Information for the Physician Zofran® 2 mg/ml Injection (ondansetron)

Please refer to the Summary of Product Characteristics (SPC) for further details on this product.

Trade Name of the Medicinal Product

Zofran® 2 mg/ml Injection Qualitative and Quantitative Composition

Zofran® 2 mg/ml Injection:

• 4 ml glass ampoules each containing 8 mg ondansetron (as hydrochloride dihydrate) in aqueous solution for intravenous or intramuscular administration.

Posology and Method of Administration

Chemotherapy and Radiotherapy Adults

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Zofran should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy: Zofran can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration. For most patients receiving emetogenic chemotherapy or radiotherapy, Zofran 8 mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly. To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Zofran should be continued for up to 5 days after a course of treatment.

Highly emetogenic chemotherapy: For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, Zofran can be given either by rectal, intravenous or intramuscular administration. Zofran has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:

•    A single dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy.

•    A dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8 mg two to four hours apart, or by a constant infusion of

1 mg/hour for up to 24 hours.

•    A single dose of 32 mg diluted in 50-100 ml of saline or other compatible infusion fluid (See Instructions for Use/Handling) and infused over not less than 15 minutes immediately before chemotherapy.

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

The efficacy of Zofran in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Zofran should be continued for up to 5 days after a course of treatment.

Paediatric Population:

CINV in children aged > 6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight - see below.

Dosing by BSA:

Zofran should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m². The intravenous dose must not exceed 8 mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days (see SPC for dosing tables). The total daily dose must not exceed adult dose of 32 mg.

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing. Zofran should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg. Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days (see SPC for further details).

Zofran injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes.

There are no data form controlled clinical trials on the use of Zofran in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Zofran for radiotherapy-induced nausea and vomiting in children.

Elderly

Zofran is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.

Renal Impairment

No alteration of daily dosage or frequency of dosing, or route of administration are required.

Hepatic Impairment

Clearance of Zofran is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded. Post-Operative Nausea and Vomiting (PONV)

Adults

For the prevention of PONV Zofran can be administered orally or by intravenous or intramuscular injection. Zofran may be administered as a single dose of 4 mg given by intramuscular or slow intravenous injection at induction of anaesthesia. For treatment of established PONV a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.

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Information for the User Zofran® 2 mg/ml Injection (ondansetron)

Read all of this leaflet carefully before you start taking this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions about your illness or your medicine, ask your doctor, nurse or pharmacist.

•    The name of this medicine is Zofran 2mg/ml Injection but it will be referred to as Zofran injection throughout the remainder of this leaflet.

•    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

In this leaflet:

1    What Zofran injection is and what is it used for

2    Before you have Zofran injection

3    How to have Zofran injection

4    Possible side effects

5    How to store Zofran injection

6    Further information

1    What Zofran injection is and what it is used for

Zofran injection contains a medicine called ondansetron. This belongs to a group of medicines called anti-emetics.

Zofran injection is used for:

•    preventing nausea and vomiting caused by chemotherapy or radiotherapy for cancer

•    preventing nausea and vomiting after surgery.

Ask your doctor, nurse or pharmacist if you would like any further explanation about these uses.

2    Before you have Zofran injection

Do not have Zofran injection if:

•    you are taking apomorphine (used to treat Parkinson's disease)

•    you are allergic (hypersensitive) to ondansetron or any of the other ingredients in Zofran injection (listed in Section 6).

If you are not sure, talk to your doctor, nurse or pharmacist before having Zofran injection.

Take special care with Zofran injection

Check with your doctor or pharmacist before having Zofran injection if:

•    you have ever had heart problems

•    you have an uneven heart beat (arrhythmias)

•    you are allergic to medicines similar to ondansetron, such as granisetron (known as ‘Kytril')

•    you have liver problems

•    you have a blockage in your gut

•    you have problems with the levels of salts in your blood, such as potassium, sodium and magnesium.

If you are not sure if any of the above apply to you, talk to your doctor, nurse or pharmacist before having Zofran injection.

Taking other medicines

Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because Zofran can affect the way some medicines work. Also some other medicines can affect the way Zofran works.

In particular, tell your doctor, nurse or pharmacist if you are taking any of the following medicines:

•    carbamazepine or phenytoin used to treat epilepsy

•    rifampicin used to treat infections such as tuberculosis (TB)

•    anti-arrhythmic medicines used to treat an uneven heart beat

•    beta-blocker medicines used to treat certain heart or eye problems, anxiety or prevent migraines

•    tramadol, a pain killer

•    medicines that affect the heart (such as haloperidol or methadone)

•    cancer medicines (especially anthracyclines and trastuzumab).

If you are not sure if any of the above applies to you, talk to your doctor, nurse or pharmacist before having Zofran injection.

Zofran injection should not be given in the same syringe or infusion (drip) as any other medication.

Pregnancy and breast-feeding

It is not known if Zofran is safe during pregnancy. Talk to your doctor before having Zofran injection if you are pregnant or might become pregnant.

Do not breast-feed if you have Zofran. This is because small amounts pass into the mother's milk. Ask your doctor or midwife for advice.

Important information about some of the ingredients of Zofran injection

This medicine contains sodium citrate and sodium chloride. This means that Zofran injection contains 7 mg of sodium per 4 mg dose. If you are on a low sodium diet, speak to your doctor, nurse or pharmacist before you have Zofran injection.

3 How to have Zofran injection

Zofran injection is normally given by a nurse or doctor. The dose you have been prescribed will depend on the treatment you are having.

To prevent nausea and vomiting from chemotherapy or radiotherapy

On the day of chemotherapy or radiotherapy

•    the usual adult dose is 8 mg given by an injection into your vein or muscle, just before your treatment, and another 8 mg twelve hours later. After chemotherapy, your medicine will usually be given by mouth as an 8 mg Zofran tablet or 10 ml (8 mg) Zofran syrup.

On the following days

•    the usual adult dose is one 8 mg tablet or 10 ml (8 mg) syrup taken twice a day

•    this may be given for up to 5 days.

If your chemotherapy or radiotherapy is likely to cause severe nausea and vomiting, you may be given more than the usual dose of Zofran. Your doctor will decide this.

Children aged 6 months and adolescents

The doctor will decide the dose. Look at the label for more information On the day of chemotherapy or radiotherapy

•    the first dose is given by an injection into the vein, just before your child's treatment. After chemotherapy, your child's medicine will usually be given by mouth; the usual dose is a 4 mg Zofran tablet or 5 ml (4 mg) Zofran syrup twelve hours later.

On the following days

•    one 4 mg tablet or 5 ml (4 mg) syrup twice a day

•    this can be given for up to five days.

Children (aged over 1 month and adolescents)

Oral formulation:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow i.v. injection is recommended for this purpose.

Injection:

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of o ndansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients, having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg. There is no data on the use of Zofran in the treatment of PONV in children below 2 years of age.

Elderly

There is limited experience in the use of Zofran in the prevention and treatment of PONV in the elderly, however Zofran is well tolerated in patients over 65 years receiving chemotherapy.

Renal impairment

No alteration of daily dosage or frequency of dosing, or route of administration are required.

Hepatic impairment

Clearance of Zofran is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded. Poor sparteine/debrisoquine metabolism

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

Instructions for Use/Handling

Zofran Injection should not be autoclaved.

Compatibility with intravenous fluids

Zofran injection should only be admixed with those infusion solutions which are recommended:

•    Sodium Chloride Intravenous Infusion BP 0.9%w/v

•    Glucose Intravenous Infusion BP 5%w/v

•    Mannitol Intravenous Infusion BP 10%w/v

•    Ringers Intravenous Infusion

•    Potassium Chloride 0.3%w/v and Sodium Chloride 0.9%w/v Intravenous Infusion BP

•    Potassium Chloride 0.3%w/v and Glucose 5%w/v Intravenous Infusion BP

In keeping with good pharmaceutical practice dilutions of Zofran injection in intravenous fluids should be prepared at the time of infusion or stored at 2 - 8°C for no more than 24 hours before the start of ad ministration. Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or Type 1 glass bottles. Dilutions of Zofran in sodium chloride 0.9%w/v or in glucose 5%w/v have been demonstrated to be stable in polypropylene syringes. It is considered that Zofran injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.

Compatibility with other drugs

Zofran may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Zofran giving set for ondansetron concentrations of 16 to 160 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml respectively);

Cisplatin: Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours. 5-Fluorouracil: Concentrations up to 0.8 mg/ml (e.g. 2.4g in 3 litres or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.

Carboplatin: Concentrations in the range 0.18 mg/ml to 9.9 mg/ml (e.g. 90 mg in 500 ml to 990 mg in 100 ml), administered over ten minutes to one hour.

Etoposide: Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250 mg in 1 litre), administered over thirty minutes to one hour.

Ceftazidime: Doses in the range 250 mg to 2000 mg reconstituted with Water for Injections BP as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide: Doses in the range 100 mg to 1 g, reconstituted with Water for Injections BP, 5 ml per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.

Doxorubicin: Doses in the range 10-100 mg reconstituted with Water for Injections BP, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.

Dexamethasone: Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of ondansetron diluted in 50-100 ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram - 2.5 mg/ml for dexamethasone sodium phosphate and 8 microgram - 1 mg/ml for ondansetron.

Shelf Life

•    36 months (unopened)

•    24 hours (dilutions stored 2 - 8°C)

Special Precautions for Storage

•    Protect from light

•    Do not store above 30°C

Dilutions of Zofran injection in compatible intravenous infusion fluids are stable under normal room lighting conditions or daylight for at least 24 hours, thus no protection from light is necessary while infusion takes place.

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To prevent nausea and vomiting after an operation

•    The usual dose for adults is 4 mg given by an injection into your vein or muscle. This will be given just before your operation.

•    For children aged over 1 month and adolescents, the doctor will decide the dose. The maximum dose is 4 mg given as an injection into the vein. This will be given just before the operation.

To treat nausea and vomiting after an operation

•    The usual adult dose is 4 mg given by an injection into your vein or muscle.

•    For children aged over 1 month and adolescents, the doctor will decide the dose. The maximum dose is 4 mg given as an injection into the vein.

Patients with moderate or severe liver problems

The total daily dose should not be more than 8 mg.

If you keep feeling or being sick

Zofran injection should start to work soon after having the injection. If you continue to be sick or feel sick, tell your doctor or nurse.

If you have more Zofran injection than you should

Your doctor or nurse will give you Zofran injection so it is unlikely that you will receive too much. If you think you have been given too much or have missed a dose, tell your doctor or nurse.

4)    Possible side effects

Like all medicines, Zofran injection can cause side effects, although not everybody gets them.

Allergic reactions

If you have an allergic reaction, tell your doctor or a member of the medical staff straight away. The signs may include:

•    sudden wheezing and chest pain or chest tightness

•    swelling of your eyelids, face, lips, mouth or tongue

•    skin rash - red spots or lumps under your skin (hives) anywhere on your body

•    collapse.

Other side effects include:

Very common (affects more than 1 in 10 people)

•    headache.

Common (affects less than 1 in 10 people)

•    a feeling of warmth or flushing

•    constipation

•    changes to liver function test results (if you have Zofran injection with a medicine called cisplatin, otherwise this side effect is uncommon)

•    irritation and redness at the site of injection.

Uncommon (affects less than 1 in 100 people)

•    hiccups

•    low blood pressure, which can make you feel faint or dizzy

•    uneven heart beat

•    chest pain

•    fits

•    unusual body movements or shaking.

Rare (affects less than 1 in 1,000 people)

•    feeling dizzy or light headed

•    blurred vision

•    disturbance in heart rhythm (sometimes causing a sudden loss of consciousness).

Very rare (affects less than 1 in 10,000 people)

•    poor vision or temporary loss of eyesight, which usually comes back within 20 minutes.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

5)    How to store Zofran injection

•    Keep out of the reach and sight of children.

•    Do not use Zofran injection after the expiry date which is stated on the pack after ‘Exp'.

•    Do not store above 30°C. Protect from light.

•    When Zofran injection is diluted in intravenous fluids:

•    it must be stored at 2 - 8°C for not more than 24 h ours

•    it does not need to be protected from light during infusion.

•    If your medicine becomes discoloured, or shows any other signs of deterioration, return it to your pharmacist.

•    Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6)    Further information

What Zofran injection contains

The active ingredient is ondansetron. Each 4 ml Zofran injection ampoule contains 8mg ondansetron as ondansetron hydrochloride dihydrate (2mg/ml) solution for injection.

The other ingredients are citric acid monohydrate, sodium citrate, sodium chloride and water for Injections.

What Zofran injection looks like and contents of the pack

Zofran injection comes in clear glass snap-ring ampoules containing a clear aqueous solution. Zofran injection is available in 4 ml (8 mg) glass ampoules in a pack size of 5 individual ampoules.

PL: 33532/0259 Zofran 2mg/ml Injection The manufacturer is

GlaxoSmithKline Manufacturing S.p.A, Strada Provinciale Asolana, 90, 43056 San Polo di Torrile, Parma, Italy. GlaxoSmithKline Pharmaceuticals S.A., ul. Grunwaldzka 189, 60-322, Poznan, Poland.

Procured from within the EU by the Product licence holder: MPT Pharma Ltd, Westgate Business Park, Unit 5-7 Tintagel Way, Aldridge, Walsall WS9 8ER.    POMT

Repackaged by xxxxxxxxxxxxxxxxxxxxxxxxxxxxx Leaflet date: 18^th June 2012

Zofran is a registered trademark of the GlaxoSmithKline group of companies