Zolestad 4 mg/100 ml, oplossing voor infusie

1. What is and what it is used for

The active substance in Zolestad 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).

Follow carefully all instructions given to you by your doctor.

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

You should not be given Zolestad:

• if you are breast-feeding.
• if you are allergic (hypersensitive) to zoledronic acid, another bisphosphonate (the group of substances to which Zolestad 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 Zolestad:

• 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 Zolestad.

Patients aged 65 years and over

Zolestad 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

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

Other medicines and Zolestad

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), 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 Zolestad are unknown.
• Anti-angiogenic medicines (used to treat cancer), since the combination of these with Zolestad has been associated with reports of osteonecrosis of the jaw (ONJ).

Pregnancy and breast-feeding

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

You must not be given Zolestad 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.

Zolestad contains sodium citrate

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

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

− Zolestad 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 Zolestad 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 Zolestad is given

• If you are being treated for the prevention of bone complications due to bone metastases, you will be given one infusion of Zolestad 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 Zolestad.

How Zolestad is given

• Zolestad 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 Zolestad 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.

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.

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 more 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 more 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, 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.
• 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 (may affect more 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).

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

• Fainting due to low blood pressure.
• Severe bone, joint and/or muscle pain, occasionally incapacitating.
• 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.

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

<the national reporting system per country will be addressed at national phase>

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

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The expiry date refers to the last day of that month.
• The unopened vial does not require any special storage conditions.
• After first opening: 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. The refrigerated solution should then be equilibrated to room temperature prior to administration.
• Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Zolestad 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 Zolestad looks like and the contents of the pack

Zolestad solution for infusion is a clear, colourless solution, free from visible particles.

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

Zolestad 4mg/100ml solution for infusion is supplied as packs containing: 1 vial

4 vials

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

STADA Arzneimittel AG

Stadastr.2-18

61118 Bad Vilbel

Duitsland

Manufacturer:

Agila Specialties Polska Sp. Zo.o.

10, Daniszewska Str.

03-230 Warschau

Polen

Sanochemia Pharmazeutica AG

Landeggerstrasse 7

A - 2491 Neufeld an der Leitha

Oostenrijk

STADA Arzneimittel AG

Stadastr.2-18

61118 Bad Vilbel

Duitsland

Cell pharm GmbH Theodor-Heuss-Str. 52 61118 Bad Vilbel Duitsland

In het register ingeschreven onder

Zolestad 4 mg/100 ml, oplossing voor infusie RVG 112516

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

Nederland: Zolestad 4mg/100ml, oplossing voor infusie

Duitsland: Zolestad 4mg/100ml Infusionslösung

This leaflet was last approved in juli 2013

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The following information is intended for healthcare professionals only:

How to prepare and administer Zolestad

• Zolestad contains 4 mg of zoledronic acid in 100 ml of infusion solution for immediate use in patients with normal renal function.
• 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 must not be further diluted or mixed with other infusion solutions. It 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 Zolestad to ensure that they are adequately hydrated.
• Zolestad solution for infusion 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 Zolestad 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.

Table 1: Preparation of reduced doses of Zolestad 4 mg/100 ml solution for infusion

Baseline	Remove the	Replace with	Adjusted
creatinine	following	the	dose (mg
clearance	amount of	following	zoledronic
(ml/min)	Zolestad	volume of	acid in

	solution for	sterile	100 ml)
	infusion	sodium
	(ml)	chloride 9
		mg/ml
		(0,9%) or 5%
		glucose
		solution for
		injection
		(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.
• Since no data are available on the compatibility of zoledronic acid with other intravenously administered substances, Zolestad must not be mixed with other medications/substances and should always be given through a separate infusion line.

How to store Zolestad

• Keep Zolestad out of the reach and sight of children.
• Do not use Zolestad after the expiry date stated on the pack.
• This medicinal product does not require any special storage conditions.
• The diluted Zolestad infusion solution should be used immediately in order to avoid microbial contamination.