamide dose is given as an i.v. bolus, then an infusion of 100% (w/w) of the ifosfamide over 24 hours, followed by a further 12-hour infusion of 60% (w/w) of the ifosfamide dose. Total mesna dose = 180% of the ifosfamide dose.

Example dosage schedule:

Where ifosfamide is used as a long-term infusion:

An initial 20% (w/w) of the first 24 hours ifosfamide dose is given as an i.v. bolus as the ifosfamide infusion starts. Then each 24 hour infusion of ifosfamide 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 of ifosfamide) should be commenced as the ifosfamide-mesna infusion finishes.

Example dosage schedule:

The final 12-hour infusion of mesna, after long-term or 24 hour infusion of ifosfamide, may be replaced by boluses at 28, 32 and 36 hours, each of 20% (w/w) of the ifosfamide dose, or by oral mesna.

Mesna can be mixed in the same infusion bag as the ifosfamide.

Oral use of mesna Vials: Mesna has been shown to be effective when taken orally. Compared with intravenous administration, overall availability of mesna in urine after oral administration is approximately 50%; the onset of urinary excretion is delayed by up to 2 hours and is more prolonged than following intravenous dosing.

With the exception of continuous long-term infusions of oxazaphosphorines with mesna, intravenously administered mesna may be replaced by oral administration of mesna. The dosage should be 40% w/w of the dosage of the oxazaphosphorines. The contents of the ampoule should be added to a flavoured soft drink (e.g. orange juice, cola). This mixture is stable when refrigerated in a sealed container for 24 hours.

For intermittent oxazaphosphorine therapy following an initial intravenous injection of mesna at a dose of 20% (w/w) of the oxazaphosphorine dose, oral mesna (40% w/w) should be administered at 2 hours and again at 6 hours after the initial intravenous dose. Alternatively, three oral doses of mesna may be administered, replacing the i.v. dose with an oral dose (40% w/w) 2 hours prior to administration of oxazaphosphorines.

Example dosage schedule:

Where ifosfamide is used as a long-term continuous infusion with concomitant mesna, oral mesna may be taken as the infusion of ifosfamide and mesna finishes, then at 2 hours and 6 hours after the time at the finish of the infusion. All oral mesna doses should be 40% (w/w) of the final 24 hour ifosfamide dose.

Example dosage schedule:

Mesna is also available for oral administration as Mesna Tablets. For further information see the Summary of Product Characteristics for Mesna Tablets or contact Baxter Healthcare Limited.

Children

Children generally micturate 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.

Elderly

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 mesna or any of the excipients.

4.4 Special warnings and precautions for use

WARNINGS

Hypersensitivity

Hypersensitivity reactions to mesna have been reported following administration of mesna as an uroprotectant. These include various skin and subcutaneous tissue symptoms (see Section 4.8).

In addition, cases of severe bullous and ulcerative skin and mucosal reactions were reported.

In some cases, skin reactions were accompanied by one or more other symptoms, such as fever, cardiovascular symptoms, pulmonary symptoms, haematological abnormalities, nausea, vomiting, pain in the extremities, arthralgia, myalgia, malaise, and conjunctivitis (see Section 4.8).

Some reactions have presented as anaphylaxis.

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

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.

Prescribers should be aware that:

– severe as well as minor reactions were reported with the use of mesna in regimens to treat both severe systemic autoimmune disease and malignancy and that mesna should be suspected in any hypersensitivity reaction,

– these reactions may occur with first exposure or after several months of exposure and in some cases can be life threatening,

– the occurrence and severity of reactions appeared to vary with the dose administered with a tendency to shorter intervals following subsequent exposures,

– 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.

ThiolCompounds:

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.

PRECAUTIONS

Mesna does not prevent hemorrhagic cystitis in all patients. Patients should be monitored accordingly.

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

Sodium content

Mesna solution for injection contains approximately 59 mg of sodium per 400 mg mesna.

Lab test interferences

Mesna treatment may cause false positive reactions in nitroprusside sodium-based urine tests (including dipstick tests) for ketone bodies. 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).

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.

See also Section 4.8 for information on laboratory test abnormalities observed in pharmacokinetic studies.

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 ifosfamide 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.

Food does not influence the absorption and urinary elimination of mesna.

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of mesna in pregnant or lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing mesna.

Pregnancy and lactation are contraindications for cytostatic treatment, and consequently Mesna is not likely to be used under these circumstances.

Should an individual patient be undergoing oxazaphosphorine therapy during pregnancy then Mesna should be administered to this patient.

Mothers should not breast-feed whilst being treated with these drugs.

Animal studies have shown no evidence of embryotoxic or teratogenic effects of mesna.

4.7 Effects on ability to drive and use machines

Patients undergoing treatment with mesna may experience undesirable effects (including, e.g., syncope, light-headedness, lethargy/drowsiness, dizziness, and blurred vision) which could affect the ability to drive or use machines. The decision to drive or operate machinery should be made on an individual basis.

4.8 Undesirable effects

The most frequently occurring adverse reactions (> 10%) associated with use of mesna are: headache, infusion site reactions, abdominal pain/colic, lightheadedness, lethargy/drowsiness, pyrexia, rash, diarrhoea, nausea, flushing, and influenza-like illness.

The most severe adverse reactions associated with use of mesna are: bullous skin reactions, anaphylaxis, and drug rash with eosinophilia and systemic symptoms (DRESS).

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.

ADR 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), Unknown (adverse reactions reported in the post-marketing experience)

¹Oral, rectal

²Including nonpruritic, pruritic, erythema/erythematous, eczematous, papular, and/or macular rashes.

³with eosinophilia and systemic symptoms

⁴mucocutaneous, mucosal, oral, vulvovaginal, anorectal

• Time to onset and experience with re-exposure

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.

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

• 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.

• In-vivo effect on lymphocyte counts

In pharmacokinetics studies in healthy volunteers, administration 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.

• In-vivo effect on serum phosphorus levels

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

These phenomena should be considered when interpreting laboratory results.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

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 4g to 7g of mesna can cause symptoms such as nausea, vomiting, abdominal pain/colic, diarrhoea, headache, fatigue, limb and joint pains, rash, flushing, hypotension, bradycardia, tachycardia, paresthesia, fever, and bronchospasm.

A markedly increased rate of nausea, vomiting and diarrhoea 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 to mesna is not known.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mesna is an antidote, and offers the possibility of reliably preventing urotoxic side- effects associated with aggressive cancer chemotherapy using oxazaphosphorine cytostatics. Extensive and wide-ranging pharmacological and toxicological investigations have shown that mesna has no intrinsic pharmacodynamics and low toxicity. The pharmacological and toxicological inertness of mesna administered systemically and its excellent detoxifying effect in the efferent urinary tract and bladder, are due to the nature of its pharmacokinetics.

5.2 Pharmacokinetic properties

Mesna, a free thiol, is easily and rapidly transformed by auto-oxidation into its only metabolite mesna-disulphide (dimesna). 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 (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

Nothing relevant.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate, Sodium Hydroxide, Water for Injections.

6.2 Incompatibilities

Mesna is incompatible with platinum derivatives (e.g. Cisplatin, carboplatin and nitrogen mustard) and must not be mixed in the same infusion solution.

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

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store protected from light, below 30°C.

6.5 Nature and contents of container

15 clear glass Vials containing a clear colourless sterile aqueous solution of mesna in a folded cardboard box.

1. a) Each vial contains:
   Mesna 200mg
   Water for Injection 2ml
2. b) Each vial contains:
   Mesna 1g
   Water for Injection 10ml

6.6 Special precautions for disposal and other handling

No special instructions necessary.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Mesna Injection 200mg/2ml, 1g/10ml Taj Pharma
(Mesna Injection)

Package Leaflet: Important for the user

What is the most important information I should know about Mesna.

What is in this leaflet:

1) What is Mesna
2) What should I tell my doctor before receiving Mesna
3) How will I receive Mesna
4) What are the possible side effects of Mesna
5) How should I store Mesna tablets
6) What are the ingredients in Mesna

1) WHAT IS MESNA

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

It is not known if Mesna is safe and effective in children.

Who should not receive Mesna?

Do not take Mesna if you are allergic to Mesna or any of the ingredients in Mesna. See the end of this leaflet for a complete list of ingredients in Mesna.

2) WHAT SHOULD I TELL MY DOCTOR BEFORE RECEIVING MESNA

What should I tell my doctor before receiving Mesna?

Before you receive MESNA, tell your doctor if you:

• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Mesna will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Mesna passes into your breast milk. You and your doctor should decide if you will receive Mesna or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

3) How will I receive Mesna

• 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:

1. Mesna intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4 and 8 hours after you receive ifosfamide.
2. 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 doctor tells you to take it.
• You may need to take half of a MESNA tablet for your complete dose. Each tablet has a groove in the middle that will make it easier to break the tablet in half.
• During treatment with Mesna,you should drink 4 to 8 cups of liquid (1 to 2 liters) each day, whether you receive Mesna by intravenous infusion or take Mesna tablets by mouth.
• Tell your doctor if you:

vomit within 2 hours of taking Mesna tablets by mouth o miss a dose of Mesna tablets

have pink or red colored urine

4) WHAT ARE THE POSSIBLE SIDE EFFECTS OF MESNA

Mesna may cause serious side effects, including:

See “What is the most important information I should know about Mesna?”

• Mesna that is given by intravenous infusion contains the preservative benzyl alcohol. Benzyl alcohol has been shown to cause serious side effects and death in newborn, premature, and low-birth weight babies. Mesna tablets do not contain benzyl alcohol.

The most common side effects of Mesna 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

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Mesna. For more information, ask your doctor or pharmacist.

5) HOW SHOULD I STORE MESNA TABLETS

• Store Mesna tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Mesna and all medicines out of the reach of children.

General information about the safe and effective use of Mesna

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Mesna for a condition for which it was not prescribed. Do not give Mesna to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Mesna that is written for health professionals.

6. WHAT ARE THE INGREDIENTS IN MESNA

Active ingredient: mesna

Inactive ingredients:

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

Mesna tablets: calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).