Roche Products Limited

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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).

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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

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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/