Zoledronic Acid Ennogen 4 mg / 5 ml Concentration for solution for infusion – patient leaflet, side effects, dosage

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

The active substance in Zoledronic Acid Ennogen is zoledronic acid monohydrate, which belongs to a group of substances called bisphosphonates. Zoledronic acid monohydrate 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).

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

Follow carefully all instructions given to you by your doctor. • blood tests

Your doctor will carry out before you start treatment with Zoledronic Acid Ennogen and will check your response to treatment at regular intervals.

Do not take Zoledronic Acid Ennogen:

• if you are breast-feeding.

• if you are allergic to zoledronic acid monohydrate, another

  bisphosphonate (the group of substances to which Zoledronic Acid Ennogen belongs), or 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 Ennogen: • kidney problem.

if you have or have had a

• pain, swelling or numbness

  if you have or have had of the jaw, a feeling of heaviness in the jaw or loosening of a tooth. Your doctor may recommend a dental examination before you start treatment with Zoledronic Acid Ennogen.

• dental treatment

  if you are having or are due to undergo dental surgery, tell your dentist that you are being treated with Zoledronic Acid Ennogen and inform your doctor about your dental treatment.

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

Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth such as loose teeth, pain or swelling, or non-healing of 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 Ennogen. Irregular

heart beat (cardiac 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 straight away. if you have pre-existing hypocalcaemia, it must be corrected before initiating the first dose of Zoledronic acid Ennogen. You will be given adequate calcium and vitamin D supplements.

Patients aged 65 years and over

Zoledronic Acid Ennogen 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

Zoledronic Acid Ennogen is not recommended for use in adolescents

and children below the age of 18 years.

Other medicines and Zoledronic Acid Ennogen

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),

  calcitonin (a type of medicine used to treat post-menopausal osteoporosis and hypercalcaemia), loop (a type of

  diuretics medicine to treat high blood pressure or oedema) or other calcium-lowering medicines, 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.

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

  used to treat osteoporosis and other non-cancer diseases of the bone), or any other bisphosphonate, since the combined effects of these medicines taken together with Zoledronic Acid Ennogen are unknown.

• Certain medicines to treat cancer (anti-angiogenic medicines),

  since the combination of these with Zoledronic Acid Ennogen has been associated with an increased risk of osteonecrosis of the jaw (ONJ).

Pregnancy, breast-feeding and fertility

You should not be given Zoledronic Acid Ennogen if you are pregnant. Tell your doctor if you are or think that you may be pregnant. You must not be given Zoledronic Acid Ennogen 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

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

Zoledronic Acid Ennogen contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial (5 ml), essentially “sodium-free”.

that is to say

If your doctor uses a solution of common salt to dilute Zoledronic Acid Ennogen, the dose of sodium received would be larger.

3. How Zoledronic Acid Ennogen is used

• Zoledronic Acid Ennogen 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 Zoledronic Acid Ennogen 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 Zoledronic Acid Ennogen is given

• If you are being treated for the prevention of bone complications

  due to bone metastases, you will be given one infusion of Zoledronic Acid Ennogen every three to four weeks.

  • If you are being treated to reduce the amount of calcium in your

    blood, you will normally only be given one infusion of Zoledronic Acid Ennogen.

How Zoledronic Acid Ennogen is given

• Zoledronic Acid Ennogen 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 Zoledronic Acid Ennogen than you should be

If you have received doses higher than those recommended, you will be carefully monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of calcium, phosphorous and magnesium) and/or changes in kidney function, including severe kidney impairment. If your level of calcium falls too low, you may have to be given supplemental calcium by infusion.

4. Possible side effects

Like all medicines, 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 immediately about any of the following serious side effects:

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 non-healing

  sores inside the mouth or jaw, 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 Ennogen or after stopping treatment.

• Irregular heart rhythm (atrial fibrillation) has been seen in

  patients receiving Zoledronic Acid Ennogen for postmenopausal osteoporosis. It is currently unclear whether Zoledronic Acid Ennogen causes this irregular heart rhythm but you should report it to your doctor if you experience such symptoms after you have received Zoledronic Acid Ennogen.

• shortness of breath, swelling mainly

  Severe allergic reaction:

  of the face and throat.

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

• As a consequence of low calcium values: irregular heart beat

  (cardiac arrhythmia; secondary to hypocalcaemia). • A kidney function disorder called Fanconi syndrome (will

  normally be determined by your doctor with certain urine tests).

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

• As a consequence of low calcium values: seizures, numbness

  and tetany (secondary to hypocalcaemia).

• T ear pain, discharge from the ear,

  alk to your doctor if you have and/or an . These could be signs of bone damage in

  ear infection

  the ear.

• Osteonecrosis has also very rarely been seen occurring with

  other bones than the jaw, especially the hip or thigh. Tell your doctor immediately if you experience symptoms, such as new onset or worsening of aches, pain or stiffness while being treated with Zoledronic acid Ennogen or after stopping treatment.

Not known: frequency cannot be estimated from the available data

• Inflammation of the kidney (tubulointerstitial nephritis): signs

  and symptoms may include decreased volume of the urine, blood in the urine, nausea, feeling generally unwell

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 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 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 up to 1 in 100 people):

• Hypersensitivity reactions.
• Low blood pressure.

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

How to prepare and administer Zoledronic Acid Ennogen

• To prepare an infusion solution containing 4 mg zoledronic acid,

  further dilute the Zoledronic Acid Ennogen concentrate (5.0 ml) with 100 ml of calcium-free or other divalent cation-free infusion solution. If a lower dose of Zoledronic Acid Ennogen 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 used for dilution must be either 0.9% w/v sodium chloride or 5% w/v glucose solution.

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

Instructions for preparing reduced doses of Zoledronic Acid Ennogen: 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 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 then be equilibrated to room temperature prior to administration.

The solution containing zoledronic acid monohydrate 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 Ennogen 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 Ennogen.

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

How to store Zoledronic Acid Ennogen

• Keep Zoledronic Acid Ennogen out of the sight and reach of children.
• Do not use Zoledronic Acid Ennogen after the expiry date stated on the pack.
• The unopened vial does not require any specific storage conditions.
• The diluted Zoledronic Acid Ennogen infusion solution should be used immediately in order to avoid microbial contamination.

Date of revision: September 2025.

• 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, trembling, tingling or numbness of the hands or feet, diarrhoea, constipation, abdominal pain, dry mouth.
• 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. • Weight increase.
• Increased sweating.
• Sleepiness.
• Blurred vision, 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 up to 1 in 1,000 people):

• Slow heart beat.
• 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).
• Flu-like symptoms including arthritis and joint swelling. • Painful redness and/or swelling of the eye.

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. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

1. 5. How to store Zoledronic Acid Ennogen

Keep 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'.

This medicinal product does not require any special storage conditions.

After dilution: 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 then be equilibrated to room temperature prior to administration.

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

6. Contents of the pack and other information

What Zoledronic Acid Ennogen contains

• The active substance of Zoledronic Acid Ennogen is zoledronic acid monohydrate. One vial contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. • The other ingredients are: mannitol, sodium citrate, water for injections.

What Zoledronic Acid Ennogen looks like and contents of the pack

Zoledronic Acid Ennogen is supplied as a liquid concentrate in a vial. It is a clear and colourless solution, practically free from visible particles. One vial contains 4 mg of zoledronic acid.

Each pack contains the vial with concentrate. Zoledronic Acid Ennogen is supplied as unit packs containing 1,4 or 10 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder

Ennogen IP Ltd,

Unit G4,

Riverside Industrial Estate,

Riverside Way, Dartford,

DA1 5BS, UK.

Manufacturer

Ennogen Healthcare International Ltd,

Unit G3,

Riverside Industrial Estate,

Riverside Way, Dartford,

DA1 5BS, United Kingdom.

This leaflet was last revised in September 2025

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

Zoledronic acid monohydrate

Package leaflet: Information for the user

ENV02