Module 1 - Section 3.1 SPC, Labelling and    p_ag_e 1/9

Package Leaflet

Common Technical Document    SynthonBV

Zoledronic acid (as monohydrate) 4 mg/ 5 ml

concentrate for solution for infusion

1.3.1    Package Leaflet

Package leaflet: Information for the user Zoledronic acid 4 mg/5 ml Concentrate for solution for infusion

Zoledronic acid

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.

What is in this leaflet

1.    What    Zoledronic acid is and what it is used for

2.    What    you need to know before you are given Zoledronic acid

3.    How Zoledronic acid is used

4.    Possible side effects

5.    How to store Zoledronic acid

6.    Contents of the pack and other information

1.    What Zoledronic acid is and what it is used for

The active substance in Zoledronic acid 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).

2.    What you need to know before you are given Zoledronic acid

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 acidbelongs), 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.

Other medicines and Zoledronic acid

Tell your doctor or pharmacist 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), 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, 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 reports of osteonecrosis of the jaw (ONJ).

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.

Pregnancy and breast-feeding

You should not be given Zoledronic acid if you are pregnant. Tell your doctor if you are pregnant, think that you may be pregnant or planning to have a baby.

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 less than 1 mmol sodium (23 mg) per vial (5 ml), i.e. essentially “sodium-free”.

3. How Zoledronic acid 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, nurse or pharmacist.

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 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.

-    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.

Very rare (may affect up to 1 in 10,000 people):

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

Low counts of white blood cells and blood platelets • Hypersensitivity reactions • Anxiety, sleep disturbances • Dizziness, tingling or numbness of the hands or feet, taste disturbance, increased or decreased sensitivity to stimulation, tremor, somnolence • Tearing of the eye, eye sensitivity to light • High blood pressure, low blood pressure, sudden coldness with fainting, limpness or collapse • Difficulty breathing, cough • Diarrhoea, constipation, abdominal pain, indigestion, inflammation of the mouth, dry mouth • Itching, rash, increased sweating • Muscle cramps • Kidney failure, blood in the urine, proteins in the urine • Feeling of weakness, swelling of the ankles, feet or fingers, skin reactions (redness and swelling) at the infusion site, chest pain , weight increase, hives • Low level of magnesium and potassium in the blood. Your doctor will monitor this and take any necessary measures.

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

Slow heart beat • 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 • Severe reduction in blood cells which can cause weakness, bruising or make infections more likely • Serious allergic reaction which causes swelling of the face or throat • High levels of blood potassium which can cause abnormal heart rhythm, high levels of blood sodium which can cause confusion, muscle twitching or abnormal heart rhythm • Interstitial lung disease (inflammation of the tissue around the air sacks of the lungs)

Very rare (may affect up to 1 in 10,000 people)

Painful redness and/or swelling of the eye.

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

5.    How to store Zoledronic acid

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

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

Do not use this medicine after the expiry date which is stated on the carton and on the vial. The expiry date refers to the last days of that month.

This medicinal product does not require any special storage conditions.

After first opening, Zoledronic acid should be used immediately. If the solution is not used immediately, 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. The refrigerated solution should then be equilibrated to room temperature prior to administration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.    Contents of the pack and other information

What Zoledronic acid contains

-    The active substance is zoledronic acid. One vial contains 4 mg of zoledronic acid (anhydrous) corresponding to 4.264 mg zoledronic acid monohydrate.

-    The other ingredients are: mannitol (E421), sodium citrate dihydrate (E331), sodium hydroxide (E524) for pH-adjustment, hydrochloric acid (E507) for pH adjustment and water for injections.

What Zoledronic acid looks like and contents of the pack

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

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

Each pack contains the vial with concentrate. Zoledronic acid is supplied as packs containing 1, 4, 5 or 10 vials.

Not all pack sizes may be marketed.

Marketing Authorisation Holder:

Synthon BV Microweg 22 6545 CM Nijmegen The Netherlands

Manufacturers:

Synthon BV Microweg 22 6545 CM Nijmegen The Netherlands

Synthon Hispania SL Castello 1, Poligono Las Salinas 08830 Sant Boi de Llobregat Spain

This leaflet was last revised in August 2013

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

The following information is intended for healthcare professionals only:

How to prepare and administer Zoledronic acid

-To prepare an infusion solution containing 4 mg zoledronic acid, further dilute the Zoledronic acid concentrate (5.0 ml) with 100 ml of calcium-free or other divalent cation-free infusion solution. If a lower dose of Zoledronic acid is required, first withdraw the appropriate volume as indicated below and then dilute it further with 100 ml of infusion solution. To avoid potential incompatibilities, the infusion solution used for dilution must be either 9 mg/ml sodium chloride or 50 mg/ml glucose solution.

Do not mix Zoledronic acid concentrate with calcium-containing or other divalent cation-containing solutions such as lactated Ringer’s solution.

Instructions for preparing reduced doses of Zoledronic acid: Withdraw the appropriate volume of the liquid concentrate, as follows:

-    4.4 ml for 3.5 mg dose

-    4.1 ml for 3.3 mg dose

-    3.8 ml for 3.0 mg dose

- 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.

-From a microbiological point of view, the diluted 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. The refrigerated solution should be equilibrated to room temperature prior to administration.

-The solution containing zoledronic acid is given as a single 15-minute intravenous infusion in 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.

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

-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.

How to store Zoledronic acid

-Keep Zoledronic acid out of the reach and sight of children.

-Do not use Zoledronic acid after the expiry date stated on the pack.

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

The diluted Zoledronic acid infusion solution should be used immediately in order to avoid microbial contamination.