PACKAGE LEAFLET: INFORMATION FOR THE USER

Zoledronic Acid 4 mg powder and solvent for solution for infusion

Zoledronic acid

Read all of this leaflet carefully before you are given Zoledronic Acid

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

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

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

In this leaflet

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

2.    Before you are given Zoledronic Acid

3.    How Zoledronic Acid is used

4.    Possible side effects

5.    How to store Zoledronic Acid

6.    Further 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 cases where it is too high due to the presence of a tumour in adult patients. 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.    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 (hypersensitive) to zoledronic acid, another bisphosphonate (the group of substances to which Zoledronic Acid belongs), or any of the other ingredients of Zoledronic Acid (see section “FURTHER INFORMATION”

Before you are given Zoledronic Acid, tell your doctor:

•    if you have or have had a liver problem

•    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

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines

obtained without a prescription. 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 or any other medicines which may harm your kidneys.

Aclasta (a medicine that also contains zoledronic acid and is used to treat osteoporosis and other noncancer diseases of the bone), or any other bisphosphonate, since the combined effects of these medicines taken together with Zoledronic Acid are unknown.

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.

Use in children

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 or think that you may be pregnant.

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

Ask your doctor for advice before taking any medicine while you are pregnant or breast-feeding.

Driving and using machines

The effects of Zoledronic Acid on driving, using machines and performing other tasks that need your full attention have not been studied. However, adverse reactions, such as dizziness and somnolence, may affect the ability to drive or use machines, therefore caution should be exercised with the use of Zoledronic Acid along with driving and operating of machinery or performing other tasks that need full attention.

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 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.

How often you will be given Zoledronic Acid

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

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, Zoledronic Acid can cause side effects, although not everybody gets them. The most common ones are usually mild and will probably disappear after a short time.

The frequency of possible side effects listed below is defined using the following convention:

•    very common: affects more than 1 user in 10

•    common: affects 1 to 10 users in 100

•    uncommon: affects 1 to 10 users in 1,000

•    rare: affects 1 to 10 users in 10,000

•    very rare: affects less than 1 user in 10,000

•    not known: frequency cannot be estimated from the available data

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

Very common:

•    Low level of phosphate in the blood Common:

•    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, as reported with other bisphosphonates (the group of substances to which Zoledronic acid belongs)

•    Blood tests indicating changes in kidney function (higher levels of creatinine), including severe kidney impairment. Such changes are also known to occur with other medicinal products of this kind. In addition, some cases of kidney disease have been reported

•    Low level of red blood cells (anaemia)

•    Low level of calcium in the blood

Uncommon:

•    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

•    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, sleep disturbances, tingling or numbness of the hands or feet, diarrhoea

•    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

•    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

•    Sleepiness

•    Tearing of the eye, eye sensitivity to light

•    Sudden coldness with fainting, limpness or collapse

•    Difficulty in breathing with wheezing or coughing

•    Urticaria

Rare:

•    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

Very rare:

•    Fainting due to low blood pressure

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

•    Painful redness and/or swelling of the eye

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.

Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side effects via the internet at www.mhra.gov.uk/yellowcard. Alternatively you can call Freephone 0808 100 3352 (available from 10 a.m. to 2 p.m. Mondays to Fridays) or fill in a paper form available from your local pharmacy.”

5.    HOW TO STORE ZOLEDRONIC ACID

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

6.    FURTHER INFORMATION What Zoledronic Acid contains

•    The active substance of Zoledronic Acid is zoledronic acid One vial contains 4 mg zoledronic acid, corresponding to 4.66 mg zoledronic acid hemypentahydrate.

•    The other ingredients are: mannitol, sodium citrate

| What Zoledronic Acid looks like and contents of the pack

Zoledronic Acid is supplied as a White to off-white powder in a vial | One vial contains 4 mg of zoledronic acid. Each pack contains the vial with powder, together with a 5 ml ampoule containing clear, colourless_water for injections, which is used to dissolve the powder. Zoledronic Acid is supplied as packs containing 1 vial and 1 ampoule.

Marketing Authorisation Holder

Ibigen S.r.l. - Via Fossignano, 2 04011 Aprilia (LT) - Italy Telefono: +39 (0)6 921501 Fax: +39 (0)6 92150500 e-mail: info@ibigen.it

Manufacturer

Istituto Biochimico Italiano S.p.A.

Via Fossignano, 2 04011 - Aprilia Italy

INFORMATION FOR THE HEALTHCARE PROFESSIONAL How to prepare and administer Zoledronic Acid

•    To prepare an infusion solution containing 4 mg Zoledronic Acid, add 5 ml of water for injections from the ampoule supplied in the pack to the vial containing the zoledronic acid powder under aseptic conditions. Shake the vial gently to dissolve the powder

•    Further dilute the Zoledronic Acid reconstituted solution (5 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 of the reconstituted solution (4 mg/5 ml) 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 0.9% w/v sodium chloride or 5% w/v glucose solution.

Do not mix Zoledronic Acid reconstituted solution 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 reconstituted solution (4 mg/5 ml), 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 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 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions

•    The solution containing Zoledronic Acid is given as a single 15-minute intravenous infusion. The hydration status of patients must be assessed prior to and following administration of Zoledronic Acid to assure that they are adequately hydrated

•    Studies with glass bottles, several types of infusion bags and infusion lines made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9% w/v sodium chloride solution or 5% w/v glucose solution) 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

•    After dilution: The diluted solution for infusion should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user.