Zometa: detailed information

Package leaflet: Information for the user

Zometa 4 mg powder and solvent for infusion solution

zoledronic acid
Please read 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 questions, ask your doctor, pharmacist, or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

What Zometa is and what it is used for
What you need to know before you are given Zometa
How Zometa is used
Possible side effects
How to store Zometa
Contents of the pack and other information

1. What Zometa is and what it is used for

The active substance of Zometa is zoledronic acid, belonging to a group of substances called bisphosphonates. Zoledronic acid works by binding to bone and slowing down its rate of metabolism. It is used:

To prevent bone complications, such as fractures, in adult patients with bone metastases (spread of the tumor from the primary tumor site to the bones).
To reduce the amount of calcium in the blood in adult patients in whom it is too high due to the presence of a tumor. Tumors can accelerate normal bone metabolism, resulting in increased release of calcium from bone. This condition is known as tumor-induced hypercalcemia (TIH).

2. What you should know before being given Zometa

Carefully follow all instructions provided to you by your doctor.
Before starting treatment with Zometa, your doctor will perform blood tests and will monitor your
response to treatment at regular intervals.
Zometa must not be given to you:

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

Warnings and precautions
Talk to your doctor before being given Zometa:

if you have or have had kidney problems.
if you have or have had pain, swelling or numbness in the jaw or a sensation of heaviness in the jaw, or tooth loss. Your doctor may recommend that you undergo a dental examination before starting treatment with Zometa.
if you are currently undergoing dental treatments or need dental surgery, inform your dentist that you are being treated with Zometa and inform your doctor about your dental treatments.

During treatment with Zometa, you must maintain good oral hygiene (including regular tooth cleaning) and have routine dental check-ups.
Immediately inform your doctor and dentist if you experience any mouth or dental problems such as tooth loss, pain, swelling, failure of wounds to heal, or discharge, as these may be signs of a condition called osteonecrosis of the jaw.
Patients receiving chemotherapy and/or radiotherapy, those taking steroids, those undergoing dental surgery, those not receiving routine dental care, those with gum disease, smokers, or those previously treated with bisphosphonates (used to treat or prevent bone disorders) have a higher risk of developing osteonecrosis of the jaw.
Low levels of calcium in the blood (hypocalcemia) have been reported in patients treated with Zometa, which may sometimes cause muscle cramps, dry skin, or a burning sensation. Cases of irregular heartbeat (cardiac arrhythmia), seizures, and muscle spasms or contractions (tetany) secondary to severe hypocalcemia have also been reported. In some cases, hypocalcemia may be life-threatening. If any of these conditions apply to you, inform your doctor immediately. If you have pre-existing hypocalcemia, it must be corrected before the first dose of Zometa is administered. You will be given an adequate supplement of calcium and vitamin D.
Patients aged 65 years and older
Zometa can be administered to patients aged 65 years and older. There is no evidence that additional precautions are required.
Children and adolescents
Zometa is not recommended for use in adolescents and children under 18 years of age.
Other medicines and Zometa
Inform your doctor if you are taking, have recently taken, or might take any other medicines. It is particularly important that you inform your doctor if you are also taking:

Aminoglycosides (medicines used to treat serious infections), calcitonin (a medicine used to treat postmenopausal osteoporosis and hypercalcemia), loop diuretics (a type of medicine used to treat high blood pressure or edema), or other medicines that lower calcium levels, as combining these with bisphosphonates may cause a marked decrease in blood calcium concentration.
Thalidomide (a medicine used to treat certain types of blood cancers involving the bones) or any other medicine that may be harmful to the kidneys.
Aclasta (a medicine that also contains zoledronic acid and is used to treat osteoporosis and other non-oncological bone disorders), or any other bisphosphonate, since the combined effects of these medicines when taken together with Zometa are unknown.
Anti-angiogenic medicines (used to treat cancer), as the combination of these with Zometa has been associated with an increased risk of jaw osteonecrosis.

Pregnancy and breastfeeding
Zometa must not be given to you if you are pregnant. Inform your doctor if you are pregnant or suspect you may be pregnant.
Zometa must not be given to you if you are breastfeeding.
Ask your doctor for advice before taking any medicine during pregnancy or while breastfeeding.
Driving and using machines
Drowsiness and somnolence have been reported very rarely with the use of Zometa. Therefore, you should exercise extreme caution when driving, operating machinery, or performing other activities requiring full attention.
Zometa contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially “sodium-free”. If your doctor uses a saline solution to dilute Zometa, the amount of sodium received would be higher.

3. How Zometa is used

Zometa must only be administered by healthcare professionals trained in the use of intravenous bisphosphonates, i.e. through a vein.
Your doctor will recommend that you drink sufficient water before each treatment to help prevent dehydration.
Carefully follow all other instructions given by your doctor, pharmacist, or nurse.

How much Zometa is administered

The usual single dose is 4 mg.
If you have kidney problems, your doctor will administer a reduced dose based on the severity of your renal impairment.

How often Zometa is administered

If you are being treated to prevent bone complications due to bone metastases, you will receive a Zometa infusion every three or four weeks.
If you are being treated to reduce the level of calcium in the blood, you will usually receive a single Zometa infusion.

How Zometa is administered

Zometa is administered intravenously as an infusion lasting at least 15 minutes and must be given as a single intravenous solution via a separate infusion line.

Patients with not excessively high blood calcium levels may also be prescribed daily calcium and vitamin D supplements.
If you have been given more Zometa than you should have received
If doses higher than recommended have been administered, you must be closely monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of calcium, phosphate, and magnesium) and/or changes in renal function, including severe kidney impairment. If calcium levels become too low, you may require intravenous calcium supplementation.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The most common ones are usually mild and may disappear in a short time.
Tell your doctor if any of the following serious side effects occur:

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

Severe kidney failure (this will be confirmed by your doctor through specific blood tests).
Low levels of calcium in the blood.

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

Pain in the mouth, teeth and/or jaw, swelling or failure of wounds to heal inside the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or tooth loss. These may be signs of jaw damage (osteonecrosis). If you experience such symptoms during or after stopping treatment with Zometa, inform your doctor and dentist immediately.
In patients treated with zoledronic acid for postmenopausal osteoporosis, an irregular heart rhythm (atrial fibrillation) has been observed. It is currently unknown whether zoledronic acid causes this irregular heart rhythm, but you should report such symptoms to your doctor if they occur after receiving zoledronic acid.
Severe allergic reactions: difficulty breathing, swelling, especially of the face and throat.

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

As a consequence of low calcium levels: irregular heartbeat (cardiac arrhythmia secondary to hypocalcemia).
A kidney function disorder called Fanconi syndrome (usually diagnosed by your doctor through urine tests).

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

As a consequence of low calcium levels: seizures, numbness, and tetany (secondary to hypocalcemia).
Contact your doctor if you experience ear pain, ear discharge, and/or ear infection. These episodes could be signs of bone damage in the ear.
Osteonecrosis has very rarely occurred in other bones besides the jaw, particularly in the hip or thigh. If you experience symptoms such as onset or worsening of pain, or pain or stiffness during or after stopping treatment with Zometa, inform your doctor immediately.
Not known: frequency cannot be estimated from the available data
Inflammation of the kidney (tubulointerstitial nephritis): signs and symptoms may include reduced urine volume, blood in the urine, nausea, and a general feeling of being unwell.

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

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

Low levels of phosphate in the blood.

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

Headache and a flu-like syndrome with fever, fatigue, weakness, drowsiness, chills, and bone, joint, and/or muscle pain. In most cases, no specific treatment is needed and symptoms disappear within a short time (a few hours or days).
Gastrointestinal reactions such as nausea and vomiting, as well as loss of appetite.
Conjunctivitis.
Low levels of red blood cells in the blood (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, tremor, tingling or numbness in the hands or feet, diarrhoea, constipation, abdominal pain, dry mouth.
Low levels of white blood cells and platelets in the blood.
Low levels of magnesium and potassium in the blood. Your doctor will monitor these and take necessary measures.
Weight gain.
Increased sweating.
Drowsiness.
Blurred vision, eye lesions, light sensitivity.
Sudden chills with fainting, weakness, or collapse.
Breathing difficulties with wheezing or cough.
Hives.

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

Slow heart rate.
Confusion.
Rarely, an unusual fracture of the femur may occur, particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness, or discomfort in the thigh, hip, or groin, as this may be an early sign of a possible femur fracture.
Interstitial lung disease (inflammation of the lung tissue).
Flu-like symptoms including arthritis and joint swelling.
Painful redness and/or swelling of the eyes.

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 disabling.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the national reporting system listed in Annex V.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Zometa

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

6. Package contents and other information

What Zometa contains

The active substance in Zometa is zoledronic acid. One vial contains 4 mg of zoledronic acid, equivalent to 4.264 mg of zoledronic acid monohydrate.
The other ingredients are mannitol and sodium citrate.

Description of the appearance of Zometa and contents of the pack
Zometa is supplied as a powder in a vial. One vial contains 4 mg of zoledronic
acid.
Each pack contains the powder vial with one 5 ml vial of water for injections to be used for dissolving the powder.
Zometa is available in single packs containing either 1 or 40 vials and 1 or 4 vials of solvent, and in multiple packs containing 10 (10 x 1+1) vials and solvent vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Phoenix Labs Unlimited Company
Suite 12, Bunkilla Plaza
Bracetown Business Park
Clonee, County Meath
Ireland
Manufacturer
Novartis Pharma GmbH
Roonstrasse 25
D-90429 Nuremberg
Germany
For further information about this medicinal product, please contact the Marketing Authorisation Holder directly or, if available, the local representative:
BE, BG, CZ, DK, DE, EE, IE, EL
HR, IT, CY, LV, LT, LU, HU, Arriani Pharmaceuticals SA
MT, NL, AT, PL, PT, RO, SI, Lavriou Avenue 85
SK, FI, SE and UK(NI) 190 02 Paiania Attica
Phoenix Labs Unlimited Company Greece
Suite 12, Bunkilla Plaza Tel: +30 210 6683000
Bracetown Business Park
Clonee, County Meath
Ireland
Email: [email protected]
Tel: +353 1 468 8900
ES FR
EUROMED PHARMA SPAIN S.L Exploitant de l’autorisation de mise sur le marché :
C/Eduard Maristany, 430-432 EURODEP PHARMA
08919 Badalona (Barcelona) 10 RUE ANTOINE DE SAINT EXUPERY
Spain ZAC DU PARC DE COMPANS
Tel: + 34 932 684 208 77290 MITRY MORY
Fax: + 34 933 150 469 [email protected]
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu .
INFORMATION FOR HEALTHCARE PROFESSIONALS
How to prepare and administer Zometa

To prepare an infusion solution containing 4 mg of zoledronic acid, add, under sterile conditions, 5 ml of water for injections, using the dedicated vial provided in the product pack, to the vial containing Zometa powder. Gently shake the vial to dissolve the powder.
Further dilute the reconstituted Zometa solution (5 ml) with 100 ml of infusion solution free of calcium or other bivalent cations. If a reduced dose of Zometa is required, first withdraw the appropriate volume of reconstituted solution (4 mg/5 ml) as indicated below, then further dilute it in 100 ml of infusion solution. To avoid potential incompatibilities, the infusion solution used for dilution must be either 0.9% w/v sodium chloride solution or 5% w/v glucose solution.

The reconstituted Zometa solution must not be mixed with solutions containing calcium or other bivalent cations, such as lactated Ringer's solution.
Instructions for preparing reduced doses of Zometa:
Withdraw the appropriate volume of reconstituted solution (4 mg/5 ml) as follows:

4.4 ml for the 3.5 mg dose
4.1 ml for the 3.3 mg dose
3.8 ml for the 3.0 mg dose
For single use only. Any unused solution should be discarded. Only use a clear, particle-free, colourless solution. Aseptic techniques must be followed during the preparation of the infusion.
From a microbiological standpoint, the reconstituted and diluted infusion solution should be used immediately after first opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C - 8°C. Refrigerated solution must be brought to room temperature before administration.
The solution containing zoledronic acid must be administered as a single infusion lasting 15 minutes via a separate infusion line. The hydration status of patients should be assessed before and after administration of Zometa to ensure adequate hydration.
Studies performed with infusion lines made of polyvinyl chloride, polyethylene and polypropylene have shown no incompatibility with Zometa.
Since compatibility data with other intravenously administered substances are not available, Zometa must not be mixed with other medicinal products and/or substances and must always be administered via a separate infusion line.

How to store Zometa

Keep Zometa out of the sight and reach of children.
Do not use Zometa after the expiry date stated on the pack.
The unopened vial does not require any special storage conditions.
The diluted Zometa infusion solution should be used immediately to avoid microbiological contamination.

Package leaflet: information for the user

Zometa 4 mg/5 ml concentrate for solution for infusion

zoledronic acid
Please read 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 questions, ask your doctor, pharmacist or nurse.
If you get any side effects, including side effects not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Zometa is and what it is used for
What you need to know before you are given Zometa
How Zometa is used
Possible side effects
How to store Zometa
Contents of the pack and other information

1. What Zometa is and what it is used for

The active substance of Zometa is zoledronic acid, which belongs to a group of substances called
bisphosphonates. Zoledronic acid works by binding to bone and slowing down its rate of
metabolism. It is used:

To prevent bone complications, such as fractures, in adult patients with bone metastases (spread of the tumour from the primary tumour site to the bones).
To reduce the amount of calcium in the blood in adult patients in whom it is too high due to the presence of a tumour. Tumours can accelerate normal bone metabolism, leading to increased release of calcium from bone. This condition is known as tumour-induced hypercalcaemia (TIH).

2. What you need to know before you are given Zometa

Follow carefully all instructions given to you by your doctor.
Before starting treatment with Zometa, your doctor will perform blood tests and will monitor your response to treatment at regular intervals.

Zometa must not be given to you:

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

Warnings and precautions
Talk to your doctor before you are given Zometa:

if you have or have had kidney problems.
if you have or have had pain, swelling or numbness in the jaw/mandible or a feeling of heaviness in the jaw/mandible or tooth loss. Your doctor may recommend that you undergo a dental examination before starting treatment with Zometa.
if you are currently undergoing dental treatments or need to undergo dental surgery, inform your dentist that you are being treated with Zometa and inform your doctor about your dental treatments.

During treatment with Zometa, you must maintain good oral hygiene (including regular tooth cleaning) and should receive routine dental check-ups.
Immediately inform your doctor and dentist if you experience any problems with your mouth or teeth such as tooth loss, pain, swelling or failure of wounds to heal, or discharge, as these may be signs of a condition called osteonecrosis of the jaw/mandible.
Patients receiving chemotherapy and/or radiotherapy, those taking steroids, those undergoing dental surgery, those not receiving routine dental care, those with gum disease, smokers, or those previously treated with bisphosphonates (used to treat or prevent bone disorders) have a higher risk of developing osteonecrosis of the jaw/mandible.
Low levels of calcium in the blood (hypocalcaemia) have been reported in patients treated with Zometa, which may sometimes cause muscle cramps, dry skin, or a burning sensation. Cases of irregular heartbeat (cardiac arrhythmia), seizures, and muscle spasms or contractions (tetany) secondary to severe hypocalcaemia have also been reported. In some cases, hypocalcaemia may be life-threatening. If any of these conditions apply to you, inform your doctor immediately. If you have a pre-existing condition of hypocalcaemia, it must be treated before the first dose of Zometa is administered.
You will be given an adequate supplement of calcium and vitamin D.

Patients aged 65 years and older
Zometa can be administered to patients aged 65 years and older. There is no evidence that additional precautions are required.

Children and adolescents
Zometa is not recommended for use in adolescents and children under 18 years of age.

Other medicines and Zometa
Inform your doctor if you are taking, have recently taken, or might take any other medicines. It is particularly important that you inform your doctor if you are also taking:

Aminoglycosides (medicines used in the treatment of serious infections), calcitonin (a type of medicine used to treat postmenopausal osteoporosis and hypercalcaemia), loop diuretics (a type of medicine used to treat high blood pressure or oedema), or other medicines that lower calcium levels, as the combination of these substances with bisphosphonates may cause a marked decrease in blood calcium concentration.
Thalidomide (a medicine used to treat certain types of blood cancers involving the bones) or any other medicine that may be harmful to the kidneys.
Aclasta (a medicine which also contains zoledronic acid and is used to treat osteoporosis and other non-oncological bone disorders), or any other bisphosphonate, since the combined effects of these medicines when taken together with Zometa are unknown.
Anti-angiogenic medicines (used to treat cancer), as the combination of these with Zometa has been associated with an increased risk of osteonecrosis of the jaw.

Driving and use of machines
Drowsiness and somnolence have very rarely occurred with the use of Zometa. You should therefore exercise maximum caution when driving, operating machinery, or performing other activities requiring full attention.

Zometa contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially "sodium-free". If your doctor uses a saline solution to dilute Zometa, the amount of sodium received would be higher.

3. How Zometa is used

Zometa must be administered only by healthcare professionals trained in the use of intravenous bisphosphonates, i.e. through a vein.
Your doctor will recommend that you drink sufficient water before each treatment to help prevent dehydration.
Carefully follow all other instructions given by your doctor, pharmacist, or nurse.

How much Zometa is administered

The usual single dose is 4 mg.
If you have kidney problems, your doctor will administer a reduced dose based on the severity of your renal impairment.

How often Zometa is administered

If you are being treated to prevent bone complications caused by bone metastases, you will receive a Zometa infusion every three to four weeks.
If you are being treated to reduce the level of calcium in the blood, you will normally receive a single Zometa infusion.

How Zometa is administered

Zometa is administered intravenously as an infusion lasting at least 15 minutes and must be given as a single intravenous solution through a separate infusion line.

Patients with not too high blood calcium levels may also be prescribed daily calcium and vitamin D supplements.
If you have been given more Zometa than you should have received
If doses higher than recommended have been administered, you must be closely monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of calcium, phosphate, and magnesium) and/or changes in renal function, including severe kidney impairment. If calcium levels become too low, you may require intravenous calcium supplementation.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. The most common ones are usually mild and may disappear within a short time.
Tell your doctor if any of the following serious side effects occur:
Common (may affect up to 1 in 10 people):

Severe kidney failure (this will be confirmed by your doctor through specific blood tests).
Low levels of calcium in the blood.

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

Pain in the mouth, teeth and/or jaw, swelling or failure of mouth or jaw wounds to heal, discharge, numbness or heaviness in the jaw, or tooth loss. These may be signs of jaw bone damage (osteonecrosis). If you experience any of these symptoms during or after stopping treatment with Zometa, inform your doctor and dentist immediately.
In patients treated with zoledronic acid for postmenopausal osteoporosis, an irregular heart rhythm (atrial fibrillation) has been observed. It is currently unknown whether zoledronic acid causes this irregular heart rhythm, but you should report any such symptoms to your doctor after receiving zoledronic acid.
Severe allergic reactions: shortness of breath, swelling, particularly of the face and throat.

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

As a consequence of low calcium levels: irregular heartbeat (cardiac arrhythmia secondary to hypocalcaemia).
A kidney function disorder called Fanconi syndrome (usually diagnosed by your doctor through certain urine tests).

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

As a consequence of low calcium levels: seizures, numbness, and tetany (secondary to hypocalcaemia).
Contact your doctor if you experience ear pain, ear discharge, and/or ear infection. These episodes could be signs of bone damage in the ear.
Osteonecrosis has very rarely occurred in other bones besides the jaw, particularly in the hip or thigh. If you experience symptoms such as onset or worsening of pain, pain or stiffness during or after stopping treatment with Zometa, inform your doctor immediately.

Not known: frequency cannot be estimated from the available data

Inflammation of the kidney (tubulointerstitial nephritis): signs and symptoms may include decreased urine volume, blood in the urine, nausea, and a general feeling of being unwell.

Tell your doctor as soon as possible if any of the following side effects occur:
Very common (may affect more than 1 in 10 people):

Low levels of phosphates in the blood.

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

Headache and flu-like symptoms including fever, fatigue, weakness, drowsiness, chills, and bone, joint, and/or muscle pain. In most cases, no specific treatment is needed and symptoms disappear within a short time (a few hours or days).
Gastrointestinal reactions such as nausea and vomiting, as well as loss of appetite.
Conjunctivitis.
Low levels of red blood cells in the blood (anaemia).

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

Hypersensitivity reactions.
Low blood pressure.
Chest pain.
Infusion site reactions (redness and swelling), skin rash, itching.
High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste disturbances, tremor, tingling or numbness in the hands or feet, diarrhoea, constipation, abdominal pain,
dry mouth.
Low levels of white blood cells and platelets in the blood.
Low levels of magnesium and potassium in the blood. Your doctor will monitor these and take necessary measures.
Weight gain.
Increased sweating.
Drowsiness.
Blurred vision, eye lesions, light sensitivity.
Sudden chills with fainting, weakness, or collapse.
Breathing difficulties with wheezing or cough.
Hives.

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

Slow heart rate.
Confusion.
Rarely, an unusual fracture of the femur may occur, particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness, or discomfort in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.
Interstitial lung disease (inflammation of lung tissue).
Influenza-like symptoms including arthritis and joint swelling.
Painful redness and/or swelling of the eyes.

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 disabling.
Osteonecrosis has very rarely occurred in other bones besides the jaw, particularly in the hip or thigh. If you experience symptoms such as onset or worsening of pain, pain or stiffness during or after stopping treatment with Zometa, inform your doctor immediately.

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zometa

Your doctor, pharmacist or nurse will know how to store Zometa appropriately (see
section 6).

6. Package contents and other information

What Zometa contains

The active substance in Zometa is zoledronic acid. One vial contains 4 mg of zoledronic acid, equivalent to 4.264 mg of zoledronic acid monohydrate.
The other ingredients are mannitol, sodium citrate, and water for injections.

Description of the appearance of Zometa and package contents
Zometa is supplied as a concentrate solution in a vial. One vial contains 4 mg of zoledronic acid.
Each pack contains the concentrate vial. Zometa is available in single packs containing 1 or 4 vials and in multiple packs containing 10 (10x1) vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Phoenix Labs Unlimited Company
Suite 12, Bunkilla Plaza
Bracetown Business Park
Clonee, County Meath
Ireland
Manufacturer
Sanochemia Pharmazeutika GmbH
Landegger-Straße 7
2491 Neufeld an der Leitha
Burgenland
Austria
OR
LABORATORI FUNDACIÓ DAU
Pol. Ind. Consorci Zona Franca. c/ C, 12-14
08040 Barcelona
Spain
For further information about this medicinal product, please contact the Marketing Authorisation Holder directly or, if available, the local representative:
BE, BG, CZ, DK, DE, EE, IE, EL
HR, IT, CY, LV, LT, LU, HU, Arriani Pharmaceuticals SA
MT, NL, AT, PL, PT, RO, SI, Lavriou Avenue 85
SK, FI, SE and UK(NI) 190 02 Paiania Attica
Phoenix Labs Unlimited Company Greece
Suite 12, Bunkilla Plaza Tel: +30 210 6683000
Bracetown Business Park
Clonee, County Meath
Ireland
Email: [email protected]
Tel: +353 1 468 8900
ES FR
EUROMED PHARMA SPAIN S.L Marketing Authorisation Holder:
C/Eduard Maristany, 430-432 EURODEP PHARMA
08919 Badalona (Barcelona) 10 RUE ANTOINE DE SAINT EXUPERY
Spain ZAC DU PARC DE COMPANS
Tel: + 34 932 684 208 77290 MITRY MORY
Fax: + 34 933 150 469 [email protected]
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu

INFORMATION FOR HEALTHCARE PROFESSIONALS
How to prepare and administer Zometa

To prepare an infusion solution containing 4 mg of zoledronic acid, further dilute Zometa concentrate (5 ml) with 100 ml of infusion solution free from calcium or other bivalent cations. If a reduced dose of Zometa is required, withdraw the appropriate volume as indicated below and then further dilute it in 100 ml of infusion solution. To avoid potential incompatibilities, the infusion solution used for dilution must be either 0.9% w/v sodium chloride solution or 5% w/v glucose solution.

Zometa concentrate must not be mixed with solutions containing calcium or other
bivalent cations such as lactated Ringer's solution.
Instructions for preparing reduced doses of Zometa:
Withdraw the appropriate volume of concentrate as follows:

4.4 ml for the 3.5 mg dose
4.1 ml for the 3.3 mg dose
3.8 ml for the 3.0 mg dose
For single use only. Any unused solution must be discarded. Only use a clear, particle-free, colourless solution. Aseptic techniques must be followed during the preparation of the infusion.
From a microbiological standpoint, the diluted infusion solution should be used immediately. If not used immediately, storage during use and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C. Refrigerated solution must be brought to room temperature before administration.
The solution containing zoledronic acid should be administered as a single infusion lasting 15 minutes via a separate infusion line. The hydration status of patients should be assessed before and after administration of Zometa to ensure adequate hydration.
Compatibility studies using infusion lines made of polyvinyl chloride, polyethylene, and polypropylene have shown no incompatibility with Zometa.
Since compatibility data with other intravenous medicinal products are not available, Zometa must not be mixed with other medicinal products and/or substances and must always be administered through a separate infusion line.

How to store Zometa

Keep Zometa out of the sight and reach of children.
Do not use Zometa after the expiry date stated on the packaging.
The unopened vial does not require special storage conditions.
The diluted infusion solution of Zometa should be used immediately to avoid microbiological contamination.

Package leaflet: Information for the user

Zometa 4 mg/100 ml infusion solution

zoledronic acid
Please read 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 questions, ask your doctor, pharmacist or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Zometa is and what it is used for
What you need to know before you are given Zometa
How Zometa is used
Possible side effects
How to store Zometa
Contents of the pack and other information

1. What Zometa is and what it is used for

The active substance of Zometa is zoledronic acid, which belongs to a group of substances called bisphosphonates. Zoledronic acid works by binding to bone and slowing down its rate of metabolism. It is used:

To prevent bone complications, such as fractures, in adult patients with bone metastases (spread of the tumour from the primary tumour site to the bones).
To reduce the amount of calcium in the blood in adult patients in whom it is too high due to the presence of cancer. Tumours can accelerate normal bone metabolism, leading to increased release of calcium from bone. This condition is known as tumour-induced hypercalcaemia (TIH).

2. What you need to know before you are given Zometa

Follow carefully all instructions given to you by your doctor.
Before starting treatment with Zometa, your doctor will carry out blood tests and will monitor your
response to treatment at regular intervals.
Zometa must not be given to you:

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

Warnings and precautions
Talk to your doctor before you are given Zometa:

if you have or have had kidney problems.
if you have or have had pain, swelling or numbness in the jaw/mandible or a feeling of heaviness in the jaw/mandible or tooth loss. Your doctor may recommend that you undergo a dental examination before starting treatment with Zometa.
if you are currently undergoing dental treatments or need to have dental surgery, inform your dentist that you are being treated with Zometa and inform your doctor about your dental treatments.

During treatment with Zometa, you must maintain good oral hygiene (including regular tooth cleaning) and should receive routine dental check-ups.
Immediately inform your doctor and dentist if you experience any problems with your mouth or teeth such as tooth loss, pain, swelling or failure of wounds to heal, or discharge, as these may be signs of a condition called osteonecrosis of the jaw/mandible.
Patients receiving chemotherapy and/or radiotherapy, those taking steroids, those undergoing dental surgery, those not receiving routine dental care, those with gum disease, smokers, or those previously treated with bisphosphonates (used to treat or prevent bone disorders) have a higher risk of developing osteonecrosis of the jaw/mandible.
Low levels of calcium in the blood (hypocalcaemia) have been reported in patients treated with Zometa, which may sometimes cause muscle cramps, dry skin, or a burning sensation. Cases of irregular heartbeat (cardiac arrhythmia), seizures, and muscle spasms and contractions (tetany) secondary to severe hypocalcaemia have also been reported. In some cases, hypocalcaemia may be life-threatening. If any of these conditions apply to you, inform your doctor immediately. If you have pre-existing hypocalcaemia, it must be treated before the first dose of Zometa is administered.
You will be given an adequate supplement of calcium and vitamin D.
Patients aged 65 years and older
Zometa can be administered to patients aged 65 years and older. There is no evidence that additional precautions are required.
Children and adolescents
Zometa is not recommended for use in adolescents and children under 18 years of age.
Other medicines and Zometa
Inform your doctor if you are taking, have recently taken, or might take any other medicines. It is particularly important that you inform your doctor if you are also taking:

Aminoglycosides (medicines used to treat serious infections), calcitonin (a type of medicine used to treat postmenopausal osteoporosis and hypercalcaemia), loop diuretics (a type of medicine used to treat high blood pressure or oedema), or other medicines that lower calcium levels, as combining these with bisphosphonates may cause a marked decrease in blood calcium levels.
Thalidomide (a medicine used to treat certain types of blood cancers involving the bones) or any other medicine that may be harmful to the kidneys.
Aclasta (a medicine which also contains zoledronic acid and is used to treat osteoporosis and other non-oncological bone disorders), or any other bisphosphonate, since the combined effects of these medicines when taken together with Zometa are unknown.
Anti-angiogenic medicines (used to treat cancer), as their combination with Zometa has been associated with an increased risk of osteonecrosis of the jaw.

Pregnancy and breastfeeding
Zometa must not be given to you if you are pregnant. Inform your doctor if you are pregnant or suspect you may be pregnant.
Zometa must not be given to you if you are breastfeeding.
Ask your doctor for advice before taking any medicine during pregnancy or while breastfeeding.
Driving and using machines
Very rarely, drowsiness and numbness have been reported with the use of Zometa. Therefore, you should exercise extreme caution when driving, operating machinery, or performing other activities requiring full attention.
Zometa contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially “sodium-free”. If your doctor uses a saline solution to dilute Zometa, the amount of sodium received would be higher.

3. How Zometa is used

Zometa should only be administered by healthcare professionals trained in the use of intravenous bisphosphonates, that is, through a vein.
Your doctor will recommend that you drink sufficient water before each treatment to help prevent dehydration.
Carefully follow all other instructions given by your doctor, pharmacist, or nurse.

How much Zometa is administered

The usual single dose is 4 mg.
If you have kidney problems, your doctor will administer a reduced dose based on the severity of your renal impairment.

How often Zometa is administered

If you are being treated to prevent bone complications caused by bone metastases, you will receive a Zometa infusion every three to four weeks.
If you are being treated to reduce the amount of calcium in your blood, you will normally receive a single infusion of Zometa.

How Zometa is administered

Zometa is administered intravenously as an infusion lasting at least 15 minutes and must be given as a single intravenous solution through a separate infusion line.

Patients with blood calcium levels not too high will also be prescribed daily calcium and vitamin D supplements.
If you have been given more Zometa than you should have received
If doses higher than recommended have been administered, you must be closely monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g., abnormal levels of calcium, phosphate, and magnesium) and/or changes in renal function, including severe kidney impairment. If calcium levels drop too low, you may need to receive intravenous calcium supplementation.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The most common side effects are usually mild and may disappear in a short time.
Tell your doctor if any of the following serious side effects occur:
Common (may affect up to 1 in 10 people):

Severe kidney failure (this will be diagnosed by your doctor through specific blood tests).
Low levels of calcium in the blood.

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

Pain in the mouth, teeth and/or jaw, swelling or failure of sores in the mouth or jaw to heal, discharge, numbness or a feeling of heaviness in the jaw, or tooth loss. These may be signs of jaw damage (osteonecrosis). If you experience any of these symptoms during or after stopping treatment with Zometa, inform your doctor and dentist immediately.
In patients treated with zoledronic acid for postmenopausal osteoporosis, irregular heart rhythm (atrial fibrillation) has been observed. It is currently unknown whether zoledronic acid causes this irregular heart rhythm, but you should report such symptoms to your doctor if they occur after receiving zoledronic acid.
Severe allergic reactions: difficulty breathing, swelling, particularly of the face and throat.

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

As a consequence of low calcium levels: irregular heartbeat (cardiac arrhythmia secondary to hypocalcaemia).
A kidney function disorder called Fanconi syndrome (usually diagnosed by your doctor through specific urine tests).

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

As a consequence of low calcium levels: seizures, numbness, and tetany (secondary to hypocalcaemia).
Contact your doctor if you experience ear pain, ear discharge, and/or ear infection. These may be signs of bone damage in the ear.

Not known: frequency cannot be estimated from the available data

Inflammation of the kidney (tubulointerstitial nephritis): signs and symptoms may include reduced urine volume, blood in the urine, nausea, and general feeling of being unwell.

Tell your doctor as soon as possible if any of the following side effects occur:
Very common (may affect more than 1 in 10 people):

Low levels of phosphate in the blood.

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

Headache and a flu-like syndrome with fever, fatigue, weakness, drowsiness, chills, and bone, joint, and/or muscle pain. In most cases, no specific treatment is required and symptoms disappear within a short time (a few hours or days).
Gastrointestinal reactions such as nausea and vomiting, as well as loss of appetite.
Conjunctivitis.
Low levels of red blood cells in the blood (anaemia).

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

Hypersensitivity reactions.
Low blood pressure.
Chest pain.
Infusion site reactions (redness and swelling), skin rash, itching.
High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste disturbances, tremor, tingling or numbness in hands or feet, diarrhoea, constipation, abdominal pain, dry mouth.
Low levels of white blood cells and platelets in the blood.
Low levels of magnesium and potassium in the blood. Your doctor will monitor these and take necessary measures.
Weight gain.
Increased sweating.
Drowsiness.
Blurred vision, eye lesions, light sensitivity.
Sudden chills with fainting, weakness, or collapse.
Breathing difficulties with wheezing or cough.
Urticaria (hives).

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

Slow heart rate.
Confusion.
Rarely, an unusual femur fracture may occur, particularly in patients receiving long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness, or discomfort in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.
Interstitial lung disease (inflammation of lung tissue).
Influenza-like symptoms including arthritis and joint swelling.
Painful redness and/or swelling of the eyes.

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 disabling.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zometa

Your doctor, pharmacist or nurse knows how to store Zometa appropriately (see section 6).
After first opening, Zometa infusion solution should preferably be used immediately. If the solution is not used immediately, it must be stored in a refrigerator between 2°C – 8°C.

6. Package contents and other information

What Zometa contains

The active substance in Zometa is zoledronic acid. One vial contains 4 mg of zoledronic acid, equivalent to 4.264 mg of zoledronic acid monohydrate.
The other components are mannitol, sodium citrate, and water for injections.

Description of the appearance of Zometa and package contents
Zometa is supplied as a solution in a clear, colourless plastic vial. One vial contains 100 ml of solution.
Zometa is available in a single carton containing one vial or in multiple packs containing 4 or 5 cartons, each with one vial. Not all pack sizes may be marketed.

Marketing Authorisation Holder
Phoenix Labs Unlimited Company
Suite 12, Bunkilla Plaza
Bracetown Business Park
Clonee, County Meath
Ireland

Manufacturer
Sanochemia Pharmazeutika GmbH
Landegger-Straße 7
2491 Neufeld an der Leitha
Burgenland
Austria
OR
LABORATORI FUNDACIÓ DAU
Pol. Ind. Consorci Zona Franca. c/ C, 12-14
08040 Barcelona
Spain

For further information about this medicinal product, please contact the Marketing Authorisation Holder directly or, where available, the local representative:

BE, BG, CZ, DK, DE, EE, IE, HR, IT, CY, LV, LT, LU, HU, MT, NL, AT, PL, PT, RO, SI, SK, FI, SE and UK(NI)
Arriani Pharmaceuticals SA
Lavriou Avenue 85
190 02 Paiania Attica
Greece
Tel: +30 210 6683000
Phoenix Labs Unlimited Company
Suite 12, Bunkilla Plaza
Bracetown Business Park
Clonee, County Meath
Ireland
Email: [email protected]
Tel: +353 1 468 8900

ES, FR
EUROMED PHARMA SPAIN S.L
Exploitant de l’autorisation de mise sur le marché :
C/Eduard Maristany, 430-432
08919 Badalona (Barcelona)
Spain
Tel: +34 932 684 208
Fax: +34 933 150 469

EURODEP PHARMA
10 RUE ANTOINE DE SAINT EXUPERY
ZAC DU PARC DE COMPANS
77290 MITRY MORY
France
[email protected]

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu

INFORMATION FOR HEALTHCARE PROFESSIONALS
How to prepare and administer Zometa

Zometa 4 ml/100 ml infusion solution 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 must be discarded. Only use the solution if it is clear, free from visible particles, and colourless. Aseptic techniques must be followed during the preparation of the infusion.
From a microbiological standpoint, the infusion solution should be used immediately after first opening. If not used immediately, in-use storage times and conditions are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C, provided that dilution has been carried out under controlled and validated aseptic conditions. Refrigerated solution must be brought to room temperature before administration.
The solution containing zoledronic acid must not be further diluted or mixed with other infusion solutions. It must be administered as a single infusion over 15 minutes via a separate infusion line. The patient's hydration status must be assessed before and after administration of Zometa to ensure adequate hydration.
In patients with normal renal function, Zometa 4 mg/100 ml infusion solution should be administered immediately without any further preparation. In patients with mild to moderate renal impairment, a reduced dose must be prepared according to the instructions below.

To prepare reduced doses for patients with baseline CLcr ≤ 60 ml/min, refer to Table 1 below. Remove the volume of Zometa solution indicated from the vial and replace it 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 Zometa 4 mg/100 ml infusion solution

Baseline creatinine clearance (ml/min)	Remove the following amount of Zometa infusion solution (ml)	Replace with the following volume of sterile sodium chloride 9 mg/ml (0.9%) or glucose 5% solution for injection (ml)	Dose adjustment (mg of 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 were calculated assuming a target AUC of 0.66 (mg•hr/l) (CLcr = 75 ml/min). Administration of reduced doses in patients with renal impairment is expected to achieve an AUC value equal to that observed in patients with a creatinine clearance of 75 ml/min.

Studies conducted using various infusion lines made of polyvinyl chloride, polyethylene, and polypropylene have shown no incompatibility with Zometa.
Since compatibility data of Zometa with other intravenously administered substances are not available, Zometa must not be mixed with other medicinal products and/or substances and must always be administered through a separate infusion line.

Storage of Zometa

Keep Zometa out of the sight and reach of children.
Do not use Zometa after the expiry date stated on the packaging.
The unopened vial does not require any special storage conditions.
After opening the vial, the product should be used immediately to avoid microbiological contamination.