Underlined text has been added, text with strike through deleted:

4.6      Fertility, Ppregnancy and lactation

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.

Breast-feeding

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. Bondronat should not be used during lactation.

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

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.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drug (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

Underlined text has been added

4.4      Special warnings and  precautions for use

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate

Osteonecrosis of the jaw (ONJ)

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.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.8      Undesirable effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ³1/10), common ( ³1/100 and <1/10), uncommon ( ³1/1,000 and <1/100), rare ( ³1/10,000 and <1/1,000), and very rare ( <1/10,000).

Treatment of tumour induced hypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Table 1          Adverse  Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia  after Treatment with Bondronat

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose.

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with  Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from postmarketing experience.

Table 2          Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

**See further information below.

†Identified in postmarketing experience.

Osteonecrosis of jaw

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).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

Underlined text has been added, text with strike through deleted:

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Bondronat 2 mg

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

Bondronat 6 mg

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

Excipients: Sodium (less than 1 mmol per dose).

For a full list of excipients, see section 6.1.

4.1     Therapeutic indications

Bondronat is indicated in adults for

-        Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

-        Treatment of tumour-induced hypercalcaemia with or without metastases.

4.2     Posology and method of administration

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

For intravenous administration.

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

Posology

Prevention of Sskeletal eEvents in pPatients with Bbreast Ccancer and bBone Mmetastases

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 at least 15 minutes. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 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 characterizing 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 (see sSection 4.2) for recommendations on dosing and administration in this patient group.

Treatment of Ttumour-Iinduced hHypercalcaemia

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ³3 mmol/l or ³12 mg/dl) 4 mg is an adequate single dosage. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

* Note albumin-corrected serum calcium concentrations are calculated as follows:

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

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

Patients with renal impairment

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):

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.

Elderly

No dose adjustment is required.

Children and adolescentsPaediatric population

The safety and efficacy of Bondronat is not recommended for patients in children and adolescents below age 18 years have not been established. due to insufficient data on safety and efficacy No data are available.

Method of administration

For intravenous administration.

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

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

4.3     Contraindications

Hypocalcaemia (see section 4.4).

-        Hypersensitivity to the active substance or to any of the excipients.

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

Bondronat should not be used in children.

-        Hypocalcaemia

4.4     Special warnings and  precautions for use

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.Patients with disturbances of bone and mineral metabolism

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Overhydration should be avoided in patients at risk of cardiac failure.

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

Osteonecrosis of the jaw (ONJ)

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.

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.5     Interaction with other medicinal products and other forms of interaction

Bondronat should not be mixed with calcium containing solutions

Interaction studies have only been performed in adults.

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

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both agentssubstances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, Bondronat has been administered concomitantly with commonly used anticancer agentsantineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

Interaction studies have only been performed in adults.

4.8     Undesirable effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ³1/10%), common ( ³1%/100 and <1/10%), uncommon ( ³0.1%/1,000 and <1%/100), rare ( ³0.01%1/10,000 and <0.1%/1,000), and very rare ( £0.01%<1/10,000).

Treatment of tTumour iInduced Hhypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a determination of causality).

Table 1       Number (percentage) of Patients Reporting     Adverse Reactions  Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia  after Treatment with Bondronat

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled. Events were recorded irrespective of a determination of causality.

Frequently, decreased**See further information below

Hypocalcaemia

Decreased renal calcium excretion ismay be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Other reactions reported at lower frequency are as follows:Influenza-like illness

Immune system disorders:

Very rare:         Hypersensitivity

Skin and subcutaneous tissue disorders:

Very rare:         Angioneurotic oedema

Respiratory, thoracic and mediastinal disorders:

Very rare:         Bronchospasm

Administration of other bisphosphonates has been associated with broncho-constriction in

acetylsalicylic acid-sensitive asthmatic patients.

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

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose. 

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with  Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, occurring commonly and more frequently in the active treatment group than in placeboand from postmarketing experience.

Table 2       Adverse Drug Reactions Occurring Commonly and Greater than Placebo in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

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, hyperaesthesia, 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

**See further information below.

†Identified in postmarketing experience.

Osteonecrosis of jaw

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).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with

ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was

discontinued.

5.1     Pharmacodynamic properties

Pharmaco-therapeutic group: Drugs for treatment of bone diseases, bBisphosphonate, ATC Code: M05B A 06

[…]

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

6.6     Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.

Underlined text has been added, text with strike through deleted:

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).

Underlined text has been added, text with strike though deleted:

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