Last Updated on eMC 10-05-2016 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:25-04-2016

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

 

SUMMARY OF PRODUCT CHARACTERISTICS

 

 

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 Bondronat for oncology indications (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 Bondronat 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 Bondronat. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bondronat 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 Bondronat 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 Drug Reactions Reported for Oral Administration of Bondronat

 

System Organ Class

Common

Uncommon

Rare

Very rare

Not known

 

[ … ]

 

 

 

 

 

 

Musculoskeletal and connective tissue disorders

 

 

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

 

25 April 2015

 

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 4.2 - 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
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:20-03-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

[ … ]

 

Excipients with known effect:

Contains 88.1 mg lactose (as 92.75 mg lactose monohydrate) (equivalent to 88.1 mg anhydrous lactose).

 

[ … ]

 

4.2     Posology and method of administration

 

[ … ]

 

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

 

[ … ]

 

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below the age of 18 years have not been established. No data are available. (see section 5.1 and 5.2).

 

[ … ]

 

4.4     Special warnings and precautions for use

 

[ … ]

 

Acetylsalicylic acid and NSAIDs

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

 

[ … ]

 

4.5     Interaction with other medicinal products and other forms of interaction

 

[ … ]

 

Acetylsalicylic acid and NSAIDs

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

 

[ … ]

 

4.6     Fertility, pregnancy and lactation

 

[ … ]

 

Fertility

There are no data on the effects of ibandronic acid from in 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).

 

[ … ]

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile of Bondronat is derived from controlled clinical trials in the approved indications for the oral administration of Bondronat at the recommended dose, and from post-marketing experience. In the pooled database from the 2 pivotal phase III trials (286 patients treated with Bondronat 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Bondronat was 24 %. The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph “Description of selected adverse reactions” and section 4.4).Treatment was most frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.

 

Tabulated list of adverse reactions

Table 1 lists adverse reactions from the 2 pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with Bondronat 50 mg administered orally), and from 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.

 

Table 1       Adverse Drug Reactions Reported for Oral Administration of Bondronat

 

Adverse reactions are listed according to MedRA 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

Not known

 

[ … ]

 

 

 

 

 

 

Immune system disorders

 

 

 

Hypersensitivity†,

bronchospasm†,

angioedema†,

Anaphylactic reaction/shock†**

Asthma exacerbation

 

[ … ]

 

 

 

 

 

 

**See further information below

†Identified in post-marketing experience.

 

[ … ]

 

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 via the national reporting system listed in Appendix V(see details below).

 

Ireland

IMB Pharmacovigilance

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

 

4.9     Overdose

 

No specific information is available on the treatment of overdosage with Bondronat. However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind Bondronat. Due Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

 

5.1     Pharmacodynamic properties

 

[ … ]

 

Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 50 mg tablets was assessed in two randomized placebo controlled phase III trials with a duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg Bondronat (287 patients). The results from these trials are summarised below.

 

[ … ]

 

Paediatric population (see section 4.2 and section 5.2)

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

 

[ … ]

 

10.     DATE OF REVISION OF THE TEXT

 

20 March 2014

 

[ … ]

 

 

 

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 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • 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

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Underlined text = new text

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

 

Excipients:  with known effect:

Contains 92.75 mg lactose monohydrate. (equivalent to 88.1 mg anhydrous lactose).

 

For a the full list of excipients, see section 6.1.

 

 

4.2     Posology and method of administration

 

[…]

 

Patients with hepatic impairment

No dosagedose adjustment is required (see section 5.2).

 

Patients with renal impairment

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

 

[…]

 

Elderly population (> 65 years)

No dose adjustment is necessary. (see section 5.2).

 

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available. (see section 5.1 and 5.2).

 

Method of administration

For oral use.

 

Bondronat tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking Bondronat tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Plain water Water may be taken at any time during the course of Bondronat treatment (see section 4.5). Water with a high concentration of calcium should not be used. If there is 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.

 

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

 

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

 

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

-                

-                    

-                 Plain wWater is the only drink that should be taken with Bondronat.

 

Please note that some mineral water may have a high concentration of calcium and therefore should not be used.

 

4.3       Contraindications

 

 

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

-        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.

 

4.4     Special warnings and precautions for use

 

[…]

 

Patients with known hypersensitivity to other bisphosphonates

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

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Interaction studies have only been performed in adults.

 

DrugMedicinal product -Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Bondronat tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

 

Bioavailability was reduced by approximately 75% when Bondronat tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2).

 

Interactions with other medicinal productsDrug-Drug Interactions

 

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.

When co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

 

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

 

 

H2-antagonists or other medicinal products that increase gastric pH.

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when Bondronat is administered with H2-antagonists or other drugsmedicinal products that increase gastric pH.

 

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

 

Aminoglycosides

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

 

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

 

 

4.7     Effects on ability to drive and use machines

 

On the basis of the

 

No studies on the effectspharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bondronat 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 Bondronat is derived from controlled clinical trials in the approved indications for the oral administration of Bondronat at the recommended dose, and from post-marketing experience.

 

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

 

Adverse reactions are ranked under heading of frequency, the24 %. Treatment was most frequent first, using the following convention: very common ( ³1/10), common ( ³1/100 and <1/10), uncommon ( ³1/1,000 and <1/100), rare ( ³1/10,000 and <1/1,000), very rare ( <1/10,000).frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.

 

Tabulated list of adverse reactions

Table 1 lists adverse reactions from the pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with Bondronat 50 mg administered orally), and from post-marketing experience.

 

 

 

Table 1 lists adverse drug reactions

 

Table 1       Adverse Drug Reactions Reported for Oral Administration of Bondronat

 

Adverse reactions are listed according to MedRA 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

Very common

Common

Uncommon

Rare

Very rare

Blood and lymphatic system disorders

 

 

Anaemia

 

 

Immune system disorders

 

 

 

 

Hypersensitivity†,

bronchospasm†,

angioedema†,

Anaphylactic reaction/shock†**

Metabolism and nutrition disorders

 

Hypocalcaemia**

 

 

 

Nervous system disorders

 

 

Paraesthesia, dysgeusia (taste perversion)

 

 

Eye disorders

 

 

 

Ocular inflammation†**

 

Gastrointestinal disorders

 

Oesophagitis, abdominal pain, dyspepsia, nausea

Haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth

 

 

Skin and subcutatneous tissue disorders

 

 

Pruritus

 

 

Musculoskeletal and connective tissue disorders

 

 

 

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

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Azotaemia (uraemia)

 

 

General disorders and administration site conditions

 

Asthenia

Chest pain, influenza-like illness, malaise, pain

 

 

Investigations

 

 

Blood parathyroid hormone increased

 

 

**See further information below

†Identified in post-marketing experience.

 

Description of selected adverse reactions

 

Hypocalcaemia

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

 

[…]

 

Anaphylactic reaction/shock

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

 

 

5.1     Pharmacodynamic properties

 

Pharmaco-therapeutic group: DrugsMedicinal products for treatment of bone diseases, bisphosphonate, ATC Code: M05BA06

 

[…]

 

Paediatric population (see section 4.2 and section 5.2)

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

 

5.2    Pharmacokinetic properties

 

Absorption

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration. 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. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.

 

[…]

 

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction with other medicinal products, due to displacement is unlikely.

 

[…]

 

The secretory pathway of renal elimination does not appear to include known acidic or basic transport systems involved in the excretion of other active substances In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.

 

[…]

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 since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment.  Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

 

Elderly (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 Bondronat in patients less than 18 years old.

 

5.3     Preclinical safety data

 

[…]

Reproductive toxicity:

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

 

[…]

 

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 Authorisationauthorisation:  25 June 1996

 

Date of lastlatest renewal: 25 June 2006

 

 

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:26-07-2011

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:

 

4.6      Fertility, Ppregnancy and lactation

 

Pregnancy

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

 

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation.

 

Fertility

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

5.3      Preclinical safety data

 

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

 

Mutagenicity/Carcinogenicity:

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

 

Reproductive toxicity:

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

 

Reasons for adding or updating:

  • 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:

4.4      Special warnings and precautions for use

 

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

 

Gastrointestinal irritation

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

 

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

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

 

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

 

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

 

Osteonecrosis of the jaw

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

Atypical fractures of the femur

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

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

 

Renal function

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

 

Rare hereditary problems

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

 

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

 

4.8      Undesirable effects

 

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

 

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

 

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

 

Table 1 lists adverse drug reactions

 

Table 1          Adverse Drug Reactions Reported for Oral Administration of Bondronat

 

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Blood and lymphatic system disorders

 

 

Anaemia

 

 

Metabolism and nutrition disorders

 

Hypocalcaemia

 

 

 

Nervous system disorders

 

 

Paraesthesia, dysgeusia (taste perversion)

 

 

Eye disorders

 

 

 

Ocular inflammation†**

 

Gastrointestinal disorders

 

Oesophagitis, abdominal pain, dyspepsia, nausea

Haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth

 

 

Skin and subcutatneous tissue disorders

 

 

Pruritus

 

 

Musculoskeletal and connective tissue disorders

 

 

 

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

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Azotaemia (uraemia)

 

 

General disorders and administration site conditions

 

Asthenia

Chest pain, influenza-like illness, malaise, pain

 

 

Investigations

 

 

Blood parathyroid hormone increased

 

 

**See further information below

†Identified in postmarketing experience.

 

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

Ocular inflammation

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

 

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • 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 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 6 - Instructions for use, handling and disposal

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

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

 

Excipients: Contains 92.75 mg lactose monohydrate.

 

For a full list of excipients, see section 6.1.

 

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

 

4.1     Therapeutic indications

 

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

 

4.2     Posology and method of administration

 

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

 

For oral use.

 

Posology

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

 

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

 

Patients with renal impairment

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

 

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

 

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

 

Elderly

No dose adjustment is necessary.

 

Paediatric population

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

 

Method of administration

For oral use.

 

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

 

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

 

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

 

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

 

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

 

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

 

Patients with renal impairment

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

 

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

 

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

 

Elderly

No dose adjustment is necessary.

 

Children and adolescents

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

 

4.3     Contraindications

 

-        Hypersensitivity to ibandronic acid or to any of the excipients

-        Hypocalcaemia

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

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

-     Hypocalcaemia

-     Hypersensitivity to ibandronic acid or to any of the excipients

 

See also section 4.4.

 

Bondronat should not be used in children.

 

 

4.4     Special warnings and precautions for use

 

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

 

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

 

Gastrointestinal irritation

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

 

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

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

 

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

 

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

 

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

 

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

 

Osteonecrosis of the jaw

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

Renal function

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

 

Rare hereditary problems

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

 

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

 

4.8     Undesirable effects

 

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

 

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

 

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

 

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

 

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

 

Adverse Reaction

Placebo

p. o. daily

(n=277 patients)

No. (%)

Bondronat 50 mg

p.o. daily

(n=286 patients)

No. (%)

Metabolism and Nutrition Disorders

 

 

          Hypocalcaemia

14 (5.1)

27 (9.4)

Gastrointestinal Disorders

 

 

          Dyspepsia

13 (4.7)

20 (7.0)

          Nausea

4 (1.4)

10 (3.5)

          Abdominal Pain

2 (0.7)

6 (2.1)

          Oesophagitis

2 (0.7)

6 (2.1)

General Disorders

 

 

          Asthenia

2 (0.7)

4 (1.4)

 

Adverse drug reactions occurring at a frequency <1%:

 

The following list provides

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Blood and lymphatic system disorders

 

 

Anaemia

 

 

Metabolism and nutrition disorders

 

Hypocalcaemia

 

 

 

Nervous system disorders

 

 

Paraesthesia, dysgeusia (taste perversion)

 

 

Eye disorders

 

 

 

Ocular inflammation†**

 

Gastrointestinal disorders

 

Oesophagitis, abdominal pain, dyspepsia, nausea

Haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth

 

 

Skin and subcutatneous tissue disorders

 

 

Pruritus

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Azotaemia (uraemia)

 

 

General disorders and administration site conditions

 

Asthenia

Chest pain, influenza-like illness, malaise, pain

 

 

Investigations

 

 

Blood parathyroid hormone increased

 

 

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

 

Uncommon:

Blood and Lymphatic System Disorders     anaemia

Nervous System Disorders                          paraesthesia, dysgeusia (taste perversion)

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

Skin and Subcutaneous Tissue Disorders   pruritus

Renal and Urinary Disorders                       azotaemia (uraemia)

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

Investigations                                                Blood parathyroid hormone increased

 

†Identified in postmarketing experience.

 

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

Ocular inflammation

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

 

5.1     Pharmacodynamic properties

 

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

 

[…]

 

Paediatric population

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

 

6.6     Special precautions for disposal and other handling

 

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

 

Reasons for adding or updating:

  • 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 5.2 - Pharmacokinetic Properties

Date of revision of text on the SPC:25-01-2010

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:

 

4.2     Posology and method of administration

 

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

 

Patients with renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 ml/min.(CLcr ≥50 and <80 mL/min).

 

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

 

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

 

4.3     Contraindications

 

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

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

-     Hypocalcaemia

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

 

See also section 4.4.

 

4.4     Special warnings and precautions for use

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

 

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

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

 

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

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

 

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

 

5.2     Pharmacokinetic properties

Pharmacokinetics in Special Populations

 

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

 

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition.  There are only very few data available on patients with African origin.

 

Patients with renal impairment

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinine clearance (CLcr).  No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr >30 ml/min).  Subjects with severe renal impairment (CLcr  £ 30 ml/min) receiving oral administration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function (CLcr ≥80 mL/min). Total clearance of ibandronic acid was reduced to 44 ml/min in the subjects with severe renal impairment compared with 129 mL/min in subjects with normal renal function. After intravenous administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with severe renal impairment. However, there was no reduction in tolerability associated with the increase in exposure. No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).   Reduction of the oral dose to one 50 mg tablet once weekly is recommended in patients with severe renal impairment (CLcr <30 ml/min) (see Section 4.2). For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) an adjustment in the dose is recommended (see Section 4.2).

 

Reasons for adding or updating:

  • Removal of Black Triangle

Date of revision of text on the SPC:10-03-2009

Legal Category:POM

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Removal of the black triangle

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  • Change to section 6. 3 - Shelf Life

Date of revision of text on the SPC:10-03-2009

Legal Category:POM

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Shelf life increased to 5 years

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  • Change to section 6. 3 - Shelf Life

Date of revision of text on the SPC:01-09-2007

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Shelf life extended from 2 to 3 years

Reasons for adding or updating:

  • Improved Electronic Presentation

Reasons for adding or updating:

  • Change to section 6. 3 - Shelf Life

Reasons for adding or updating:

  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text

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9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation:  25 June 1996

 

Date of last renewal: 25 June 2006

 

 

10.     DATE OF REVISION OF THE TEXT

 

June 2006March 2007

 

 

 

Reasons for adding or updating:

  • Change to section 2 - qualitative and quantitative composition
  • Change to section 3 - pharmaceutical form
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.3 - Contra-indications
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 4.9 - Overdose
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 9 - Date of Renewal of Authorisation
  • Change to section 10 (date of (partial) revision of the text

Date of revision of text on the SPC:01-06-2006

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

 

2.                 QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Qualitative composition

 

Ibandronic acid, monosodium salt, monohydrate.

 

Quantitative composition

 

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

 

Excipients:

For a full list of excipients, see section 6.1.

 

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

 

3.                 PHARMACEUTICAL form

 

Film-coated tablets of oblong shape.

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

 

4.2               Posology and method of administration

 

Adults:

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

 

Special Dosage Instructions:

Patients with hepatic impairment

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

 

 

Children and adolescents

Safety and efficacy have not been established in patients less than 18 years old.Bondronat is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.

 

4.3               Contraindications

 

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

 

Bondronat should not be used in children.

 

4.4               Special warnings and special precautions for use

 

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

 

4.5             Interaction with other medicinal products and other forms of interaction

 

Interaction studies have only been performed in adults.

 

4.6            Pregnancy and lactation

 

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration.  Bondronat should not be used during lactation.Consequently, caution should be exercised when prescribing Bondronat to breast-feeding women.

 

4.8               Undesirable effects

 

Uncommon:

Blood and Lymphatic System Disorders       anaemia

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

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

 

Skin and Subcutaneous Tissue Disorders    pruritus

Renal &and Urinary Disorders                     Aazotaemia (uraemia)

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

Investigations                                                Blood parathyroid hormone increased

 

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the

reports refer to cancer patients, but such cases have also been reported in patients treated for

osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local

infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids

and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

4.9     Overdose

 

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

 

5.3     Preclinical safety data

 

As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity in animal studies. Effects in non-clinical studies Toxic effects in animals were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

 

6.4       Special precautions for storage

 

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

 

6.5               Nature and contents of container

 

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

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation:  24 October 2003

 

 

10.     DATE OF REVISION OF THE TEXT

 

November 2005June 2006

 

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

 

 

                                                                                                                                                    

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 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 6. 3 - Shelf Life

Reasons for adding or updating:

  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 6. 3 - Shelf Life

Reasons for adding or updating:

  • New SPC for new product