Zoledronic Acid 4mg/5ml Concentrate for solution for infusion

^oledronic acid I

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

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Clf you have any furtherquestions.askyourdoctor, nurse or pharmacist.

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

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What is in this leaflet

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

What you need to know before you are given Zoledronic Acid Concentrate

y. How ZoledronicAcid Concentrate is given If. Possible side effects 15. How to store ZoledronicAcid Concentrate p. Contents of the pack and other information

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

^The active substance in Zoledronic Acid Concentrate is zoledronic acid, Ivhich belongs to a group of substances called bisphosphonates. Zoledronic fecid works by attaching itself to the bone and slowing down the rate of bone phange. It is used:

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

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2. What you need to know before you are given Zoledronic Acid Concentrate

Follow carefully all instructions given to you by yourdoctor.

|Your doctor will carry out blood tests before you start treatment with ^oledronic Acid Concentrate and will check your response to treatment at regularintervals.

You should not be given ZoledronicAcid Concentrate:

if you are breast-feeding.

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

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Warnings and precautions

Before you are given ZoledronicAcid Concentrate, tell your doctor:

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of heaviness in the jaw or loosening of a tooth. Your doctor may recommend a dental examination before you start treatment with ZoledronicAcid Concentrate.

U if you are having dental treatment or are due to undergo dental surgery, I tell your dentist that you are being treated with Zoledronic Acid |    Concentrate and inform yourdoctor about your dental treatment.

While being treated with this Zoledronic Acid Concentrate, you should maintain good oral hygiene (including regular teeth brushing) and receive Iroutine dental check-ups.

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pontact your doctor and dentist immediately if you experience any problems (vith your mouth or teeth such as loose teeth, pain or swelling, or non-healing pf sores or discharge, as these could be signs of a condition called osteonecrosis of the jaw.

Patients who are undergoing chemotherapy and/or radiotherapy, who are taking steroids, who are undergoing dental surgery, who do not receive routine dental care, who have gum disease, who are smokers, or who were previously treated with a bisphosphonate (used to treat or prevent bone disorders) may have a higher risk of developing osteonecrosis of the jaw.

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 Concentrate. Irregular heart beat (cardiacj 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 straigh! away. If you have pre-existing hypocalcaemia, it must be corrected beford initiating the first dose of Zoledronic Acid Concentrate. You will be giver| adequate calcium and vitamin D supplements.

Patients aged 65 years and over

ZoledronicAcid Concentrate can be given to people aged 65 years and over) There is no evidence to suggest that any extra precautions are needed. I

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Children and adolescents    |

ZoledronicAcid Concentrate is not recommended for use in adolescents an^ children below the age of 18 years.

Other medicines and Zoledronic Acid Concentrate

Please tell your doctor if you are taking or have recently taken any otheil medicines, including medicines obtained without a prescription. It is| especially important that you tell yourdoctor 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 thd 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.

•    Aclasta (a medicine that also contains zoledronic acid and is used to treat

osteoporosis and other non-cancer diseases of the bone), or any otheil bisphosphonate, since the combined effects of these medicines takerl togetherwith ZoledronicAcid Concentrate are unknown.    |

•    Anti-angiogenic medicines (used to treat cancer), since the combination ofthese with ZoledronicAcid Concentrate has been associated with an increased riskofosteonecrosisofthejaw(ONJ).

Pregnancy and breast-feeding

You should not be given ZoledronicAcid Concentrate if you are pregnant. Tell your doctor if you are or think thatyou may be pregnant.

You must not be given ZoledronicAcid Concentrate 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    I

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

3. How Zoledronic Acid Concentrate is given

professionals trained in administering bisphosphonates intravenously) i.e. through a vein.

treatment to help prevent dehydration.

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nurse or pharmacist.    I

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How much ZoledronicAcid Concentrate is given    |

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If you are being treated for the prevention of bone complications due td bone metastases, you will be given one infusion of Zoledronic Aci^ Concentrate 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 Ada

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depending on the severity of your kidney problem.

How often you will be given ZoledronicAcid Concentrate

Concentrate.

How Zoledronic Acid Concentrate is given

zoledronic Acid Concentrate 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.

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

!f you are given more Zoledronic Acid Concentrate than you should be

f you have received doses higher than those recommended, you must be fcarefully monitored by your doctor. This is because you may develop serum Electrolyte abnormalities (e.g. abnormal levels of calcium, phosphorus and piagnesium) 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

Pike all medicines, this medicine can cause side effects, although not (everybody gets them. The most common ones are usually mild and will

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

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

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with certain specific blood tests).

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

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| the mouth orjaw, discharge, 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 while being treated with Zoledronic Acid Concentrate or after stopping treatment.

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I 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 afteryou have received zoledronic acid.

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I and throat.

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

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arrhythmia; secondary to hypocalcaemia). determined by yourdoctorwith certain urine tests).

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

(secondary to hypocalcaemia).

ear infection. These could be signs of bone damage in the ear.

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

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

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

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I weakness, drowsiness, chills and bone, joint and/or muscle ache. In I most cases no specific treatment is required and the symptoms I    disappear after a short time (couple of hours ordays).

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appetite.

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

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C Chest pain.

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

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

•    Low counts ofwhite blood cells and blood platelets.

•    Low level of magnesium and potassium in the blood. Your doctor will

monitorthis 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.    I

•    Difficulty in breathing with wheezing or coughing.    I

• Urticaria.    |

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-terml treatment for osteoporosis may occur rarely. Contact your doctor ifyoj experience pain, weakness or discomfort in your thigh, hip orgroin 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.

•    Painfulrednessand/orswellingoftheeye.    I

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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. Thisl includes any possible side effects not listed in this leaflet. You can also repor) side effects directly via the Yellow Card Scheme atj www.mhra.aov.uk/vellowcard.

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

5. Howto store Zoledronic Acid Concentrate

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

6. Contents of the pack and other information

What Zoledronic Acid Concentrate contains

• The active substance of ZoledronicAcid Concentrate is zoledronic acid.

•    The other ingredients are: mannitol, sodium citrate and water for injection.

What Zoledronic Acid Concentrate looks like and contents of the pack I

ZoledronicAcid Concentrate is supplied as a liquid concentrate in a vial. One| vialcontains4mgofzoledronicacid.

ZoledronicAcid Concentrate is supplied in packs containing 1,4,10 or 2^ vials.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Morningside Healthcare Ltd.

115 Narborough Road,

Leicester LE30PA, UK

Manufacturer

Morningside Pharmaceuticals Ltd.

5 Pavilion Way,

Castle Business Park,

Loughborough, LE115GW, UK

This leaflet was last revised in August 2016.

.Information forthe Healthcare Professional

Howto prepare and administer Zoledronic Acid Concentrate

To prepare an infusion solution containing 4 mg zoledronic acid, further dilute |he ZoledronicAcid Concentrate (5.0 ml) with 100 ml of calcium-free or other divalent cation-free infusion solution.

If a lower dose of ZoledronicAcid Concentrate 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 |jsed for dilution must be either 0.9% w/v sodium chloride or 5% w/v glucose solution.

Do not mix Zoledronic Acid Concentrate with calcium-containing or other divalent cation-containing solutions such as lactated Ringer's solution.

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Instructions for preparing reduced doses of ZoledronicAcid Concentrate: 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 clea) solution free from particles and discolouration should be used. Aseptic! techniques must be followed during the preparation of the infusion.    I

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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 when diluted with 100ml of 0.9% w/v sodium chloride solution or 5% w/v glucose solution. The refrigerated solution .sttauldiheD teequilikatfidtaraQmifimperaiurapriartiiadmiriisiraiiDQ__I

hhe 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 Concentrate 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 Concentrate.

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|Since no data are available on the compatibility of Zoledronic Acid poncentrate with other intravenously administered substances, Zoledronic Acid Concentrate must not be mixed with other medications/substances and should always be given through a separate infusion line.

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How to store Zoledronic Acid Concentrate

• Keep ZoledronicAcid Concentrate out of the sight and reach of children.

•    Do not use Zoledronic Acid Concentrate after the expiry date stated on the pack.

•    The unopened vial does not require any specific storage conditions.

•    The diluted ZoledronicAcid Concentrate infusion solution should be used immediately in orderto avoid microbial contamination.