Roche Products (Ireland) Ltd

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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.

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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. 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.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue Bondronat and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Since NSAIDS are associated with gastrointestinal irritation, caution should be taken during concomitant oral medication with Bondronat.

Osteonecrosis of the jaw

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.

Renal function

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.

Rare hereditary problems

Bondronat tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

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

4.8      Undesirable effects

The safety profile of Bondronat is derived from controlled clinical trials in the approved indication for the oral administration of Bondronat at the recommended dose, and from postmarketing experience.

In the pooled database from the 2 pivotal phase III trials (286 patients treated with Bondronat 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Bondronat was 27%.

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), very rare ( <1/10,000).

Table 1 lists adverse drug reactions

Table 1          Adverse Drug Reactions Reported for Oral Administration of Bondronat

**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

Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronic sodium monohydrate).

Excipients: Contains 92.75 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Bondronat tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

4.1     Therapeutic indications

Bondronat is indicated in adults for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

4.2     Posology and method of administration

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

For oral use.

Posology

The recommended dose is one 50 mg film-coated tablet daily.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

Patients with renal impairment

No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).

For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended (see section 5.2).

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly

No dose adjustment is necessary.

Paediatric population

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

Method of administration

For oral use.

Bondronat tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking Bondronat tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Plain water may be taken at any time during the course of Bondronat treatment.

-        The tablets should be swallowed whole with a full glass of plain water (180 to 240 ml) while the patient is standing or sitting in an upright position.

-        Patients should not lie down for 60 minutes after taking Bondronat.

-        Patients should not chew, suck or crush the tablet because of a potential for oropharyngeal ulceration.

-        Plain water is the only drink that should be taken with Bondronat. Please note that some mineral waters may have a higher concentration of calcium and therefore should not be used.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

Patients with renal impairment

No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).

For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended (see section 5.2).

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly

No dose adjustment is necessary.

Children and adolescents

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

4.3     Contraindications

-        Hypersensitivity to ibandronic acid or to any of the excipients

-        Hypocalcaemia

-        Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

-        Inability to stand or sit upright for at least 60 minutes

-     Hypocalcaemia

-     Hypersensitivity to ibandronic acid or to any of the excipients

See also section 4.4.

Bondronat should not be used in children.

4.4     Special warnings and precautions for use

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

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. 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.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue Bondronat and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Since NSAIDS are associated with gastrointestinal irritation, caution should be taken during concomitant oral medication with Bondronat.

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.

Bondronat tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Osteonecrosis of the jaw

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.

Renal function

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.

Rare hereditary problems

Bondronat tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

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

4.8     Undesirable effects

The safety profile of Bondronat is derived from controlled clinical trials in the approved indication and afterfor the oral administration of Bondronat at the recommended dose, and from postmarketing experience.

In the pooled database from the 2 pivotal phase III trials (286 patients treated with Bondronat 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Bondronat was 27%.

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), very rare ( £0.01%<1/10,000).

Table 1 lists common adverse drug reactions from the pooled phase III trials. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo-treated patients are excluded.

Table 1       Adverse ReactionsReported Commonly and Greater than PlaceboAdverse Drug Reactions Reported for Oral Administration of Bondronat

Adverse drug reactions occurring at a frequency <1%:

The following list provides

**See further information on adverse drug reactions reported in study MF 4414 and MF 4434 occurring more frequently with Bondronat 50 mg than with placebo:below

Uncommon:

Blood and Lymphatic System Disorders     anaemia

Nervous System Disorders                          paraesthesia, dysgeusia (taste perversion)

Gastrointestinal Disorders                           haemorrhage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth
 

Skin and Subcutaneous Tissue Disorders   pruritus

Renal and Urinary Disorders                       azotaemia (uraemia)

General Disorders:                                       chest pain, influenza-like illness, malaise, pain

Investigations                                                Blood parathyroid hormone increased

†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

No specialAny unused product or waste material should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.

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4.2     Posology and method of administration

-        Patients should not chew, or suck or crush the tablet because of a potential for oropharyngeal ulceration.

Patients with renal impairment

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.(CLcr ≥50 and <80 mL/min).

For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended (see section 5.2).

Below 30 ml/min creatinine clearance For patients with severe renal impairment (CLcr <30 mL/min), the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

4.3     Contraindications

-     Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

-     Inability to stand or sit upright for at least 60 minutes

-     Hypocalcaemia

-     Hypersensitivity to ibandronic acid or to any of the excipients.

See also section 4.4.

4.4     Special warnings and precautions for use

Oral bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore, patients should pay particular attention to the dosing instructions (see section 4.2).

Physicians should be alert to signs or symptoms signalling a possible oesophageal reaction during therapy, and patients should be instructed to discontinue Bondronat and seek medical attention if they develop symptoms of oesophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain, or heartburn.

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Bondronat and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

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

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinine clearance (CLcr).  No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr >30 ml/min).  Subjects with severe renal impairment (CLcr  £ 30 ml/min) receiving oral administration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function (CLcr ≥80 mL/min). Total clearance of ibandronic acid was reduced to 44 ml/min in the subjects with severe renal impairment compared with 129 mL/min in subjects with normal renal function. 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. No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).   Reduction of the oral dose to one 50 mg tablet once weekly is recommended in patients with severe renal impairment (CLcr <30 ml/min) (see Section 4.2). For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) an adjustment in the dose is recommended (see Section 4.2).

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

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:  25 June 1996

Date of last renewal: 25 June 2006

10.     DATE OF REVISION OF THE TEXT

June 2006March 2007

Text underlined and also in red has been added, text with strike though has been deleted:

2.                 QUALITATIVE AND QUANTITATIVE COMPOSITION

Qualitative composition

Ibandronic acid, monosodium salt, monohydrate.

Quantitative composition

Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronic sodium monohydrate).

Excipients:

For a full list of excipients, see section 6.1.

Bondronat tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency of glucose-galactose malabsorption.

3.                 PHARMACEUTICAL form

Film-coated tablets of oblong shape.

White to off-white film-coated tabletsin colour, of oblong shape engraved “L2/IT” on one side and “IT” on the other side.

4.2               Posology and method of administration

Adults:

The recommended dose is one 50 mg film-coated tablet daily.

Special Dosage Instructions:

Patients with hepatic impairment

No dosage adjustment is expected to be necessaryrequired (see Sectionsection 5.2).

Children and adolescents

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 is contraindicated in patients with hypersensitivityHypersensitivity to ibandronic acid or to any of the excipients.

Bondronat should not be used in children.

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 preventative 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

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.  Bondronat should not be used during lactation.Consequently, caution should be exercised when prescribing Bondronat to breast-feeding women.

4.8               Undesirable effects

Uncommon:

Blood and Lymphatic System Disorders       anaemia

Nervous System Disorders                           dysgeusia (taste perversion); paraesthesia, dysgeusia (taste perversion)

Gastrointestinal Disorders                            haemorrhage, duodenal ulcer, abdominal pain,gastritis, dysphagia, abdominal pain, dry mouth, duodenal ulcer
haemorrhage, dysphagia, gastritis

Skin and Subcutaneous Tissue Disorders    pruritus

Renal &and Urinary Disorders                     Aazotaemia (uraemia)

General Disorders:                                        chest pain, influenza-like illness, malaise, pain NOS

Investigations                                                Blood parathyroid hormone increased

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).

4.9     Overdose

No case of overdose has been reportedSo far, no case of overdosing with Bondronat film-coated tablets has been reported.

5.3     Preclinical safety data

As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity in animal studies. Effects in non-clinical studies Toxic effects in animals 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.

6.4       Special precautions for storage

Store in the original package in order to protect from moisture.

6.5               Nature and contents of container

Bondronat 50 mg film coated tablets are supplied in blisters (Aaluminium) containing 7 tablets, which are presented as packs containing 28 or 84 tablets. Not all pack sizes may be marketed.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:  24 October 2003

10.     DATE OF REVISION OF THE TEXT

November 2005June 2006

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