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

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

Follow carefully all instructions given by your doctor.

Your doctor will perform blood tests before you start treatment with Actavis Zoledronic Acid and will monitor your response to treatment at regular intervals.

You should not be given Actavis Zoledronic Acid

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

Warnings and precautions

Tell your doctor before you are given Actavis Zoledronic Acid:

• if you have or have had a kidney problem.
• if you have or have had pain, swelling or numbnessof the jaw, or a feeling of heaviness in the jaw or loss of a tooth. Your doctor may recommend that you undergo a dental examination before starting treatment with Actavis Zoledronic Acid.
• if you are receiving dental treatmentor are going to undergo dental surgery, inform your dentist that you are being treated with Actavis Zoledronic Acid and inform your doctor about your dental treatment.

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

Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth, such as tooth loss, pain or swelling, or difficulty healing of mouth ulcers or discharge, as these may be signs of a condition called osteonecrosis of the jaw.

Patient who are receiving chemotherapy and/or radiotherapy, who are taking corticosteroids, who are undergoing dental surgery, who do not receive routine dental care, who have gum disease, who are smokers or who have received prior treatment with a bisphosphonate (used to treat or prevent bone disorders) may be at greater risk of developing osteonecrosis of the jaw.

Reduced levels of calcium in the blood (hypocalcemia) have been described, sometimes manifesting as muscle cramps, dry skin and a burning sensation in patients who have received zoledronic acid. Irregular heart rhythm (cardiac arrhythmia), convulsions, spasms and involuntary muscle contractions (tetany) secondary to severe hypocalcemia have been described. In some cases, hypocalcemia can be life-threatening. If you have any of these conditions, inform your doctor immediately. If you have pre-existing hypocalcemia, it should be corrected before you receive the first dose of Actavis Zoledronic Acid. You will be given adequate calcium and vitamin D supplements.

Patient over 65 years

Actavis Zoledronic Acid can be given to people over 65 years. There is no evidence to suggest that special precautions are needed.

Children and adolescents

Actavis Zoledronic Acid is not recommended for use in adolescents and children under 18 years.

Other medicines and Actavis Zoledronic Acid

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

• Aminoglycosides (medicines used to treat severe 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, as the combination of these with bisphosphonates can significantly lower blood calcium levels.
• Talidomide (a medicine used to treat a type of blood cancer that affects the bone) or any other medicine that may harm the kidneys.
• Other medicines that contain zoledronic acid, used to treat osteoporosis and other non-cancerous bone diseases, or any other bisphosphonate, as the combined effects of these medicines given with Actavis Zoledronic Acid are unknown.
• Anti-angiogenic medicines (used to treat cancer), as the combination of these medicines with zoledronic acid has been associated with a higher risk of osteonecrosis of the jaw (ONJ).

Pregnancy and breast-feeding

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

You should not be given Actavis Zoledronic Acid if you are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Driving and using machines

In rare cases, somnolence and drowsiness have been observed with the use of zoledronic acid. You should therefore be careful when driving, using machines or performing other activities that require a lot of attention.

Actavis Zoledronic Acid contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. it is essentially “sodium-free”.

3. How Actavis Zoledronic Acid is given

• Actavis Zoledronic Acid should only be given by healthcare professionals experienced in the administration of bisphosphonates by intravenous infusion, i.e. administered into a vein.
• Your doctor will recommend that you drink a sufficient amount of water before each treatment to help prevent dehydration.
• Follow carefully all other instructions given by your doctor, pharmacist or nurse.

How much Actavis Zoledronic Acid 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 Actavis Zoledronic Acid is given

• If you are being treated to prevent bone complications due to bone metastases, you will be given an infusion of Actavis Zoledronic Acid every 3 to 4 weeks.
• If you are being treated to reduce the amount of calcium in the blood, you will usually only be given a single infusion of Actavis Zoledronic Acid.

How Actavis Zoledronic Acid is given

• Actavis Zoledronic Acid is given as a drip (infusion) into a vein that should last at least 15 minutes and should be given as a single intravenous infusion in a separate infusion line.

Patient who do not have high levels of calcium in the blood will also be prescribed calcium and vitamin D supplements to take every day.

If you are given more Actavis Zoledronic Acid than you should

If you have received doses higher than those recommended, you should be closely monitored by your doctor. This is because you may develop changes in the levels of certain substances in the blood (e.g. abnormal levels of calcium, phosphorus and magnesium) and/or changes in kidney function, including severe kidney failure. If the level of calcium becomes too low, you may need to be given a calcium supplement by infusion.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if you get any of the following side effects:

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

• Severe kidney impairment (usually determined by your doctor with a specific blood test).
• 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 difficulty healing of ulcers in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or tooth loss. These may be signs of damage to the jawbone (osteonecrosis). Tell your doctor and dentist immediately if you get these symptoms while being treated with Actavis Zoledronic Acid or after stopping treatment.
• Irregular heart rhythm (atrial fibrillation) has been observed in patients treated with zoledronic acid for postmenopausal osteoporosis. It is not known whether zoledronic acid causes this irregular heart rhythm, but you should tell your doctor if you get these symptoms after receiving zoledronic acid.
• Severe allergic reaction: 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 heart rhythm (cardiac arrhythmia; secondary to hypocalcemia).
• A condition affecting kidney function called Fanconi syndrome (your doctor will usually detect this with a urine test).

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

• As a consequence of low calcium levels: convulsions, numbness and tetany (secondary to hypocalcemia).
• Tell your doctor if you get ear pain, ear discharge or an ear infection. These could be symptoms of damage to the bones of the ear.
• Osteonecrosis has also been rarely observed in other bones, especially in the hip or thigh. Tell your doctor immediately if you get symptoms such as onset or worsening of pain, weakness or discomfort in the thigh, hip or groin, as these may be early signs of a possible fracture of the thigh.

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

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

• Low level of phosphates in the blood.

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

• Headache and flu-like symptoms that include fever, fatigue, weakness, drowsiness, chills and pain in bones, joints and/or muscles. In most cases, no specific treatment is required and the symptoms disappear after a short period (a few hours or days).
• Gastrointestinal reactions such as nausea and vomiting, as well as loss of appetite.
• Conjunctivitis.
• Low level 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, rash, itching.
• High blood pressure, difficulty breathing, dizziness, anxiety, sleep disorders, changes in taste, tremors, tingling or numbness of the hands or feet, diarrhea, constipation, abdominal pain, dry mouth.
• Decreased number of white blood cells and platelets.
• Low level of magnesium and potassium in the blood. Your doctor will monitor this and take any necessary measures.
• Weight gain.
• Increased sweating.
• Numbness.
• Blurred vision, tearing, sensitivity of the eyes to light.
• Sudden cooling with fainting, weakness or collapse.
• Difficulty breathing with wheezing or coughing.
• Hives.

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

• Decreased heart rate.
• Confusion.
• Atypical fractures of the thigh bone (femur) that can occur rarely, especially in patients on long-term treatment for osteoporosis. Tell your doctor if you notice pain, weakness or discomfort in the thigh, hip or groin, as these may be early signs of a possible fracture of the femur.
• Interstitial lung disease (inflammation of the tissue surrounding the air sacs in the lungs).
• Symptoms similar to flu, including arthritis and swelling of the joints.
• Painful redness of the eye and/or swelling.

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

• Fainting due to low blood pressure.
• Severe pain in bones, joints and/or muscles, 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 national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storing Actavis Zoledronic Acid

Your doctor, pharmacist or nurse knows how to store Actavis Zoledronic Acid properly.

6. Container contents and additional information

Composition of Zoledronic Acid Actavis

• The active ingredient is zoledronic acid. One vial contains 4 mg of zoledronic acid (as monohydrate)
• The other components are: mannitol, citrate, and water for injectable preparations.

Appearance of the product and container contents

Zoledronic Acid Actavis is supplied in a plastic vial as a clear and colorless concentrate for solution for infusion (sterile concentrate). One vial contains 5 ml of solution.

Zoledronic Acid Actavis is supplied in packs containing 1, 4, or 10 vials. Only certain pack sizes may be marketed.

Marketing authorization holder

Actavis Group PTC ehf.

Dalshraun 1

220 Hafnarfjörður

Iceland

Manufacturers

Actavis Italy S.p.A.

Via Pasteur 10

20014 Nerviano (MI)

Italy

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Date of last revision of this leaflet:{month/year}.

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website http://www.ema.europa.eu.

This information is intended only for healthcare professionals:

How to prepare and administer Zoledronic Acid Actavis

• To prepare the infusion solution containing 4 mg of Zoledronic Acid Actavis, Zoledronic Acid Actavis concentrate (5.0 ml) should be diluted with 100 ml of calcium-free infusion solution or other divalent cation-free infusion solution. If a lower dose of Zoledronic Acid Actavis is required, the appropriate volume should be withdrawn as indicated below and then diluted with 100 ml of infusion solution. To avoid potential incompatibilities, the infusion solution used for dilution should be 0.9% w/v sodium chloride or 5% w/v glucose solution.

Do not mix Zoledronic Acid Actavis concentrate with solutions containing calcium or other divalent cations, such as lactated Ringer's solution.

Instructions for preparing lower doses of Zoledronic Acid Actavis: Withdraw the appropriate volume of the liquid concentrate as indicated below:

• 4.4 ml for a dose of 3.5 mg
• 4.1 ml for a dose of 3.3 mg
• 3.8 ml for a dose of 3.0 mg

• For single use. Any unused portion of the solution should be discarded. Only clear solutions free of particles and discoloration should be used. Aseptic techniques should be used during the preparation of the infusion.

• Shelf-life after dilution: Chemical and physical stability has been demonstrated for 24 hours at 2 - 8°C and at 25°C after dilution in 100 ml of 0.9% w/v sodium chloride solution or in 100 ml of 5% w/v glucose solution. From a microbiological point of view, the diluted infusion solution should be used immediately. If not used immediately, the storage times and conditions are the responsibility of the user and should not normally exceed 24 hours at 2 - 8°C. If stored in a refrigerator, the solution should be allowed to reach room temperature before administration.

• The solution containing zoledronic acid is administered as a single intravenous infusion over 15 minutes in a separate infusion line. Before and after administration of Zoledronic Acid Actavis, the patient's hydration status should be assessed to ensure they are adequately hydrated.

• Since no data are available on the compatibility of Zoledronic Acid Actavis with other substances administered intravenously, Zoledronic Acid Actavis should not be mixed with other medicinal products/substances and should always be administered through a separate infusion line.

Storage of Zoledronic Acid Actavis

• Keep Zoledronic Acid Actavis out of the sight and reach of children.
• Do not use Zoledronic Acid Actavis after the expiry date stated on the vial and on the outer packaging after EXP.
• This medicinal product does not require any special storage conditions.
• For storage conditions of Zoledronic Acid Actavis after dilution, see "Shelf-life after dilution" above.