Package leaflet: Information for the user

Zoledronic acid Mylan 4 mg/100 ml solution for infusion

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

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

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

•    If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Zoledronic acid Mylan 4 mg/100 ml solution for infusion is and what it is used for

2.    What you need to know before you are given Zoledronic acid Mylan 4 mg/100 ml solution for infusion

3.    How Zoledronic acid Mylan 4 mg/100 ml solution for infusion is used

4.    Possible side effects

5.    How to store Zoledronic acid Mylan 4 mg/100 ml solution for infusion

6.    Contents of the pack and other information

1.    What Zoledronic acid Mylan 4 mg/100 ml solution for infusion is and what it is used for

The active substance in Zoledronic acid Mylan 4 mg/100 ml solution for infusion is zoledronic acid, which belongs to a group of substances called bisphosphonates. Zoledronic acid works by attaching itself to the bone and slowing down the rate of bone change. It is used:

•    To prevent bone complications, e.g. fractures, in adult patients with bone metastases (spread of cancer from primary site to the bone).

•    To reduce the amount of calcium in the blood in adult patients where it is too high due to the presence of a tumour. Tumours can accelerate normal bone change in such a way that the release of calcium from bone is increased. This condition is known as tumour-induced hypercalcaemia (TIH).

The product will be referred to Zoledronic acid for the remaining portion of this leaflet.

2.    What you need to know before you are given Zoledronic acid Mylan 4 mg/100 ml solution for infusion

Follow carefully all instructions given to you by your doctor.

Your doctor will carry out blood tests before you start treatment with Zoledronic acid and will check your response to treatment at regular intervals.

You should not be given Zoledronic acid:

•    if you are breast-feeding.

•    if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which Zoledronic acid belongs), or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Zoledronic acid:

•    if you have or have had a kidney problem.

•    if you have or have had pain, swelling or numbness of the jaw, a feeling of heaviness in the jaw or loosening of a tooth.

•    if you are having dental treatment or are due to undergo dental surgery, tell your dentist that you are being treated with zoledronic acid.

Reduced levels of calcium in the blood (hypocalcaemia), sometimes leading to muscle cramps, dry skin, burning sensation, have been reported in patients treated with zoledronic acid. Irregular heart beat (cardiac arrhythmia), seizures, spasm and twitching (tetany) have been reported as secondary to severe hypocalcaemia. In some instances the hypocalcaemia may be life-threatening. If any of these apply to you, tell your doctor straight away. If you have pre-existing hypocalcaemia, it must be corrected before initiating the first dose of zoledronic acid. You will be given adequate calcium and vitamin D supplements.

Patients aged 65 years and over

Zoledronic acid can be given to people aged 65 years and over. There is no evidence to suggest that any extra precautions are needed.

Children and adolescents

Zoledronic acid is not recommended for use in adolescents and children below the age of 18 years.

Other medicines and Zoledronic acid

Tell your doctor if you are taking, have recently taken or might take any other medicines. It is especially important that you tell your doctor if you are also taking:

• Aminoglycosides (medicines used to treat severe infections), calcitonin (a type of medicine used to treat post-menopausal osteoporosis and hypercalcaemia), loop diuretics (a type of medicine to treat high blood pressure or oedema) or other calcium-lowering medicines, since the combination .........^.................

of these with bisphosphonates may cause the calcium level in the blood to become too low.

•    Thalidomide (a medicine used to treat

a certain type of blood cancer involving the bone) or any other medicines which may harm your kidneys.

•    Other medicines that also contain zoledronic acid and which are used to treat osteoporosis and other non-cancer diseases of the bone, or any other bisphosphonate, since the combined effects of these medicines taken together with Zoledronic acid are unknown.

•    Anti-angiogenic medicines (used to treat cancer), since the combination of these with zoledronic acid has been associated with an increased risk of osteonecrosis of the jaw (ONJ).

Pregnancy and breast-feeding

You should not be given Zoledronic acid if you are pregnant. Tell your doctor if you are or think that you may be pregnant.

You must not be given Zoledronic acid if you are breast-feeding.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking any medicine

Driving and using machines

There have been very rare cases of drowsiness and sleepiness with the use of zoledronic acid. You should therefore be careful when driving, using machinery or performing other tasks that need full attention.

Zoledronic acid contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (100ml), i.e. essentially 'sodium-free'

3. How Zoledronic acid Mylan 4 mg/100 ml solution for infusion is used

•    Zoledronic acid must only be given by healthcare professionals trained in administering bisphosphonates intravenously, i.e. through a vein.

•    Your doctor will recommend that you drink enough water before each treatment to help prevent dehydration.

•    Carefully follow all the other instructions given to you by your doctor, pharmacist or nurse.

How much Zoledronic acid is given

•    The usual single dose given is 4 mg.

If you have a kidney problem, your doctor will give you a lower dose depending on the severity of your kidney problem.

How often Zoledronic acid is given

•    If you are being treated for the prevention of bone complications due to bone metastases, you will be given one infusion of Zoledronic acid every three to four weeks.

•    If you are being treated to reduce the amount of calcium in your blood, you will normally only be given one infusion of Zoledronic acid.

How Zoledronic acid is given

•    Zoledronic acid is given as a drip (infusion) into a vein which should take at least 15 minutes and should be administered as a single intravenous solution in a separate infusion line.

Patients whose blood calcium levels are not too high will also be prescribed calcium and vitamin D supplements to be taken each day.

If you are given more Zoledronic acid than you should be

If you have received doses higher than those recommended, you must be carefully monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of calcium, phosphorus and magnesium) and/ or changes in kidney function, including severe kidney impairment. If your level of calcium falls too low, you may have to be given supplemental calcium by infusion.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The most common ones are usually mild and will probably disappear after a short time.

Tell your doctor about any of the following serious side effects straight away:

Common (may affect up to 1 in 10 people):

•    Severe kidney impairment (will normally be determined by your doctor with certain specific blood tests).

•    Low level of calcium in the blood.

Uncommon (may affect up to 1 in 100 people):

•    Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could be signs of bone damage in the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms.

....J-......................

The following information is intended for healthcare professionals only:

How to prepare and administer Zoledronic acid

•    For single use only. Any unused solution should be discarded. Only clear solution free from particles and discolouration should be used. Aseptic techniques must be followed during the preparation of the infusion.

•    If refrigerated, allow the refrigerated solution to reach room temperature before administration.

•    It is given as a single 15-minute intravenous infusion. Since no data are available on the compatibility of zoledronic acid with other intravenously administered substances, Zoledronic acid must not be mixed with other medications/substances and should always be given through a separate infusion line.The hydration status of patients must be assessed prior to and following administration of Zoledronic acid to ensure that they are adequately hydrated.

•    Zoledronic acid can be used immediately without further preparation for patients with normal renal function. In patients with mild to moderate renal impairment, reduced doses should be prepared as instructed below.

To prepare reduced doses for patients with baseline CLcr < 60 ml/min, refer to Table 1 below.

Remove the volume of Zoledronic acid solution indicated from the vial and replace with an

equal volume of sterile sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% glucose

solution for injection.

•    Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving zoledronic acid for postmenopausal osteoporosis. It

is currently unclear whether zoledronic acid causes this irregular heart rhythm but you should report it to your doctor if you experience such symptoms after you have received zoledronic acid.

•    Severe allergic reaction: shortness of breath, swelling mainly of the face and throat.

Rare (may affect up to 1 in 1,000 people):

• As a consequence of low calcium values: irregular heart beat (cardiac arrhythmia; secondary to hypocalcaemia).

Very rare (may affect up to 1 in

10.000    people):

•    As a consequence of low calcium values: seizures, numbness and tetany (secondary to hypocalcaemia).

Tell your doctor about any of the following side effects as soon as possible:

Very common (may affect more than 1 in 10 people):

•    Low level of phosphate in the blood.

Common (may affect up to 1 in 10 people):

•    Headache and a flu-like syndrome consisting of fever, fatigue, weakness, drowsiness, chills and bone, joint and/or muscle ache. In most cases no specific treatment is required and the symptoms disappear after a short time (couple of hours or days).

•    Gastrointestinal reactions such as nausea and vomiting as well as loss of appetite.

•    Conjunctivitis.

•    Low level of red blood cells (anaemia).

Uncommon (may affect up to 1 in 100 people):

•    Hypersensitivity reactions.

•    Low blood pressure.

•    Chest pain.

•    Skin reactions (redness and swelling) at the infusion site, rash, itching.

•    High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste disturbances, trembling, tingling or numbness of the hands or feet, diarrhoea, constipation, abdominal pain, dry mouth.

•    Low counts of white blood cells and blood platelets.

•    Low level of magnesium and potassium in the blood. Your doctor will monitor this and take any necessary measures.

•    Weight increase.

•    Increased sweating.

•    Sleepiness.

•    Blurred vision, tearing of the eye, eye sensitivity to light.

•    Sudden coldness with fainting, limpness or collapse.

•    Difficulty in breathing with wheezing or coughing.

•    Urticaria.

Rare (may affect up to 1 in 1,000 people):

•    Slow heartbeat.

•    Confusion.

•    Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or groin as this may be an early indication of a possible fracture of the thigh bone.

•    Interstitial lung disease (inflammation of the tissue around the air sacks of the lungs).

•    Flu-like symptoms including arthritis and joint swelling.

•    Painful redness and/or swelling of the eye.

Very rare (may affect up to 1 in

10.000    people):

•    Fainting due to low blood pressure.

•    Severe bone, joint and/or muscle pain, occasionally incapacitating.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system:

UK

The Yellow Card Scheme, at www.mhra.gov.uk/yellowcard

Ireland

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

E-mail: imbpharmacovigilance@imb.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.    How to store Zoledronic acid Mylan 4 mg/100 ml solution for infusion

Your doctor, pharmacist or nurse knows how to store Zoledronic acid properly (see section 6).

6.    Contents of the pack and other information

What Zoledronic acid contains

•    The active substance is zoledronic acid. One vial contains 4 mg zoledronic acid, corresponding to 4.26 mg zoledronic acid monohydrate.

•    The other ingredients are:

•    mannitol (E421) sodium citrate (E331) water for injections.

What Zoledronic acid looks like and the contents of the pack

Zoledronic acid is a clear, colourless solution, free from visible particles.

Zoledronic acid is supplied as a solution in a vial. One vial contains 4 mg of zoledronic acid.

Zoledronic acid is supplied as packs containing:

1,4 or 5 vials.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Generics [UK] Ltd., Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

Manufacturer

Agila Specialties Polska Sp. Zo.o., 10, Daniszewska Str., 03-230 Warsaw, Poland

Sanochemia Pharmazeutica AG,

Landeggerstrasse 7, A - 2491 Neufeld an der Leitha, Austria

This leaflet was last revised in

12/2014

This medicinal product is authorised in the Member States of the EEA under the following names:

A............A............A............A

Table 1: Preparation of reduced doses of Zoledronic acid

Baseline creatinine clearance (ml/min)	Remove the following amount of Zoledronic acid(ml)	Replace with the following volume of sterile sodium chloride 9 mg/ml (0.9%) or 5% glucose solution for injection (ml)	Adjusted dose (mg zoledronic acid in 100 ml)
50-60	12.0	12.0	3.5
40-49	18.0	18.0	3.3
30-39	25.0	25.0	3.0

*Doses have been calculated assuming target AUC of 0.66 (mg^hr/l) (CLcr = 75 ml/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min.

•    Studies with several types of infusion lines made from polyvinylchloride, polyethylene and polypropylene showed no incompatibility with zoledronic acid.

How to store Zoledronic acid

•    Keep this medicine out of the sight and reach of children.

•    Do not use Zoledronic acid after the expiry date stated on the pack. The expiry date refers to the last day of that month.

•    This medicinal product does not require any special storage conditions.

•    After first opening or after preparation of reduced zoledronic acid doses (as described above): chemical and physical stability has been demonstrated for 24 hours at 2°C - 8°C and at 25°C. From a microbiological point of view, the solution for infusion 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 2°C - 8°C.

•    Do not throw away any medicines via wastewater. These measures will help protect the environment.

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