Last Updated on eMC 05-05-2016 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:21-04-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

Strike through text = deleted text

 

 

4.4       Special warnings and precautions for use

 

[ …]

 

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bonviva for osteoporosis (see section 4.8).

 

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.

 

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bonviva in patients with concomitant risk factors.

 

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

-        Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

-        Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking

-        Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck

-        Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions

 

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bonviva. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bonviva administration.

 

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Bonviva treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

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.

 

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

 

[ …]

 

4.8       Undesirable effects

 

[ …]

 

Table 1: Adverse 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 post-marketing experience.

 

System Organ Class

Common

Uncommon

Rare

Very rare

 

[ …]

 

 

 

 

 

Musculoskeletal and connective tissue disorders

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Back pain

Atypical subtrochanteric and diaphyseal femoral fractures

Osteonecrosis of jaw*

Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)†

 

[ …]

 

 

 

 

 

*See further information below

†Identified in post-marketing experience.

 

 

[ …]

 

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.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).

 

 

[ …]

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

21 April 2016

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:28-05-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8 - Undesirable effects

Stevens-Johnson Syndrome, Erythema Multiforme, Dermatitis Bullous added as very rare Skin and subcutaneous tissues disorders

Section 10 - DATE OF REVISION OF THE TEXT

Updated to 28 May 2015

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:18-12-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined text = new text
Strike though text = deleted text

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

[ … ]

 

Excipients with known effect:

Contains 154.6 mg anhydrous lactose (equivalent to 162.75 mg lactose monohydrate) (equivalent to 154.6 mg anhydrous lactose).

 

[ … ]

 

 

4.4       Special warnings and precautions for use

 

[ … ]

 

Physicians should be alert to any signs or symptoms signallingsignaling 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.

 

[ … ]

 

Galactose intolerance

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

 

4.5       Interaction with other medicinal products and other forms of interaction

 

[ … ]

 

Acetylsalicylic acid and NSAIDs 

In a two-year study in postmenopausal women with osteoporosis (BM 16549), the incidence of upper gastrointestinal events in patients concomitantly taking acetylsalicylic acid or NSAIDs was similar in patients taking ibandronic acid 2.5 mg daily or 150 mg once monthly after one and two years.


Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).


[ … ]

 

4.6       Fertility, pregnancy and lactation

 

Pregnancy

Bonviva is only for use in postmenopausal women and must not be taken by women of childbearing potential.

 

[ … ]

 

4.8       Undesirable effects

 

Summary of the safety profile

The safety profile of Bonviva is derived from controlled clinical trials and post-marketing experience. The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, ocular inflammation, (see paragraph “Description of selected adverse reactions” and section 4.4).

The most frequently reported adverse reactions were are arthralgia and  influenza-like symptoms. These symptoms are typically in association with the first dose, generally of short duration, mild or moderate in intensity, and usually resolve during continuing treatment without requiring remedial measures (please see paragraph “Influenza like illness”).

 

Tabulated list of adverse reactions

In table 1 an complete list overview of known adverse reactions is presented . 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).


[ … ]

 

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined  using the following convention: very common (>1/10),  common (≥ 1/100 to < 1/10),  uncommon (≥ 1/1,000 to < 1/100),  rare (≥ 1/10,000 to < 1/1,000),very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 1: Adverse 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 post-marketing experience.

 

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined  using the following convention: very common (>1/10),  common (≥ 1/100 to < 1/10),  uncommon (≥ 1/1,000 to < 1/100),  rare (≥ 1/10,000 to < 1/1,000) ,very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

System Organ Class

Common

Uncommon

Rare

Very rare

Immune system disorders

 

Asthma exacerbation

Hypersensitivity reaction

Anaphylactic reaction/shock*†

 

 

[ … ]

 

 

 

 

 

 

[ … ]

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below)

via the national reporting system listed in Appendix V.


Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie


Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt


United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 23.02.2004

Date of latest renewal: 18.12.201323.02.2009

10.     DATE OF REVISION OF THE TEXT

18 December 2013

 

[ … ]

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:15-11-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underline text = new text
Struck through text = deleted text

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each film-coated tablet contains 150 mg ibandronic acid (as ibandronic acid sodium monohydrate).

 

Excipients:  with known effect:

Contains 162.75 mg lactose monohydrate. (equivalent to 154.6 mg anhydrous lactose).

 

For athe full list of excipients, see section 6.1.

 

[ … ]

 

4.2       Posology and method of administration

 

[ … ]

 

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).

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

 

[ … ]

 

Elderly population (>65 years)

No dose adjustment is required (see section 5.2).

 

Paediatric population

There is no relevant use of Bonviva in children below 18 years, and Bonviva was not studied in the paediatricthis population. (see section 5.1 and section 5.2).

 

[ … ]

 

-        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. Water with a high concentration of calcium should not be used. If there is a concern regarding potentially high levels of calcium in the tap water (hard water) , it is advised to use bottled water with a low mineral content.

-           Patients should not lie down for 1 hour after taking Bonviva..-          

Plain water -     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.

 

4.3       Contraindications

 

-           Hypersensitivity to ibandronic acid or to any of the excipients. listed in section 6.1

 

[ … ]

 

4.4       Special warnings and precautions for use

 

[ … ]

 

Gastrointestinal disordersirritation

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 experiencesreactions 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.

 

[ … ]

 

Since Nonsteroidal Anti-Inflammatory Drugsmedicinal products and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.

 

[ … ]

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Medicinal product-Food Interaction

Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium, including milk, 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 (see section 4.2).

 

Interactions with other medicinal products

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

 

Calcium supplements, antacids and some oral medicinal products containing multivalent cations

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.

 

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats. Furthermore, plasma protein binding is approximately 85 % - 87 % (determined in vitro at therapeutic concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation. The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.

Acetylsalicylic acid and NSAIDs 

 

In a two-year study in postmenopausal women with osteoporosis (BM 16549), the incidence of upper gastrointestinal events in patients concomitantly taking aspirinacetylsalicylic acid or NSAIDs was similar in patients taking ibandronic acid 2.5 mg daily or 150 mg once monthly after one and two years.

 

H2 blockers or proton pump inhibitors

Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of ibandronic acid, 14 % and 18 % of patients used histamine (H2) blockers or proton pump inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in the patients treated with Bonviva 150 mg once monthly was similar to that in patients treated with ibandronic acid 2.5 mg daily.

 

[ … ]

 

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.

 

4.6       Fertility, pregnancy and lactation

 

[ … ]

 

Bonviva should not be used during lactationbreast-feeding.

 

[ … ]

 

4.7       Effects on ability to drive and use machines

 

No studies onOn the effectsbasis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bonviva has no or negligible influence on the ability to drive and use machines have been performed..

 

4.8       Undesirable effects

 

Summary of the safety profile

The safety profile of Bonviva is derived from controlled clinical trials and post marketingpost-marketing experience. The most frequently reported adverse reactions were arthralgia and  influenza-like symptoms. These symptoms are typically in association with the first dose, generally of short duration, mild or moderate in intensity, and usually resolve during continuing treatment without requiring remedial measures (please see paragraph “Influenza like illness”).

 

Tabulated list of adverse reactions

In table 1 an overview of adverse reactions is presented . 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), rare (≥ 1/10,000 to < 1/1,000) and very rare (<1/10,000). 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 postmarketingpost-marketing experience.

 

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined  using the following convention: very common (>1/10),  common (≥ 1/100 to < 1/10),  uncommon (≥ 1/1,000 to < 1/100),  rare (≥ 1/10,000 to < 1/1,000) ,very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

 

System Organ Class

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

Hypersensitivity reaction

Anaphylactic reaction/shock*†

Nervous system disorders

Headache

Dizziness

 

 

Eye disorders

 

 

Ocular inflammation*

 

Gastrointestinal disorders*

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

Duodenitis

 

Skin and subcutaneous tissues disorders

Rash

 

Angioedema, Face oedema, Urticaria

 

Musculoskeletal, and  connective tissue and bone disorders

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Back pain

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Osteonecrosis of jaw*

General disorders and administration site conditions

Influenza like illness*

Fatigue

 

 

*See further information below

†Identified in postmarketingpost-marketing experience.

 

Description of selected adverse reactions

 

Gastrointestinal adverse eventsreactions

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.

 

[ … ]

 

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.

 

4.9       Overdose

 

No specific information is available on the treatment of over dosageoverdose with Bonviva.

However, based on a knowledge of this class of compounds, oral over-dosageoverdose may result in upper gastrointestinal adverse reactions (such as upset stomach, dyspepsia, oesophagitis, gastritis, or ulcer) or hypocalcaemia. Milk or antacids should be given to bind Bonviva, and any adverse reactions treated symptomatically. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

 

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: DrugsMedicinal products for treatment of bone diseases, bisphosphonates, ATC code: M05BA06M05-BA06

 

[ … ]

 

Paediatric population (see section 4.2 and section 5.2)

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

 

5.2       Pharmacokinetic properties

 

[ … ]

 

Absorption

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration and plasma concentrations increase in a dose-proportional manner up to 50 mg oral intake, with greater than dose-proportional increases seen above this dose. Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6 %. The extent of absorption is impaired when taken together with food or beverages (other than plain water). Bioavailability is reduced by about 90 % when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before the first food of the day. Both bioavailability and BMD gains are reduced when food or beverage is taken less than 60 minutes after ibandronic acid is ingested.

 

[ … ]

 

The secretory pathway appears not 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.

 

[ … ]

 

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid which is not metabolised but is cleared by renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patients with hepatic impairment.

 

Elderly population (see section 4.2)

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age this is the only factor to take into consideration (see renal impairment section).

 

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of Bonviva in these age groups.

 

[ … ]

 

6.6       Special precautions for disposal

 

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

 

[ … ]

 

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 23.02.2004/23

Date of latest renewal: 23.02.2009

 

 

10.     DATE OF REVISION OF THE TEXT

 

15 November 2012

 

[ … ]

 

Reasons for adding or updating:

  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 5.3 - Preclinical Safety Data

Date of revision of text on the SPC:27-07-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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).

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:29-06-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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

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.

System Organ Class

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

Hypersensitivity reaction

 

Nervous system disorders

Headache

Dizziness

 

 

Eye disorders

 

 

Ocular inflammation*

 

Gastrointestinal disorders*

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

Duodenitis

 

Skin and subcutaneous tissues disorders

Rash

 

Angioedema, Face oedema, Urticaria

 

Musculoskeletal, connective tissue and bone disorders

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Back pain

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Osteonecrosis of jaw*

General disorders and administration site conditions

Influenza like illness*

Fatigue

 

 

*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.

 

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 6. 6 - Instructions for use, handling and disposal

Date of revision of text on the SPC:14-04-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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.

 

System Organ Class

Frequency

Adverse reactions

Immune system disorders

Rare

Hypersensitivity reaction

Nervous system disorders

Common

Headache

 

Uncommon

Dizziness

Gastrointestinal disorders

Common

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

 

Uncommon

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

 

Rare

Duodenitis

Skin and subcutaneous tissues disorders

Common

Rash

 

Rare

Angioedema, Face oedema, Urticaria

Musculoskeletal, connective tissue and bone disorders

Common

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

 

Uncommon

Back pain

General disorders and administration site conditions

Common

Influenza like illness*

 

Uncommon

Fatigue

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.

System Organ Class

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

Hypersensitivity reaction

 

Nervous system disorders

Headache

Dizziness

 

 

Eye disorders

 

 

Ocular inflammation*

 

Gastrointestinal disorders*

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

Duodenitis

 

Skin and subcutaneous tissues disorders

Rash

 

Angioedema, Face oedema, Urticaria

 

Musculoskeletal, connective tissue and bone disorders

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Back pain

 

Osteonecrosis of jaw*

General disorders and administration site conditions

Influenza like illness*

Fatigue

 

 

*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.

 

Reasons for adding or updating:

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use

Date of revision of text on the SPC:08-02-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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.

 

Reasons for adding or updating:

  • Change to section 6. 3 - Shelf Life
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:11-12-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underline text = new text
Struck through text = deleted text

6.3       Shelf life

 

3 years5 years.

 

 

10.     DATE OF REVISION OF THE TEXT

 

2 July 200911 December 2009

Reasons for adding or updating:

  • Removal of Black Triangle

Date of revision of text on the SPC:02-07-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Removal of the black triangle

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:02-07-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

 

 

One year data in study BM 16549

Three year data in study MF 4411

System Organ Class/ Adverse reaction

Bonviva 150 mg once monthly

(N=396)

(%)

ibandronic acid 2.5 mg daily

(N=395)

(%)

ibandronic acid 2.5 mg daily

(N=977)

(%)

Placebo

(N=975)

(%)

Gastrointestinal system

 

 

 

 

Gastro-oesophageal reflux disease

0.5

1.0

0.4

0.1

Diarrhoea

2.5

1.8

1.4

1.0

Abdominal pain

3.5

2.8

2.1

2.9

Dyspepsia

3.3

5.8

4.3

2.9

Nausea

3.3

3.5

1.8

2.3

Flatulence

0.5

1.0

0.4

0.7

Nervous system

 

 

 

 

Headache

0.8

1.5

0.8

0.6

General disorders

 

 

 

 

Influenza like illness*

3.3

0.3

0.3

0.2

Fatigue

1.0

0.3

0.3

0.4

Musculoskeletal system

 

 

 

 

Arthralgia

1.0

0.3

0.4

0.4

Myalgia

1.5

0.3

1.8

0.8

Skin disorders

 

 

 

 

Rash

0.8

1.0

1.2

0.7

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

 

 

Two year cumulative data in study BM 16549

Three year data in study MF 4411

System Organ Class/ Adverse reaction

Bonviva 150 mg once monthly

(N=396)

(%)

ibandronic acid 2.5 mg daily

(N=395)

(%)

ibandronic acid 2.5 mg daily

(N=977)

(%)

Placebo

(N=975)

(%)

Gastrointestinal system

 

 

 

 

Gastritis

1.0

0.3

0.7

0.5

Gastro-oesophageal reflux disease

0.8

1.0

0.5

0.1

Oesophagitis

0

1.0

0.5

0.4

Diarrhoea

2.5

2.0

1.4

1.0

Abdominal pain

4.0

3.0

2.1

2.9

Dyspepsia

4.0

6.3

4.0

2.7

Nausea

3.0

3.5

1.8

2.3

Nervous system

 

 

 

 

Headache

0.8

1.5

0.8

0.6

General disorders

 

 

 

 

Influenza like illness*

3.3

0.3

0.3

0.2

Musculoskeletal system

 

 

 

 

Muscle cramp

0.5

1.0

0.1

0.4

Musculoskeletal pain

1.0

0.5

0

0

Arthralgia

1.0

0.5

0.4

0.4

Myalgia

1.5

0.3

1.8

0.8

Musculoskeletal stiffness

1.0

0

0

0

Skin disorders

 

 

 

 

Rash

0.8

1.0

1.2

0.7

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.

 

System Organ Class

Frequency

Adverse reactions

Immune system disorders

Rare

Hypersensitivity reaction

Nervous system disorders

Common

Headache

 

Uncommon

Dizziness

Gastrointestinal disorders

Common

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

 

Uncommon

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

 

Rare

Duodenitis

Skin and subcutaneous tissues disorders

Common

Rash

 

Rare

Angioedema, Face oedema, Urticaria

Musculoskeletal, connective tissue and bone disorders

Common

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

 

Uncommon

Back pain

General disorders and administration site conditions

Common

Influenza like illness*

 

Uncommon

Fatigue

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

 

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:23-02-2009

Legal Category:POM

Black Triangle (CHM): YES

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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.

 

Reasons for adding or updating:

  • Change to section 6. 5 - Nature and Contents of Container

Date of revision of text on the SPC:10-07-2008

Legal Category:POM

Black Triangle (CHM): YES

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6.5       Nature and contents of container

 

Bonviva 150 mg film-coated tablets are supplied in blisters (Aluminium/Aluminium)  (PVC/PVDC) containing 1 or 3 tablets.

Reasons for adding or updating:

  • Change to section 6. 3 - Shelf Life
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-10-2006

Legal Category:POM

Black Triangle (CHM): NO

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6.3       Shelf life

 

2 years.3 years.

 

10.       DATE OF REVISION OF THE TEXT

 

Updated: October 2006

Reasons for adding or updating:

  • Correction of spelling/typing errors

Reasons for adding or updating:

  • Change to section 1 - trade name
  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 10 (date of (partial) revision of the text

Date of revision of text on the SPC:01-08-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Due to detailed changes to this SPC, please cut and paste the following url into your web browser to view the change details:
 
 
 

Reasons for adding or updating:

  • Correction of spelling/typing errors

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • New SPC for new product