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4.2     Posology and method of administration

There is no evidence of a reduction in tolerability associated with an increase in exposure to ibandronate in patients with various degrees of renal impairment. However, for the prevention of skeletal events in patients with breast cancer and bone metastases the following recommendations should be followed:

For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see Section 5.2):

4.3     Contraindications

Hypocalcaemia (see section 4.4).

5.2     Pharmacokinetic properties

Pharmacokinetics in Special Populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2  mL/min), dose-adjusted mean AUC_0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC_0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C_max was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of a reduction in tolerability associated with an increase in exposure. However, an adjustment in the dose or infusion time is recommended in patients being treated for the prevention of skeletal events in patients with breast cancer and bone metastases (see section 4.2).For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (see section 4.2).

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4.2        Posology and method of administration

Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over 1 hourat least 15 minutes. For infusion, the contents of the vials(s) should only be added to 500100 ml isotonic sodium chloride solution or 500100 ml 5% glucose solution.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterising the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (Section 4.2) for recommendations on dosing and administration in this patient group.

Patients with renal impairment

There is no evidence of a reduction in tolerability associated with an increase in exposure to ibandronate in patients with various degrees of renal impairment. However, for the prevention of skeletal events in patients with breast cancer and bone metastases the following recommendations should be followed:

¹  Administration every 3 to 4 week

²  0.9% sodium chloride solution or 5% glucose solution

A 15 minute infusion time has not been studied in cancer patients with CLCr < 50 mL/min.

No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 ml/min.

Below 30 ml/min creatinine clearance, the dose for prevention of skeletal events in patients with breast cancer and bone metastases should be reduced to 2 mg every 3-4 weeks, infused over 1 hour.

5.1        Pharmacodynamic properties

In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of          < 50ml/min.

5.2        Pharmacokinetic properties

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC_0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C_max was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of a reduction in tolerability associated with an increase in exposure. However, an adjustment in the dose or infusion time is recommended in patients being treated for the prevention of skeletal events in patients with breast cancer and bone metastases (see section 4.2).

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr  ©ø 30 ml/min).  After intravenous administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with severe renal impairment.  However, there was no reduction in tolerability associated with the increase in exposure. Reduction of the intravenous dose to 2 mg infused over 1 hour every 3 - 4 weeks is recommended in patients with severe renal impairment (CLcr < 30 ml/min) (see section 4.2).

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Bondronat 2 mg

Date of First Authorisation: 25 June 1996

Date of Renewal: 12 September 2001Date of last renewal: 25 June 2006

Bondronat 6 mg

Date of first Authorisation: 25 June 1996

Date of last renewal: 25 June 2006

10.        DATE OF REVISION OF THE TEXT

June 2006March 2007

1.                                NAME OF THE MEDICINAL PRODUCT

Bondronat 2 mg/2ml

Bondronat 6 mg/6ml

Concentrate for solution for infusion

2.                                QUALITATIVE AND QUANTITATIVE COMPOSITION

Qualitative composition

Ibandronic acid, monosodium salt, monohydrate.

Quantitative composition

Bondronat 2 mg/2ml

One vial with 2 ml concentrate for solution for infusion (colourless, clear solution) contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate), corresponding to 2mg ibandronic acid.

1ml of solution contains 1.125mg ibandronic acid, monosodium salt, monohydrate, corresponding to 1mg ibandronic acid.

Bondronat 6 mg/6ml

One vial with 6 ml concentrate for solution for infusion (colourless, clear solution) contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate) corresponding to 6mg ibandronic acid.

1ml of solution contains 1.125mg ibandronic acid, monosodium salt, monohydrate, corresponding to 1mg ibandronic acid.

For excipients, see section 6.1.Excipients:

For a full list of excipients, see section 6.1.

3.                                PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless solution

4.2             Posology and method of administration

For single use only.  Only clear solution without particles should be used.

                         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 in mmol/l value to mg/dl, multiply by 4.

Safety and efficacy have not been established in patients less than 18 years old.

Bondronat is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.

4.3                   Contraindications

Bondronat concentrate for solution for infusion must not be used in known hHypersensitivity to the drug active substance or to any of the excipients.

Caution is indicated to be taken in patients with known hypersensitivity to other bisphosphonates.

Bondronat concentrate for solution for infusion should not be used in children because of lack of clinical experience.

4.4                   Special warnings and special precautions for use

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates.  Many of these patients were also receiving chemotherapy and corticosteroids.  Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible.  For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition.  For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.  Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

4.5                   Interaction with other medicinal products and other forms of interaction

Bondronat should not be mixed with calcium containing solutions.

No interaction was observed Wwhen co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

Interaction studies have only been performed in adults.

4.6                   Pregnancy and lactation

It is not known whether ibandronic acid is excreted in human milk.  Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration.  Consequently, caution should be exercised when prescribing Bondronat to breast-feeding women. Bondronat should not be used during lactation.

4.8                   Undesirable effects

The following events occurred rarely (one patient in the Bondronat group): gastroenteritis NOS, oral candidiasis, vaginitis, benign skin neoplasm, anaemia NOS, blood dyscrasia NOS, hypophosphataemia, sleep disorder, anxiety, affect lability, amnesia, paraesthesia circumoral, hyperaesthesia, hypertonia, nerve root lesion NOS, neuralgia NOS, migraine, cerebrovascular disorder NOS, parosmia, deafness, cardiovascular disorder NOS, palpitations, myocardial ischaemia, hypertension, varicose veins NOS, lymphoedema, lung oedema, stridor, gastritis NOS, cheilitis, dysphagia, mouth ulceration, cholelithiasis, rash NOS, alopecia, cystitis NOS, renal cyst NOS, urinary retention, pelvic pain NOS, injection site pain, blood alkaline phosphatase increase, weight decreased, injury, hypothermia.

Other adverse reactions reported at a lower frequency are as follows:

Uncommon:

Infection and infestation: cystitis, vaginitis, oral candidiasis

Neoplasms benign and malignant (including cysts and polyps): benign skin neoplasm

Blood and lymphatic system: anaemia, blood dyscrasia

Metabolism and nutrition disorders: hypophosphataemia

Psychiatric disorders: sleep disorder, anxiety, affection lability

Nervous system disorders: cerbrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia.

Ear and labyrinth disorders: deafness

Cardiac disorders: myocardial ischaemia, cardiovascular disorder, palpitations

Vascular disorders: hypertension, lymphoedema, varicose veins

Respiratory, thoracic and mediastinal disorders: lung oedema, stridor

Gastrointestinal disorders: gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis

Hepato-biliary disorders: cholelithiasis

Skin and subcutaneous tissue disorders: rash, alopecia

Renal and urinary disorders: urinary retention, renal cyst

Reproductive system and breast disorders: pelvic pain

General disorders and administration site conditions: hypothermia

Investigations: blood alkaline phosphatase increase, weight decrease

Injury, poisoning and procedural complications: injury, injection site pain

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates.  The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis.  Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis).  Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

5.3                   Preclinical safety data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.  As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.  in animal studies. Toxic effects in animals were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

6.2                   Incompatibilities

To avoid potential incompatibilities Bondronat concentrate for solution for infusion should only be diluted with isotonic sodium chloride solution or 5% dextroseglucose solution.

Bondronat should not be mixed with calcium containing solutions.

6.4                   Special precautions for storage

No special precautions for storage prior to reconstitution.

6.6                   Instructions for use and handling, andSpecial precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

For single use only.  Only clear solution without particles should be used.

Strict adherence to the intravenous route is recommended on parenteral administration of Bondronat concentrate for solution for infusion.

Use only isotonic saline or 5% dextrose solution as infusion solution.

Bondronat concentrate for solution for infusion should not be mixed with calcium containing solutions.

Unused solution should be discarded.

8.                     MARKETING AUTHORISATION NUMBER(S)

Bondronat 2 mg/2ml

EU/1/96/012/004          -     Packs of 1 vial

Bondronat 6 mg/6ml

EU/1/96/012/012       -    Packs of 5 vials

EU/1/96/012/011       -    Packs of 1 vial

EU/1/96/012/012       -    Packs of 5 vials

EU/1/96/012/013       -    Packs of 10 vials

9.                     DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Bondronat 2 mg/2ml

Date of First Authorisation: 25 June 1996

Date of Renewal: 12 September 2001

Bondronat 6 mg/6ml

Date of first Authorisation: 31 October 2003

 November 2003

10.                   DATE OF REVISION OF THE TEXT

November 2005April June 2006

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.eu.int/