Roche Products Limited

Test underlined has been added:

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 some reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Bonviva 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. Bonviva 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

Toxic effects, e.g. signs of renal damage, were observed in dogs only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.

Mutagenicity/Carcinogenicity:

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

Reproductive toxicity:

Specific studies for the 3-monthly dosing regimen have not been performed. In studies with daily i.v. dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in rats and rabbits. Body weight gain was decreased in F₁ offspring in rats. 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. Other adverse reactions to ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include a decreased number of implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).

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4.2         Posology and method of administration

Posology

The recommended dose is one 150 mg film-coated tablet once a month. The tablet should preferably be taken on the same date each month.

Bonviva should be taken after an overnight fast (at least 6 hours) and 1 hour before the first food or drink (other than water) of the day (see section 4.5) or any other oral medicinal products or supplementation (including calcium).

In case a dose is missed, patients should be instructed to take one Bonviva 150 mg tablet the morning after the tablet is remembered, unless the time to the next scheduled dose is within 7 days. Patients should then return to taking their dose once a month on their originally scheduled date.

If the next scheduled dose is within 7 days, patients should wait until their next dose and then continue taking one tablet once a month as originally scheduled.

Patients should not take two tablets within the same week.

Patients should receive supplemental calcium and / or vitamin D if dietary intake is inadequate (see section 4.4 and section 4.5).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established.  The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Bonviva on an individual patient basis, particularly after 5 or more years of use.

Special populations

Patients with renal impairment

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

Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min due to limited clinical experience (see section 4.4 and section 5.2).

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Elderly population

No dose adjustment is required (see section 5.2).

Paediatric population

There is no relevant use of Bonviva in children, and Bonviva was not studied in the paediatric population.

Method of administration:

For oral use.

Tablets should be swallowed whole with a glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking Bonviva.

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

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

4.4         Special warnings and precautions for use

Hypocalcaemia

Existing hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Gastrointestinal disorders

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 Bonviva 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 to 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 Bonviva 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 Nonsteroidal Anti-Inflammatory Drugs and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.

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 impairment

Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).

Galactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.8         Undesirable effects

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three year fracture study (MF4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo.

In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Bonviva 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for Bonviva 150 mg once monthly after one and two years, respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases did not lead to cessation of therapy.

The most commonly reported adverse reaction was arthralgia.

Adverse reactions considered by investigators to be causally related to Bonviva are listed below by System Organ Class.

Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions occurring in postmenopausal women receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM16549 and MF4411 and in postmarketing experience.

*See further information below

†Identified in postmarketing experience.

Gastrointestinal adverse events

Patients with a previous history of gastrointestinal disease including patients with peptic ulcer without recent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication were included in the once monthly treatment study. For these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared to the 2.5 mg daily regimen.

Influenza-like illness

Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

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 150 mg ibandronic acid (as ibandronic sodium monohydrate).

Excipients

Each film-coated tablet contains: Contains 162.75 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

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.

4.4       Special warnings and precautions for use

Hypocalcaemia

Existing hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Gastrointestinal Ddisorders

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 Bonviva 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 to 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 Bonviva 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 Nonsteroidal Anti-Inflammatory Drugs and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.

Hypocalcaemia

Existing hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Renal impairment

Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).

Osteonecrosis of the Jjaw

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 impairment

Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).

Galactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.8       Undesirable effects

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three year fracture study (MF4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo.

In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Bonviva 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for Bonviva 150 mg once monthly after one and two years, respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases did not lead to cessation of therapy.

The most commonly reported adverse reaction was arthralgia.

Adverse reactions considered by investigators to be causally related to Bonviva are listed below by System Organ Class.

Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions occurring in postmenopausal women receiving Bonviva 150150 mg once monthly or ibandronic acid 2.55 mg daily in the phase III studies BM16549 and MF4411.

MedDRA version 7.1

* Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically and in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone painpostmarketing experience.

*See further information below

†Identified in postmarketing experience.

Gastrointestinal adverse events

Patients with a previous history of gastrointestinal disease including patients with peptic ulcer without recent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication were included in the once monthly treatment study. For these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared to the 2.5 mg daily regimen.

Laboratory test findings

In the pivotal three-year study with ibandronic acid 2.5 mg daily (MF 4411) there was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, an impaired haematologic system, hypocalcaemia or hypophosphataemia. Similarly, no differences were noted between the groups in study BM 16549 after one and two years.

Post-marketing Experience

Influenza-like illness

Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

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

Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bbisphosphonates, ATC code: M05B A06

[…]

Paediatric population

Bonviva was not studied in the paediatric population, therefore no efficacy or safety data are available for this patient population.

[…]

6.5       Nature and contents of container

Bonviva 150 mg film-coated tablets are supplied in blisters (PVC/PVDC, sealed with aluminium foil) containing 1 or 3 tablets.

Not all pack sizes may be marketed.

6.6       Special precautions for disposal

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 minimised.

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

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 (see section 4.4)

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

See also section 4.4.

4.4       Special warnings and precautions for use

Gastrointestinal Disorders

Bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore patients, especially those with a history of prolonged oesophageal transit time, should pay particular attention to and be able to comply with 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 Bonviva 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 Bonviva 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 to 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 Bonviva 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.

6.3       Shelf life

3 years5 years.

10.     DATE OF REVISION OF THE TEXT

2 July 200911 December 2009

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

4.8       Undesirable effects

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three year fracture study (MF4411). ; 73 % of these patients came from the pivotal three-year treatment study (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo. The overall proportion of patients who experienced an adverse reaction, i.e. adverse event with a possible or probable relationship to trial medication, in the pivotal treatment study (MF 4411) was 19.8 % for ibandronic acid and 17.9 % for placebo.

In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Bonviva 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for Bonviva 150 mg once monthly and 21.5 % and 22.5 % for ibandronic acid 2.5 mg daily after one and two years, respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases did not lead to cessation of therapy.

The most commonly reported adverse reaction was arthralgia.

Table 1 and table 2 list adverse reactions occurring in more than 1 % of patients treated with Bonviva 150 mg monthly or 2.5 mg daily in study BM 16549 and in patients treated with ibandronic acid 2.5 mg daily in study MF 4411. The tables show the adverse reactions in the two studies that occurred with a higher incidence than in patients treated with placebo in study MF 4411. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Data at one year from BM 16549 are represented in Table 1 and cumulative data for the two years from BM 16549 are represented in table 2.

Table 1: Common adverse reactions (>1/100, ≤ 1/10) in phase III osteoporosis studies that were considered by the investigator to be possibly or probably related to treatment - One year data from study BM 16549 and three year data from placebo-controlled fracture study MF 4411

MedDRA version 6.1

* Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

Table 2: Cumulative common adverse reactions (>1/100, ≤ 1/10) in Phase III osteoporosis studies  that were considered by the investigator to be possibly or probably related to treatment - Two year data from study BM 16549 and three year data from placebo-controlled fracture study MF 4411

MedDRA version 7.1

Adverse reactions considered by investigators to be causally related to Bonviva are listed below by System Organ Class.

Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 150mg once monthly or ibandronic acid 2.5mg daily in the phase III studies BM16549 and MF4411.

MedDRA version 7.1

* Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

Adverse reactions occurring at a frequency of less than or equal to 1 %

The following list provides information on adverse reactions reported in study MF 4411 occurring more frequently with ibandronic acid 2.5 mg daily than with placebo and study BM 16549 occurring more frequently with Bonviva 150 mg once monthly than with ibandronic acid 2.5 mg daily. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

Uncommon (1/100 – 1/1,000)

Gastro-intestinal Disorders:                                                       gastritis, oesophagitis including oesophageal

                                                                                                            ulcerations or strictures, vomiting,

                                                                                                            dysphagia

Nervous System Disorders:                                                       dizziness

Musculoskeletal and Connective Tissue Disorders:         back pain

Rare (1/1,000 – 1/10,000)

Gastro-intestinal Disorders:                                                       duodenitis

Immune System Disorders:                                                        hypersensitivity reactions

Skin and Subcutaneous Tissue Disorders:                       angioedema, face oedema, urticaria

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

4.2       Posology and method of administration

·        Tablets should be swallowed whole with a glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking Bonviva.

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

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

Paediatric Population

Children and adolescents

There is no relevant useexperience of Bonviva in children, and Bonviva was not studied in the paediatric population.

Method of Administration:

For oral use.

Tablets should be swallowed whole with a glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking Bonviva.

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

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

4.4       Special warnings and precautions for use

Gastrointestinal Disorders

Bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore patients, especially those with a history of prolonged oesophageal transit time, should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).

Hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore patients, especially those with a history of prolonged oesophageal transit time, should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).

Hypocalcaemia

Existing hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

Renal impairment

Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).

Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 4.2 and section 5.2).

4.5       Interaction with other medicinal products and other forms of interaction

Drug-Food Interactions

Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk, are likely to interfere with absorption of Bonviva, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Bonviva and continue fasting for 1 hour following intake of Bonviva.

Drug-Drug Interactions

Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of Bonviva. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Bonviva and for 1 hour following intake of Bonviva.

Pharmacokinetic interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen). No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in ibandronic acid bioavailability of about 20 %, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of ibandronic acid, no dosage adjustment is considered necessary when Bonviva is administered with H2-antagonists or other active substances which increase gastric pH.

In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in ibandronic acid bioavailability of about 20 %, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of ibandronic acid, no dose adjustment is considered necessary when Bonviva is administered with H2-antagonists or other active substances which increase gastric pH.

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

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

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

6.3       Shelf life

2 years.3 years.

10.       DATE OF REVISION OF THE TEXT

Updated: October 2006