Ibandronic Acid Accord 2 mg concentrate for infusion solution

2. What you need to know before you are given Ibandronic Acid Accord

Do not receive Ibandronic Acid Accord:

• if you are allergic to ibandronic acid or any of the other ingredients of this medicine that are listed in section 6
• if you have or have had low levels of calcium in your blood

Do not receive this medicine if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before receiving Ibandronic Acid Accord.

Warnings and precautions:

A rare side effect has been reported called jawbone necrosis (death of bone tissue in the jaw) in the post-marketing period in patients who received ibandronic acid for cancer-related conditions. Jawbone necrosis can also occur after stopping treatment.

It is important to try to prevent the development of jawbone necrosis as it is a painful condition that can be difficult to treat. To reduce the risk of developing jawbone necrosis, there are some precautions you should take.

Before receiving treatment, talk to your doctor/nurse (healthcare professional) if:

• you have any dental problems or are planning to have any dental work done
• you do not receive regular dental check-ups or have not had a dental check-up for a long time
• you are a smoker (as this can increase the risk of dental problems)
• you have been treated with a bisphosphonate before (used to treat or prevent bone disorders)
• you are taking medicines called corticosteroids (such as prednisolone or dexamethasone)
• you have cancer.

Your doctor may ask you to have a dental check-up before starting treatment with ibandronic acid.

While being treated, you should maintain good oral hygiene (including regular tooth brushing) and have regular dental check-ups. If you wear dentures, you should make sure they fit properly. If you are having dental treatment or are going to have dental surgery (e.g. tooth extraction), tell your doctor about the dental treatment and inform your dentist that you are being treated with ibandronic acid.

Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth such as a loose tooth, pain, or swelling, ulcers that do not heal, or discharge, as these could be signs of jawbone necrosis.

Atypical fractures of long bones, such as the forearm (ulna) and shin (tibia), have also been reported in patients receiving long-term treatment with ibandronate. These fractures occur after minimal or no trauma and some patients experience pain in the area of the fracture before a complete fracture occurs.

Talk to your doctor, pharmacist, or nurse before taking Ibandronic Acid Accord

• if you are allergic to any other bisphosphonate
• if you have high or low levels of vitamin D, calcium, or any other mineral
• if you have kidney problems
• if you have heart problems and your doctor has recommended that you limit your daily fluid intake

• fluids.

Severe, sometimes life-threatening allergic reactions have been reported in patients treated with intravenous ibandronic acid.

You should tell your doctor or nurse immediately if you experience any of the following symptoms, such as shortness of breath/difficulty breathing, feeling of tightness in the throat, swelling of the tongue, dizziness, feeling of loss of consciousness, redness or swelling of the face, body rash, nausea, and vomiting (see section 4).

Children and adolescents

Ibandronic Acid Accord should not be used in children and adolescents under 18 years of age.

Using Ibandronic Acid Accord with other medicines

Tell your doctor or pharmacist if you are using or have recently used or might use other medicines. This is because Ibandronic Acid Accord may affect the way other medicines work. Other medicines may also affect the way Ibandronic Acid Accord works.

In particular, tell your doctor or pharmacistif you are receiving a type of injected antibiotic called an "aminoglycoside" such as gentamicin. This is because both aminoglycosides and Ibandronic Acid Accord can lower the amount of calcium in your blood.

Pregnancy and breastfeeding

Do not receive Ibandronic Acid Accord if you are pregnant, planning to become pregnant, or if you are breastfeeding. Talk to your doctor or pharmacist before using this medicine.

Driving and using machines

You can drive and use machines as it is expected that Ibandronic Acid Accord will not have a significant effect on your ability to drive and use machines. However, talk to your doctor first if you want to drive, use machines, or tools.

The medicine contains less than 1 mmol of sodium (23 mg) per vial, which is essentially "sodium-free".

3. How Ibandronic Acid Accord is given

Administration of this medicine

• Ibandronic Acid Accord is normally given by a doctor or other healthcare professional with experience in cancer treatment
• it is given by infusion into a vein

Your doctor may do regular blood tests while you are receiving Ibandronic Acid Accord. This is to check that you are receiving the correct amount of this medicine.

Amount to be given

Your doctor will decide the amount of Ibandronic Acid Accord that you will be given, depending on your condition.

If you have breast cancer that has spread to the bones, the recommended dose is 6 mg every 3-4 weeks, given by infusion into a vein over at least 15 minutes. If you have high levels of calcium in your blood due to a tumor, the recommended dose is a single dose of 2 mg or 4 mg, depending on the severity of your condition. The medicine should be given by infusion into a vein over 2 hours. A further dose may be considered if you do not respond or if your condition returns.

If you have kidney problems, your doctor will adjust the dose and infusion time.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

Tell your doctor or nurse immediately if you notice any of the following serious side effects, as you may need urgent medical treatment:

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

• persistent eye pain and inflammation
• new pain, weakness, or discomfort in the thigh, hip, or groin. These can be early symptoms of a possible unusual fracture of the thigh bone.

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

• pain or discomfort in the mouth or jaw. These can be early symptoms of serious jaw problems [necrosis (death of bone tissue) of the jawbone].
• tell your doctor if you have ear pain, discharge from the ear, and/or ear infection. These could be signs of bone damage in the ear.
• itching, swelling of the face, lips, tongue, and throat, with difficulty breathing. You may be having a severe allergic reaction that can be life-threatening (see section 2)
• severe skin reactions

Frequency not known(cannot be estimated from the available data)

• asthma attack

Other possible side effects

Common(affects more than 1 in 10 people)

• flu-like symptoms, including fever, chills, and flushing, feeling of discomfort, fatigue, bone, muscle, and joint pain. These symptoms usually disappear within a couple of hours or days. Talk to your nurse or doctor if any effect becomes troublesome or lasts more than a couple of days
• increased body temperature
• stomach pain, indigestion, vomiting, or diarrhea (intestinal losses)
• decreased levels of calcium or phosphorus in the blood
• abnormal results from blood tests such as Gamma GT or creatinine
• a heart problem called "bundle branch block"
• muscle or bone pain
• headache, feeling of dizziness or weakness
• thirst, sore throat, changes in taste
• swelling of the legs or feet
• joint pain, arthritis, or other joint problems
• parathyroid gland problems
• bruising
• infections
• a problem in your eyes called cataracts
• skin changes
• dental changes

Uncommon(affects less than 1 in 100 people)

• shaking or shivering
• excessive lowering of body temperature (hypothermia)
• a condition that affects the blood vessels in the brain called "cerebrovascular disorder" (stroke or cerebral hemorrhage)
• cerebrovascular disorder
• cardiovascular problems (including palpitations, heart attack, hypertension, varicose veins)
• blood cell disorders ("anemia")
• increased levels of alkaline phosphatase in the blood
• fluid accumulation and swelling ("lymphedema")
• fluid in the lungs
• stomach problems such as "gastroenteritis" or "gastritis"
• gallstones
• urination problems (urinary retention), cystitis (inflammation of the bladder)
• migraine
• nerve pain, nerve root injury
• deafness
• increased sensitivity to sound, taste, touch, or changes in smell
• difficulty swallowing
• mouth ulcers, swollen lips ("cheilitis"), oral thrush
• tingling or itching around the mouth
• pelvic pain, discharge, itching, or vaginal pain
• skin growth called "benign skin neoplasm"
• memory loss
• sleep disturbances, anxiety, mood changes, or emotional instability
• skin rash
• hair loss
• pain or injury at the injection site
• weight loss
• kidney cyst (fluid-filled sac in the kidney)

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are 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 Ibandronic Acid Accord

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 label. The expiry date is the last day of the month stated.

This medicine does not require any special storage conditions.

After dilution

the chemical and physical stability of the use dilution in sodium chloride 0.9% or glucose 5% solution has been demonstrated for 36 hours at 25°C and between 2°C and 8°C.

From a microbiological point of view, the 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 would normally not be longer than 24 hours at 2-8°C, unless the dilution has been made in aseptic and controlled conditions.

Do not use this medicine if you notice that the solution is not clear or contains particles.

6. Container Contents and Additional Information

Composition of Ibandronic Acid Accord

• The active ingredient is ibandronic acid.

Ibandronic Acid Accord 2 mg concentrate for solution for infusion One vial with 2 ml of concentrate for solution for infusion contains 2 mg of ibandronic acid (as 2.25 mg of sodium ibandronate monohydrate).

Ibandronic Acid Accord 6 mg concentrate for solution for infusion

A vial with 6 ml of concentrate for solution for infusion contains 6 mg of ibandronic acid (as 6.75 mg of sodium ibandronate monohydrate).

• The other components are: sodium chloride, sodium acetate trihydrate, glacial acetic acid, water for injectable preparations

Appearance of Ibandronic Acid Accord and Container Contents

Ibandronic Acid Accord is a concentrate for solution for infusion (sterile concentrate). Colorless and transparent solution.

It is presented in glass vials (type I) with a rubber stopper and aluminum seals with a removable cap.

Ibandronic Acid Accord 2 mg concentrate for solution for infusion

Each vial contains 2 ml of concentrate. Each pack contains 1 vial.

Ibandronic Acid Accord 6 mg concentrate for solution for infusion

Each vial contains 6 ml of concentrate. It is supplied in packs containing 1, 5, or 10 vials. Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,

08039 Barcelona,

Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50, 95-200 Pabianice, Poland

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

Date of Last Revision of this Leaflet {MM/YYYY}

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

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The following information is intended only for healthcare professionals

Dosage: Prevention of Bone Events in Patients with Breast Cancer and Bone Metastases

The recommended dose for the prevention of bone events in patients with breast cancer and bone metastases is 6 mg by intravenous infusion every 3-4 weeks. The dose should be infused over at least 15 minutes.

Patients with renal impairment.

No dose adjustment is required for patients with mild renal impairment (CLcr ≥ 50 and <80 ml min). patients with moderate renal impairment (clcr ≥ 30 and < 50 min) or severe min), who also have breast cancer bone metastatic disease are being treated for the prevention of events, should follow following dosing recommendations:< p>

Creatinine Clearance (ml/min)	Dose	Volume 1 and Infusion Time 2
≥ 50 CLcr <80	6 mg (6 ml of concentrate for solution for infusion)	100 ml over 15 minutes
≥ 30 CLcr <50	4 mg (4 ml of concentrate for solution for infusion)	500 ml over 1 hour
<30	2 mg (2 ml of concentrate for solution for infusion)	500 ml over 1 hour

1 Sodium chloride 0.9% solution or glucose 5% solution

2 Administration every 3-4 weeks

A 15-minute infusion time has not been studied in cancer patients with a CLcr <50 ml min.< p>

Dosage: Treatment of Tumor-Induced Hypercalcemia

Ibandronic Acid Accord is administered in a hospital setting. The dose will be determined by the doctor, taking into account the following factors:

Before treatment with Ibandronic Acid Accord, the patient should be adequately rehydrated with 9 mg/ml of a 0.9% sodium chloride solution. Both the severity of hypercalcemia and the type of tumor should be taken into account. In most patients with severe hypercalcemia (albumin-corrected serum calcium* ≥ 3 mmol/l or ≥ 12 mg/dl), 4 mg is an adequate single dose. In patients with moderate hypercalcemia (albumin-corrected serum calcium <3 mmol l or < 12 mg dl), 2 is an effective dose. the maximum dose used in clinical trials was 6 mg, but this does not provide any additional benefit terms of efficacy.< p>

• Note: Albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected serum calcium (mmol/l)	=	serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8
Or
Albumin-corrected serum calcium (mg/dl)	=	serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)].

To convert the albumin-corrected serum calcium value from mmol/l to mg/dl, multiply by 4.

In most cases, an elevated serum calcium level can be reduced to normal levels within 7 days. The median time to relapse (new increase above 3 mmol/l of albumin-corrected serum calcium) was 18-19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with the 6 mg dose.

Method and Route of Administration

Ibandronic Acid Accord concentrate for solution for infusion should be administered as an intravenous infusion.

To do this, the contents of the vial should be used as follows:

• Prevention of bone events in patients with breast cancer and bone metastases - add to 100 ml of isotonic sodium chloride solution or 100 ml of 5% dextrose solution and infuse over at least 15 minutes. See the dosing section above for patients with renal impairment.

Treatment of tumor-induced hypercalcemia - add to 500 ml of isotonic sodium chloride solution or 500 ml of 5% dextrose solution and infuse over 2 hours.

Note:

To avoid possible incompatibilities, Ibandronic Acid Accord concentrate for solution for infusion should only be mixed with isotonic sodium chloride solution or 5% dextrose solution. It should not be mixed with solutions containing calcium.

Diluted solutions are for single use. Only transparent and particle-free solutions should be administered.

It is recommended that the product be used immediately after dilution (see point 5 of this leaflet: "Storage of Ibandronic Acid Accord").

Ibandronic Acid Accord concentrate for solution for infusion should be administered intravenously. Care should be taken not to administer Ibandronic Acid Accord concentrate for solution for infusion intra-arterially or by extravasation, as it may cause tissue damage.

Frequency of Administration

For the treatment of tumor-induced hypercalcemia, Ibandronic Acid Accord concentrate for solution for infusion is generally administered as a single infusion.

For the prevention of bone events in patients with breast cancer and bone metastases, Ibandronic Acid Accord infusions are repeated at 3-4 week intervals.

Duration of Treatment

A limited number of patients (50 patients) received a second infusion for hypercalcemia. In case of recurrent hypercalcemia or insufficient efficacy, the possibility of repeating treatment may be considered.

For patients with breast cancer and bone metastases, Ibandronic Acid Accord infusions should be administered every 3-4 weeks. In clinical trials, treatment was continued for up to 96 weeks.

Overdose:

There is currently no experience with acute overdose of Ibandronic Acid Accord concentrate for solution for infusion. Given that in preclinical studies at high doses, both the kidney and liver were found to be target organs for toxicity, renal and hepatic function should be monitored.

Clinically relevant hypocalcemia (very low serum calcium levels) should be corrected by intravenous administration of calcium gluconate.