Zoledronic acid Tillomed: detailed information

Package leaflet: Information for the user

Zoledronic Acid Tillomed 4 mg/5 ml concentrate for solution for infusion

Generic medicine
Please read this leaflet carefully before you are given this medicine, as 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 Zoledronic Acid Tillomed is and what it is used for
What you need to know before using Zoledronic Acid Tillomed
How to use Zoledronic Acid Tillomed
Possible side effects
How to store Zoledronic Acid Tillomed
Contents of the pack and other information

1. What Acido Zoledronico Tillomed is and what it is used for

The active substance is zoledronic acid, which belongs to a group of substances called bisphosphonates.
Zoledronic acid works by binding to the 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, resulting in increased release of calcium from bone. This condition is known as tumour-induced hypercalcaemia (TIH).

2. What you should know before using Zoledronic Acid Tillomed

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

Zoledronic Acid Tillomed 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 Zoledronic Acid Tillomed 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 Zoledronic Acid Tillomed:

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

During treatment with Zoledronic Acid Tillomed, 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 problems in your mouth or teeth such as tooth loss, pain, swelling, or failure of sores 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 who do not receive 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.
In patients treated with Zoledronic Acid Tillomed, low levels of calcium in the blood (hypocalcemia) have been reported, 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 treated before starting the first dose of Zoledronic Acid Tillomed. You will be given adequate supplementation of calcium and vitamin D.

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

Children and adolescents
The use of Zoledronic Acid Tillomed is not recommended in adolescents and children under 18 years of age.

Other medicines and Zoledronic Acid Tillomed
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 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 bones) or any other medicine that may be harmful to the kidneys.
Aclasta (a medicine containing zoledronic acid 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 Zoledronic Acid Tillomed are unknown.
Anti-angiogenic medicines (used to treat cancer), as the combination with zoledronic acid has been associated with an increased risk of osteonecrosis of the jaw/mandible.

Pregnancy and breastfeeding
You must not be given Zoledronic Acid Tillomed if you are pregnant. If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor before receiving this medicine.

Driving and using machines
Drowsiness and somnolence have been reported very rarely with the use of Zoledronic Acid Tillomed.
Therefore, you should exercise caution when driving, operating machinery, or performing other activities requiring full attention.

Zoledronic Acid Tillomed contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e., it is essentially "sodium-free". If your doctor uses a saline solution to dilute zoledronic acid, the amount of sodium you receive may be higher.

3. How Acido Zoledronico Tillomed is used

Acido Zoledronico Tillomed must be administered only by healthcare professionals experienced 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.

Dose of Acido Zoledronico Tillomed

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.

Frequency of Acido Zoledronico Tillomed administration

If you are being treated to prevent bone complications caused by bone metastases, you will receive an infusion of Acido Zoledronico Tillomed every three to four weeks.
If you are being treated to reduce high levels of calcium in the blood, you will usually receive a single infusion of Acido Zoledronico Tillomed.

How Acido Zoledronico Tillomed is administered

Acido Zoledronico Tillomed 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 excessively elevated blood calcium levels may also be prescribed daily calcium and vitamin D supplements.
If you have been given more Acido Zoledronico Tillomed than you should have
If doses higher than those 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 be given an intravenous calcium supplement.
If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

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

Severe kidney damage (this will usually be detected 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 healing of sores inside the mouth or jaw, discharge, numbness or a sensation of
heaviness in the jaw or loss of a tooth. These may be signs of damage to the jaw (osteonecrosis). If you experience any of these symptoms during or after stopping treatment with Zoledronic Acid Tillomed, inform your doctor and dentist immediately.
Irregular heart rhythm (atrial fibrillation) has been observed in patients treated with zoledronic acid for postmenopausal osteoporosis. It is currently unknown whether zoledronic acid causes this irregular heart rhythm, but you must report to your doctor if you experience such symptoms 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 hypocalcemia).
A kidney function disorder called Fanconi syndrome (this will usually be 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 hypocalcemia).
Inform your doctor if you experience ear pain, ear discharge, and/or an ear infection. These could be signs of damage to the ear bone.
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 zoledronic acid, 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 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 after 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 (anemia).

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, 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 coughing.
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 treated for a long time 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 the tissue around the air sacs in the lungs).
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 experience 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 at the website
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zoledronic Acid Tillomed

Your doctor, pharmacist, and nurse know how to properly store Zoledronic Acid Tillomed
(see section 6).
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton/vial after EXP.
The expiry date refers to the last day of that month.
After dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8°C and at
room temperature (20–25°C).
From a microbiological standpoint, the diluted infusion solution should be used immediately. If not used
immediately, the 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. The solution stored in the refrigerator should then be brought to
room temperature before administration.

6. Package contents and other information

What Acido Zoledronico Tillomed contains

The active substance is zoledronic acid. One vial contains 4 mg of zoledronic acid, equivalent to 4.264 mg of monohydrate zoledronic acid. One ml of concentrate contains 0.8 mg of zoledronic acid as monohydrate, corresponding to 0.8 mg of (anhydrous) zoledronic acid.
The other components are: mannitol (E421), sodium citrate (E331), and water for injections.

Description of the appearance of Acido Zoledronico Tillomed and contents of the pack
Acido Zoledronico Tillomed is supplied as a liquid concentrate in a vial. One vial contains 4 mg of zoledronic acid.
Each pack contains the vial with the concentrate. Acido Zoledronico Tillomed is available in packs containing 1, 4 or 10 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Tillomed Italia S.r.l., Viale G. Richard 1, Tower A, 20143 Milan, Italy

Manufacturers
SGS Pharma Magyarorszag Kft.
Derkovits Gyula Utca 53,
Budapest XIX, 1193, Hungary
MIAS Pharma Limited
Suite 2, Stafford House, Strand Road
Portmarnock, Co. Dublin
Ireland
Tillomed Malta Limited,
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta

This medicinal product is authorised in the European Economic Area countries under the following names:
Germany Zoledronsäure Tillomed 4 mg/5 ml concentrate for solution for infusion
Spain Ácido zoledrónico Tillomed 4 mg/5 ml concentrado para solución para perfusión EFG
Italy Acido Zoledronico Tillomed
France Acide zoledronique Tillomed 4 mg/5 ml, solution à diluer pour perfusion

INFORMATION FOR HEALTHCARE PROFESSIONALS
The following information is intended exclusively for physicians or healthcare professionals (see section 3):

How to prepare and administer Acido Zoledronico Tillomed

To prepare an infusion solution containing 4 mg of zoledronic acid, further dilute Acido Zoledronico Tillomed concentrate (5 ml) with 100 ml of infusion solution free from calcium or other bivalent cations. If a reduced dose of Acido Zoledronico Tillomed is required, first withdraw the appropriate volume 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 solution of Acido Zoledronico Tillomed must not be mixed with solutions containing calcium or other bivalent cations, such as lactated Ringer's solution.

Instructions for preparing reduced-dose Acido Zoledronico Tillomed:
Withdraw the appropriate volume of liquid 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 preparation of the infusion.
After dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8°C and at room temperature (20–25°C).
From a microbiological standpoint, the diluted infusion solution should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C. The 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 must be assessed before and after administration of Acido Zoledronico Tillomed to ensure adequate hydration.
Since compatibility data with other intravenous medicinal products are not available, Acido Zoledronico Tillomed must not be mixed with other medicines and/or substances and must always be administered through a separate infusion line.

How to store Acido Zoledronico Tillomed

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