Bondronat

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 2 mg concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as sodium 
monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Bondronat is indicated in adults for  
 
- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy 

or surgery) in patients with breast cancer and bone metastases 
 
- Treatment of tumour-induced hypercalcaemia with or without metastases 
 
4.2 Posology and method of administration 
 
Patients treated with Bondronat should be given the package leaflet and the patient reminder card. 
 
Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer. 
 
Posology 
Prevention of skeletal events in patients with breast cancer and bone metastases 
 
The recommended dose for prevention of skeletal events in patients with breast cancer and bone 
metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at 
least 15 minutes.  
A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or 
mild renal impairment. There are no data available characterising the use of a shorter infusion time in 
patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients 
with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this 
patient group. 
 
Treatment of tumour-induced hypercalcaemia 
 
Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) 
sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well 
as the tumour type. In general patients with osteolytic bone metastases require lower doses than 
patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia 
(albumin-corrected serum calcium* ≥3 mmol/l or ≥12 mg/dl) 4 mg is an adequate single dose. In 
patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 



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2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add 
any further benefit in terms of efficacy. 
 
* Note albumin-corrected serum calcium concentrations are calculated as follows: 
 
Albumin-corrected  
serum calcium (mmol/l) 

= serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 
0.8 

Or 
Albumin-corrected  
serum calcium (mg/dl) 

= serum calcium (mg/dl)  + 0.8 x [4 - albumin 
(g/dl)] 

   
To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 
4. 
 
In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The 
median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 
18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 
6 mg. 
 
A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. 
Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy. 
 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion over 
2 hours. 
 
Special populations 
Patients with hepatic impairment 
No dose adjustment is required (see section 5.2). 
 
Patients with renal impairment  
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dose adjustment is necessary. 
For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment 
(CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer 
and metastatic bone disease the following dosing recommendations should be followed (see section 
5.2): 
 
Creatinine Clearance 

(ml/min) Dosage Infusion Volume 
1 and Time 2 

≥50 CLcr<80 6 mg (6 ml of concentrate for solution for infusion) 100 ml over 15 minutes 

≥30 CLcr <50 4 mg (4 ml of concentrate for solution for infusion) 500 ml over 1 hour 

<30 2 mg (2 ml of concentrate for solution for infusion) 500 ml over 1 hour 
1  0.9% sodium chloride solution or 5% glucose solution 
2  Administration every 3 to 4 week 
 
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min. 
 
Elderly population (> 65 years) 
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 section 5.2). 
 



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Method of administration 
For intravenous administration. 
 
The content of the vial is to be used as follows: 
 

• Prevention of Skeletal Events - added to 100 ml isotonic sodium chloride solution or 100 ml 
5% dextrose solution and infused over at least 15 minutes. See also dose section above for 
patients with renal impairment 

 
• Treatment of tumour-induced hypercalcaemia - added to 500 ml isotonic sodium chloride 

solution or 500 ml 5% dextrose solution and infused over 2 hours 
 
For single use only. Only clear solution without particles should be used. 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion.  
Care must be taken not to  administer Bondronat concentrate for solution for infusion via intra-arterial 
or paravenous administration, as this could lead to tissue damage. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 
- Hypocalcaemia 
 
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 for metastatic bone disease.  
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. 
 
Anaphylactic reaction/shock 
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated 
with intravenous ibandronic acid. 
Appropriate medical support and monitoring measures should be readily available when Bondronat 
intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions 
occur, immediately discontinue the injection and initiate appropriate treatment. 
 
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 
 



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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 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. 
 
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. 
 
Patients with renal impairment  
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 (see section 4.2). 
 
Patients with hepatic impairment 
As no clinical data are available, dose recommendations cannot be given for patients with severe 
hepatic insufficiency (see section 4.2). 
 
Patients with cardiac impairment 
Overhydration should be avoided in patients at risk of cardiac failure. 
 
Patients with known hypersensitivity to other bisphosphonates 
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. 
 
Excipients with known effect  
Bondronat is essentially sodium free. 
 
4.5 Interaction with other medicinal products and other forms of interaction  
 
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 



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system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not 
undergo any biotransformation. 
 
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. 
 
4.6 Fertility, pregnancy 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 breast-feeding. 
 
Fertility 
There are no data on the effects of ibandronic acid 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). 
 
4.7 Effects on ability to drive and use machines 
 
On the basis of the pharmacodynamic 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.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the 
femur, osteonecrosis for the jaw, and ocular inflammation (see paragraph “description of selected 
adverse reactions” and section 4.4). 
 
Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body 
temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is 
reported. In most cases no specific treatment is required and the symptoms subside after a couple of 
hours/days. 
In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is 
most frequently associated with asthenia followed by rise in body temperature and headache. 
 
Tabulated list of adverse reactions 
Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced 
hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in 
patients with breast cancer and bone metastases: 152 patients treated with Bondronat 6 mg), 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. 
 



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Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat 
 
System Organ 
Class 

Common Uncommon Rare Very rare Not known 

Infections and 
infestations 

Infection Cystitis, vaginitis, 
oral candidiasis 

   

Neoplasms 
benign, 
malignant and 
unspecified 

 Benign skin 
neoplasm 

   

Blood and 
lymphatic 
system disorders 

 Anaemia, blood 
dyscrasia 

   

Immune system 
disorders 

   Hypersensitivit
y†, 
bronchospasm†
, 
angioedema†, 
anaphylactic 
reaction/shock†
** 

Asthma 
exacerbation 

Endocrine 
disorders 

Parathyroid 
disorder 

    

Metabolism and 
nutrition 
disorders 

Hypocalcaemia** 
 

Hypophosphataemia    

Psychiatric 
disorders 

 Sleep disorder, 
anxiety, affection 
lability 

   

Nervous system 
disorders 

Headache, 
dizziness, 
dysgeusia (taste 
perversion) 

Cerebrovascular 
disorder, nerve root 
lesion, amnesia, 
migraine, neuralgia, 
hypertonia, 
hyperaestesia, 
paraesthesia 
circumoral, 
parosmia 

   

Eye disorders Cataract  Ocular 
inflammation†** 

  

Ear and 
labyrinth 
disorders 

 Deafness    

Cardiac 
disorders 

Bundle branch 
block 

Myocardial 
ischaemia, 
cardiovascular 
disorder, 
palpitations 

   

Respiratory, 
thoracic, and 
mediastinal 
disorders 

Pharyngitis Lung oedema, 
stridor 

   

Gastrointestinal 
disorders 

Diarrhoea, 
vomiting, 
dyspepsia, 
gastrointestinal 
pain, tooth 
disorder 

Gastroenteritis, 
gastritis, mouth 
ulceration, 
dysphagia, cheilitis 

   



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System Organ 
Class 

Common Uncommon Rare Very rare Not known 

Hepatobiliary 
disorders 

 Cholelithiasis    

Skin and 
subcutaneous 
tissue disorders 

Skin disorder, 
ecchymosis 

Rash, alopecia  Stevens-
Johnson 
Syndrome†, 
Erythema 
Multiforme†, 
Dermatitis 
Bullous† 

 

Musculoskeletal 
and connective 
tissue disorders 

Osteoarthritis, 
myalgia, 
arthralgia, joint 
disorder, 
bone pain 

 Atypical 
subtrochanteric 
and diaphyseal 
femoral 
fractures†  

Osteonecrosis  
of jaw†**   
Osteonecrosis 
of the external 
auditory canal 
(bisphosphonat
e class adverse 
reaction)† 

 

Renal and 
urinary 
disorders 

 Urinary retention, 
renal cyst 

   

Reproductive 
system and 
breast disorders 

 Pelvic pain    

General 
disorders and 
administration 
site conditions 

Pyrexia, 
influenza-like 
illness**, oedema 
peripheral, 
asthenia, thirst 

Hypothermia    

Investigations Gamma-GT 
increased, 
creatinine 
increased 

Blood alkaline 
phosphatase 
increase, weight 
decrease 

   

Injury, 
poisoning and 
procedural 
complications 

 Injury, injection site 
pain 

   

**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. 
 
Influenza-like illness 
A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In 
most cases no specific treatment was required and the symptoms subsided after a couple of hours/days. 
 
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. 
 



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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. 
 
Anaphylactic reaction/shock 
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated 
with intravenous ibandronic acid. 
 
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. 
 
4.9 Overdose 
 
Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for 
infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical 
studies with high doses, kidney and liver function should be monitored. Clinically relevant 
hypocalcaemia should be corrected by intravenous administration of calcium gluconate. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: Medicinal products for treatment of bone diseases, bisphosphonate, ATC 
Code: M05BA06. 
 
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. 
Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. 
Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear. 
 
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of 
gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption 
has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline 
previously incorporated into the skeleton. 
 
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did 
not have any effect on bone mineralisation. 
 
Bone resorption due to malignant disease is characterised by excessive bone resorption that is not 
balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, 
reducing bone resorption and thereby reducing skeletal complications of the malignant disease. 
 
Clinical studies in the treatment of tumour-induced hypercalcaemia 
Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic 
acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is 
characterised by a decrease in serum calcium and urinary calcium excretion. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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In the dose range recommended for treatment, the following response rates with the respective 
confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected 
serum calcium ≥ 3.0 mmol/l after adequate rehydration. 
 
Ibandronic 
acid dose 

% of Patients with 
Response 

90% Confidence 
Interval 

2 mg 54 44-63 

4 mg 76 62-86 

6 mg 78 64-88 

 
For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The 
median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 
days. 
 
Clinical studies in the prevention of skeletal events in patients with breast cancer and bone metastases 
Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose 
dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose 
dependent effect on skeletal events. 
 
Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg 
administered intravenously was assessed in one randomized placebo controlled phase III trial with 
duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone 
metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The 
results from this trial are summarised below. 
 
Primary efficacy endpoints 
The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite 
endpoint which had the following skeletal related events (SREs) as sub-components:  
 
- radiotherapy to bone for treatment of fractures/impending fractures  
- surgery to bone for treatment of fractures  
- vertebral fractures  
- non-vertebral fractures   
 
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a 
single 12 week period could be potentially related. Multiple events were therefore counted only once 
for the purposes of the analysis. Data from this study demonstrated a significant advantage for 
intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted 
SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there 
was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results 
are summarised in Table 2. 
 



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Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)  
 
 All Skeletal Related Events (SREs) 

Placebo 
n=158 

Bondronat 6 mg 
n=154 

 

p-value 

SMPR (per patient year) 
 

1.48 1.19 p=0.004 

Number of events (per 
patient) 
 

3.64 2.65 p=0.025 

SRE relative risk  
 

- 0.60 p=0.003 

 
Secondary efficacy endpoints 
A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg 
compared to placebo. The pain reduction was consistently below baseline throughout the entire study 
and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was 
significantly less in Bondronat treated patients compared with placebo. A tabular summary of these 
secondary efficacy results is presented in Table 3. 
 
Table 3 Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease) 
 
 Placebo 

n=158 
Bondronat 6 mg 
n=154 

 p-value 

Bone pain * 
 

0.21 -0.28 p<0.001 

Analgesic use * 
 

0.90 0.51 p=0.083 

Quality of Life * 
 

-45.4 -10.3 p=0.004 

* Mean change from baseline to last assessment. 
 
There was a marked depression of urinary markers of bone resorption (pyridinoline and 
deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to 
placebo. 
 
In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 
15 minutes was compared. No difference was observed in the indicators of renal function. The overall 
adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the 
known safety profile over longer infusion times and no new safety concerns were identified relating to 
the use of a 15 minute infusion time.  
 
A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of 
<50ml/min. 
 
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. 
 
5.2 Pharmacokinetic properties 
 
After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose 
proportional. 
 



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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 interaction with other medicinal products, 
due to displacement is unlikely. 
 
Biotransformation 
There is no evidence that ibandronic acid is metabolized in animals or humans. 
 
Elimination 
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but 
the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels 
fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration 
respectively. No systemic accumulation was observed when ibandronic acid was administered 
intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease. 
 
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal 
clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total 
clearance and is related to creatinine clearance. The difference between the apparent total and renal 
clearances is considered to reflect the uptake by bone. 
 
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. 
 
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  
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to 
creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 
21.2 mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. 
In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 
minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild 
(mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal 
impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not 
increased in patients with mild renal impairment and increased by 12% in patients with moderate renal 
impairment. For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage 
adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or 
severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in 
patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (see 
section 4.2). 
 
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% 



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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 that 
should be considered (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 
 
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 medicinal 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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Acetic acid (99%) 
Sodium acetate 
Water for injections 
 
6.2 Incompatibilities 
 
To avoid potential incompatibilities Bondronat concentrate for solution for infusion should only be 
diluted with isotonic sodium chloride solution or 5% glucose solution. 
 
Bondronat should not be mixed with calcium containing solutions. 
 
6.3 Shelf life 
 
5 years 
After reconstitution: 24 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions prior to reconstitution. 



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After reconstitution: Store at 2°C – 8°C (in a refrigerator). 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in 
controlled and validated aseptic conditions. 
 
6.5 Nature and contents of container 
 
Bondronat is supplied as packs containing 1 vial (2 ml type I glass vial with a bromobutyl rubber 
stopper). 
 
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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/96/012/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 June 1996 
 
Date of latest renewal: 25 June 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



 15 

1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 50 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 50 mg of ibandronic acid (as sodium monohydrate). 
 
Excipients with known effect: 
Contains 88.1 mg lactose (as lactose monohydrate).  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablets.  
White to off-white film-coated tablets, of oblong shape engraved “L2” on one side and “IT” on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
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. 
 
Posology 
The recommended dose is one 50 mg film-coated tablet daily. 
 
Special populations 
Patients with hepatic impairment 
No dose adjustment is required (see section 5.2).  
 
Patients with renal impairment  
No dose 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 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 the age of 18 years have not 
been established. No data are available. (see section 5.1 and 5.2). 
 



 16 

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. 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 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.  
 

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



 17 

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. 
 
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.  
 
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 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. 
 
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.  
 



 18 

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. 
 
Patients with known hypersensitivity to other bisphosphonates 
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Medicinal 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 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.  
 
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 medicinal products that 
increase gastric pH. 
 
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).  
 
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. 
 



 19 

4.6 Fertility, pregnancy 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 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). 
 
4.7 Effects on ability to drive and use machines 
 
On the basis of the pharmacodynamic 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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
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 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. 
 



 20 

Table 1 Adverse Drug Reactions Reported for Oral Administration of Bondronat 
 
System Organ 
Class 

Common Uncommon Rare Very rare Not known 

Blood and 
lymphatic 
system disorders 

 Anaemia    

Immune system 
disorders 

   Hypersensitivity†, 
bronchospasm†, 
angioedema†, 
Anaphylactic 
reaction/shock†** 

Asthma 
exacerbation 

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, 
dry mouth 

   

Skin and 
subcutaneous 
tissue disorders 

 Pruritus  Stevens-Johnson 
Syndrome†, 
Erythema 
Multiforme†, 
Dermatitis 
Bullous† 

 

Musculoskeletal 
and connective 
tissue disorders 

  Atypical 
subtrochanteric 
and diaphyseal 
femoral 
fractures†  

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

 

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. 
 



 21 

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. 
 
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. 
 
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. 
 
Anaphylactic reaction/shock 
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated 
with intravenous ibandronic acid. 
 
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. 
 
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 to the risk of oesophageal 
irritation, vomiting should not be induced and the patient should remain fully upright. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
Pharmaco-therapeutic group: Medicinal products for treatment of bone diseases, bisphosphonate, ATC 
Code: M05BA06. 
 
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. 
Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. 
Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear. 
 
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of 
gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption 
has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline 
previously incorporated into the skeleton. 
 
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did 
not have any effect on bone mineralisation. 
 
Bone resorption due to malignant disease is characterized by excessive bone resorption that is not 
balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, 
reducing bone resorption and thereby reducing skeletal complications of the malignant disease. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 22 

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose 
dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose 
dependent effect on skeletal events. 
 
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. 
 
Primary efficacy endpoints 
The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was a 
composite endpoint which had the following skeletal related events (SREs) as sub-components:  
 
- radiotherapy to bone for treatment of fractures/impending fractures 
- surgery to bone for treatment of fractures 
- vertebral fractures  
- non-vertebral fractures 
 
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a 
single 12 week period could be potentially related. Multiple events were therefore, counted only once 
in any given 12 week period for the purposes of the analysis. Pooled data from these studies 
demonstrated a significant advantage for Bondronat 50 mg p.o. over placebo in the reduction in SREs 
measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE 
for Bondronat treated patients when compared with placebo (relative risk 0.62, p=0.003). Efficacy 
results are summarised in Table 2. 
 
Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)  
 
 All Skeletal Related Events (SREs) 
 Placebo 

n=277 
Bondronat 50 mg 

n=287 
p-value 

SMPR (per patient year) 
 

1.15 0.99 p=0.041 

SRE relative risk 
 

- 0.62 p=0.003 

 
Secondary efficacy endpoints  
A statistically significant improvement in bone pain score was shown for Bondronat 50 mg compared 
to placebo. The pain reduction was consistently below baseline throughout the entire study and 
accompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in 
Quality of Life and WHO performance status was significantly less in Bondronat treated patients 
compared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminal 
telopeptide released from Type I collagen) were significantly reduced in the Bondronat group 
compared to placebo. This reduction in urinary CTx levels was significantly correlated with the 
primary efficacy endpoint SMPR (Kendall-tau-b (p<0.001)). A tabular summary of the secondary 
efficacy results is presented in Table 3. 
 



 23 

Table 3 Secondary Efficacy Results (Breast Cancer Patients with Metastatic Bone 
Disease) 

 
 Placebo 

n=277 
Bondronat 50 mg 
n=287 

p-value 

Bone pain * 
 

0.20 -0.10 p=0.001 

Analgesic use * 
 

0.85 0.60 p=0.019 

Quality of Life * 
 

-26.8 -8.3 p=0.032 

WHO performance 
score * 

0.54 0.33 p=0.008 

Urinary CTx ** 
 

10.95 -77.32 p=0.001 

* Mean change from baseline to last assessment. 
** Median change from baseline to last assessment 
 
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. 
 
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 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. 
 
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 (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been 
taken (see section 4.2). 
 
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 interaction with other medicinal products, 
due to displacement is unlikely. 
 
Biotransformation 
There is no evidence that ibandronic acid is metabolized in animals or humans. 
 
Elimination 
The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption 
(estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed 
fraction of ibandronic acid is eliminated unchanged in the faeces. 
 
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but 
the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels 



 24 

fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration 
respectively.  
 
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal 
clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total 
clearance and is related to creatinine clearance. The difference between the apparent total and renal 
clearances is considered to reflect the uptake by bone. 
 
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. 
 
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  
Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinine 
clearance (CLcr). 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. 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) or severe renal impairment (CLcr <30 mL/min) an adjustment in the dose is 
recommended (see section 4.2). 
 
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 
 
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.  
 



 25 

Mutagenicity/Carcinogenicity: 
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of 
genetic activity for ibandronic acid. 
 
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 medicinal 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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Povidone 
Cellulose, microcrystalline 
Crospovidone 
Stearic acid 
Silica, anhydrous colloidal 
 
Tablet coat: 
Hypromellose 
Titanium dioxide (E 171) 
Talc  
Macrogol 6000 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
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 (aluminium) containing 7 tablets, which 
are presented as packs containing 28 or 84 tablets. 
Not all pack sizes may be marketed. 
 
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.  
 



 26 

 
7. MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/96/012/009 
EU/1/96/012/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  25 June 1996 
 
Date of latest renewal: 25 June 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



 27 

1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 6 mg concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as sodium 
monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Bondronat is indicated in adults for  
 
- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy 

or surgery) in patients with breast cancer and bone metastases 
 
- Treatment of tumour-induced hypercalcaemia with or without metastases 
 
4.2 Posology and method of administration 
 
Patients treated with Bondronat should be given the package leaflet and the patient reminder card. 
 
Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer. 
 
Posology 
Prevention of skeletal events in patients with breast cancer and bone metastases 
 
The recommended dose for prevention of skeletal events in patients with breast cancer and bone 
metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at 
least 15 minutes.  
A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or 
mild renal impairment. There are no data available characterising the use of a shorter infusion time in 
patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients 
with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this 
patient group. 
 
Treatment of tumour-induced hypercalcaemia 
 
Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) 
sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well 
as the tumour type. In general patients with osteolytic bone metastases require lower doses than 
patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia 
(albumin-corrected serum calcium* ≥3 mmol/l or ≥12 mg/dl) 4 mg is an adequate single dose. In 
patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 



 28 

2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add 
any further benefit in terms of efficacy. 
 
* Note albumin-corrected serum calcium concentrations are calculated as follows: 
 
Albumin-corrected  
serum calcium (mmol/l) 

= serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 
0.8 

Or 
Albumin-corrected  
serum calcium (mg/dl) 

= serum calcium (mg/dl)  + 0.8 x [4 - albumin 
(g/dl)] 

   
To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 
4. 
 
In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The 
median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 
18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 
6 mg. 
 
A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. 
Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy. 
 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion over 
2 hours. 
 
Special populations 
Patients with hepatic impairment 
No dose adjustment is required (see section 5.2). 
 
Patients with renal impairment  
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no  doseadjustment is necessary. 
For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment 
(CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer 
and metastatic bone disease the following dosing recommendations should be followed (see section 
5.2): 
 
Creatinine Clearance 

(ml/min) Dosage Infusion Volume 
1 and Time 2 

≥50 CLcr<80 6 mg (6 ml of concentrate for solution for infusion) 100 ml over 15 minutes 

≥30 CLcr <50 4 mg (4 ml of concentrate for solution for infusion) 500 ml over 1 hour 

<30 2 mg (2 ml of concentrate for solution for infusion) 500 ml over 1 hour 
1  0.9% sodium chloride solution or 5% glucose solution 
2  Administration every 3 to 4 week 
 
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min. 
 
Elderly population (> 65 years) 
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 section 5.2). 
 



 29 

Method of administration 
For intravenous administration. 
 
The content of the vial is to be used as follows: 
 

• Prevention of Skeletal Events - added to 100 ml isotonic sodium chloride solution or 100 ml 
5% dextrose solution and infused over at least 15 minutes. See also dose section above for 
patients with renal impairment 

 
• Treatment of tumour-induced hypercalcaemia - added to 500 ml isotonic sodium chloride 

solution or 500 ml 5% dextrose solution and infused over 2 hours 
 
For single use only. Only clear solution without particles should be used. 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion.  
Care must be taken not to administer Bondronat concentrate for solution for infusion via intra-arterial 
or paravenous administration, as this could lead to tissue damage.. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 
- Hypocalcaemia 
 
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 for metastatic bone disease.  
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. 
 
Anaphylactic reaction/shock 
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated 
with IV ibandronic acid. 
Appropriate medical support and monitoring measures should be readily available when Bondronat 
intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions 
occur, immediately discontinue the injection and initiate appropriate treatment. 
 
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 
 



 30 

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 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. 
 
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. 
 
Patients with renal impairment  
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 (see section 4.2). 
 
Patients with hepatic impairment 
As no clinical data are available, dose recommendations cannot be given for patients with severe 
hepatic insufficiency (see section 4.2). 
 
Patients with cardiac impairment 
Overhydration should be avoided in patients at risk of cardiac failure. 
 
Patients with known hypersensitivity to other bisphosphonates 
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. 
 
Excipients with known effect 
Bondronat is essentially sodium free. 
 
4.5 Interaction with other medicinal products and other forms of interaction  
 
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 



 31 

system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not 
undergo any biotransformation. 
 
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. 
 
4.6 Fertility, pregnancy 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 breast-feeding. 
 
Fertility 
There are no data on the effects of ibandronic acid 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). 
 
4.7 Effects on ability to drive and use machines 
 
On the basis of the pharmacodynamic 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.  
 
4.8 Undesirable effects 
 
Summary of  the safety profile 
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the 
femur, osteonecrosis for the jaw and ocular inflammation (see paragraph “description of selected 
adverse reactions”and section 4.4). 
Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body 
temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is 
reported. In most cases no specific treatment was required and the symptoms subsided after a couple 
of hours/days. 
In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is 
most frequently associated with asthenia followed by rise in body temperature and headache. 
 
Tabulated list of adverse reactions 
Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced 
hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in 
patients with breast cancer and bone metastases: 152 patients treated with Bondronat 6 mg), 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. 
 



 32 

Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat 
 
System Organ 
Class 

Common Uncommon Rare Very rare Not known 

Infections and 
infestations 

Infection Cystitis, vaginitis, 
oral candidiasis 

   

Neoplasms 
benign, 
malignant and 
unspecified 

 Benign skin 
neoplasm 

   

Blood and 
lymphatic 
system disorders 

 Anaemia, blood 
dyscrasia 

   

Immune system 
disorders 

   Hypersensitivit
y†, 
bronchospasm†
, 
angioedema†, 
anaphylactic 
reaction/shock†
** 

Asthma 
exacerbation 

Endocrine 
disorders 

Parathyroid 
disorder 

    

Metabolism and 
nutrition 
disorders 

Hypocalcaemia** 
 

Hypophosphataemia    

Psychiatric 
disorders 

 Sleep disorder, 
anxiety, affection 
lability 

   

Nervous system 
disorders 

Headache, 
dizziness, 
dysgeusia (taste 
perversion) 

Cerebrovascular 
disorder, nerve root 
lesion, amnesia, 
migraine, neuralgia, 
hypertonia, 
hyperaestesia, 
paraesthesia 
circumoral, 
parosmia 

   

Eye disorders Cataract  Ocular 
inflammation†** 

  

Ear and 
labyrinth 
disorders 

 Deafness    

Cardiac 
disorders 

Bundle branch 
block 

Myocardial 
ischaemia, 
cardiovascular 
disorder, 
palpitations 

   

Respiratory, 
thoracic, and 
mediastinal 
disorders 

Pharyngitis Lung oedema, 
stridor 

   

Gastrointestinal 
disorders 

Diarrhoea, 
vomiting, 
dyspepsia, 
gastrointestinal 
pain, tooth 
disorder 

Gastroenteritis, 
gastritis, mouth 
ulceration, 
dysphagia, cheilitis 

   



 33 

System Organ 
Class 

Common Uncommon Rare Very rare Not known 

Hepatobiliary 
disorders 

 Cholelithiasis    

Skin and 
subcutaneous 
tissue disorders 

Skin disorder, 
ecchymosis 

Rash, alopecia  Stevens-
Johnson 
Syndrome†, 
Erythema 
Multiforme†, 
Dermatitis 
Bullous† 

 

Musculoskeletal 
and connective 
tissue disorders 

Osteoarthritis, 
myalgia, 
arthralgia, joint 
disorder, 
bone pain 

 Atypical 
subtrochanteric 
and diaphyseal 
femoral 
fractures†  

Osteonecrosis  
of jaw†**  
Osteonecrosis 
of the external 
auditory canal 
(bisphosphonat
e class adverse 
reaction)† 

 

Renal and 
urinary 
disorders 

 Urinary retention, 
renal cyst 

   

Reproductive 
system and 
breast disorders 

 Pelvic pain    

General 
disorders and 
administration 
site conditions 

Pyrexia, 
influenza-like 
illness**, oedema 
peripheral, 
asthenia, thirst 

Hypothermia    

Investigations Gamma-GT 
increased, 
creatinine 
increased 

Blood alkaline 
phosphatase 
increase, weight 
decrease 

   

Injury, 
poisoning and 
procedural 
complications 

 Injury, injection site 
pain 

   

**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. 
 
Influenza-like illness 
A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In 
most cases no specific treatment was required and the symptoms subsided after a couple of hours/days. 
 
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. 
 



 34 

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. 
 
Anaphylactic reaction/shock 
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated 
with intravenous ibandronic acid. 
 
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. 
 
4.9 Overdose 
 
Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for 
infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical 
studies with high doses, kidney and liver function should be monitored. Clinically relevant 
hypocalcaemia should be corrected by intravenous administration of calcium gluconate. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: Medicinal products for treatment of bone diseases, bisphosphonate, ATC 
Code: M05BA06. 
 
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. 
Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. 
Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear. 
 
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of 
gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption 
has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline 
previously incorporated into the skeleton. 
 
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did 
not have any effect on bone mineralisation. 
 
Bone resorption due to malignant disease is characterised by excessive bone resorption that is not 
balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, 
reducing bone resorption and thereby reducing skeletal complications of the malignant disease. 
 
Clinical studies in the treatment of tumour-induced hypercalcaemia 
Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic 
acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is 
characterised by a decrease in serum calcium and urinary calcium excretion. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 35 

In the dose range recommended for treatment, the following response rates with the respective 
confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected 
serum calcium ≥ 3.0 mmol/l after adequate rehydration. 
 
Ibandronic 
acid dose 

% of Patients with 
Response 

90% Confidence 
Interval 

2 mg 54 44-63 

4 mg 76 62-86 

6 mg 78 64-88 

 
For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The 
median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 
days. 
 
Clinical studies in the prevention of skeletal events in patients with breast cancer and bone metastases 
Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose 
dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose 
dependent effect on skeletal events. 
 
Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg 
administered intravenously was assessed in one randomized placebo controlled phase III trial with a 
duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone 
metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The 
results from this trial are summarised below. 
 
Primary efficacy endpoints 
The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite 
endpoint which had the following skeletal related events (SREs) as sub-components:  
 
- radiotherapy to bone for treatment of fractures/impending fractures  
- surgery to bone for treatment of fractures  
- vertebral fractures  
- non-vertebral fractures  
 
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a 
single 12 week period could be potentially related. Multiple events were therefore counted only once 
for the purposes of the analysis. Data from this study demonstrated a significant advantage for 
intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted 
SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there 
was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results 
are summarised in Table 2. 
 



 36 

Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)  
 
 All Skeletal Related Events (SREs) 

Placebo 
n=158 

Bondronat 6 mg 
n=154 

 

p-value 

SMPR (per patient year) 
 

1.48 1.19 p=0.004 

Number of events (per 
patient) 
 

3.64 2.65 p=0.025 

SRE relative risk  
 

- 0.60 p=0.003 

 
Secondary efficacy endpoints 
A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg 
compared to placebo. The pain reduction was consistently below baseline throughout the entire study 
and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was 
significantly less in Bondronat treated patients compared with placebo. A tabular summary of these 
secondary efficacy results is presented in Table 3. 
 
Table 3 Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease) 
 
 Placebo 

n=158 
Bondronat 6 mg 
n=154 

 p-value 

Bone pain * 
 

0.21 -0.28 p<0.001 

Analgesic use * 
 

0.90 0.51 p=0.083 

Quality of Life * 
 

-45.4 -10.3 p=0.004 

* Mean change from baseline to last assessment. 
 
There was a marked depression of urinary markers of bone resorption (pyridinoline and 
deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to 
placebo. 
 
In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 
15 minutes was compared. No difference was observed in the indicators of renal function. The overall 
adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the 
known safety profile over longer infusion times and no new safety concerns were identified relating to 
the use of a 15 minute infusion time.  
 
A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of 
<50ml/min. 
 
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. 
 
5.2 Pharmacokinetic properties 
 
After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose 
proportional. 
 



 37 

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 interaction with other medicinal products, 
due to displacement is unlikely. 
 
Biotransformation 
There is no evidence that ibandronic acid is metabolized in animals or humans. 
 
Elimination 
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but 
the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels 
fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration 
respectively. No systemic accumulation was observed when ibandronic acid was administered 
intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease. 
 
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal 
clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total 
clearance and is related to creatinine clearance. The difference between the apparent total and renal 
clearances is considered to reflect the uptake by bone. 
 
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. 
 
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  
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to 
creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 
21.2 mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. 
In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 
minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild 
(mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal 
impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not 
increased in patients with mild renal impairment and increased by 12% in patients with moderate renal 
impairment. For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage 
adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or 
severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in 
patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (see 
section 4.2). 
 
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% 



 38 

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 that 
should be considered (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 
 
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 medicinal 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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Acetic acid (99%) 
Sodium acetate 
Water for injections 
 
6.2 Incompatibilities 
 
To avoid potential incompatibilities Bondronat concentrate for solution for infusion should only be 
diluted with isotonic sodium chloride solution or 5% glucose solution. 
 
Bondronat should not be mixed with calcium containing solutions. 
 
6.3 Shelf life 
 
5 years 
After reconstitution: 24 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions prior to reconstitution. 



 39 

After reconstitution: Store at 2 °C – 8 °C (in a refrigerator). 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution has taken place in 
controlled and validated aseptic conditions. 
 
6.5 Nature and contents of container 
 
Bondronat is supplied as packs containing 1, 5 and 10 vials (6 ml type I glass vial with a bromobutyl 
rubber stopper). Not all pack sizes may be marketed. 
 
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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/96/012/011 
EU/1/96/012/012 
EU/1/96/012/013 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 June 1996 
 
Date of latest renewal: 25 June 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



 40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRIDUCT 
 



 41 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Concentrate for solution for infusion 
 
Waymade PLC 
Sovereign House,  
Miles Gray Road,  
Basildon, Essex,  
SS14 3FR 
United Kingdom 
 
Waymade PLC 
Josselin Road 
Burnt Mills Industrial Estate 
Basildon,   
SS13 1QF 
United Kingdom  
 
Atnahs Pharma Denmark ApS, 
Copenhagen Towers,  
Ørestads Boulevard 108, 5.tv 
DK-2300 København S,  
Denmark 
 
Film-coated tablet 
 
Waymade PLC 
Sovereign House, 
Miles Gray Road, 
Basildon, Essex,  
SS14 3FR 
United Kingdom 
 
Waymade PLC 
Josselin Road 
Burnt Mills Industrial Estate 
Basildon, 
SS13 1QF 
United Kingdom 
 
IL CSM Clinical Supplies Management GmbH 
Marie-Curie-Strasse 8 
Lörrach 
Baden-Württemberg 
79539, Germany  
 
Atnahs Pharma Denmark ApS, 
Copenhagen Towers,  
Ørestads Boulevard 108, 5.tv 
DK-2300 København S,  
Denmark 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 



 42 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Risk Management Plan (RMP)  
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorsation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

•  At the request of the European Medicines Agency.  
•  Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimization) milestone being reached. 

 
Additional risk minimisation measures  
The MAH shall ensure that a patient reminder card regarding osteonecrosis of the jaw is implemented. 



 43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 45 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer Carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 2 mg concentrate for solution for infusion 
ibandronic acid  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 2 mg of ibandronic acid (as sodium monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium acetate, sodium chloride, acetic acid and water for injections. See the package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Intravenous use, for infusion after dilution 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
This medicinal product does not require any special storage conditions prior to reconstitution. After 
dilution the infusion solution is stable for 24 hours at 2 °C - 8 °C (in a refrigerator) 
 
 



 46 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/012/004 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 



 47 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Bondronat 2 mg concentrate for solution for infusion 
ibandronic acid 
I.V. use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
 



 48 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer Carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 50 mg film-coated tablets 
ibandronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 50 mg of ibandronic acid (as sodium monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
The tablets also contain lactose monohydrate. See the package leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablets 
 
28 film-coated tablets 
84 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Do not suck, chew or crush tablets 
Read the package leaflet before use 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture 
 



 49 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/012/009: 28film-coated tablets 
EU/1/96/012/010: 84 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
bondronat 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



 50 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
Blister foil 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 50 mg film-coated tablets 
ibandronic acid 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
 



 51 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
Outer Carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bondronat 6 mg concentrate for solution for infusion 
ibandronic acid  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 6 mg of ibandronic acid (as sodium  monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium acetate, sodium chloride, acetic acid and water for injections. See the package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
5 vials 
10 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Intravenous use, for infusion after dilution 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
This medicinal product does not require any special storage conditions prior to reconstitution. After 
dilution the infusion solution is stable for 24 hours at 2 °C - 8 °C (in a refrigerator) 



 52 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/012/011: 1 vial 
EU/1/96/012/012: 5 vials 
EU/1/96/012/013: 10 vials 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 



 53 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Bondronat 6 mg concentrate for solution for infusion 
ibandronic acid  
I.V. use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
6 ml 
 
 
6. OTHER 
 
 



 54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 55 

Package leaflet: Information for the patient 
 

Bondronat 2 mg concentrate for solution for infusion 
ibandronic acid  

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again 
• If you have any further questions, ask your doctor, pharmacist or nurse 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4 
 
What is in this leaflet:  
1. What Bondronat is and what it is used for 
2. What you need to know before you receive Bondronat 
3. How to receive Bondronat 
4. Possible side effects 
5. How to store Bondronat 
6. Contents of the pack and other information 
 
 
1. What Bondronat is and what it is used for 
 
Bondronat contains the active substance ibandronic acid. This belongs to a group of medicines called 
bisphosphonates. 

 
Bondronat is used in adults and prescribed to you if you have breast cancer that has spread to your 
bones (called ‘bone‘metastases’).  
• It helps to prevent your bones from breaking (fractures) 
• It helps to prevent other bone problems that may need surgery or radiotherapy   
 
Bondronat can also be prescribed if you have a raised calcium level in your blood due to a tumour. 
 
Bondronat works by reducing the amount of calcium that is lost from your bones. This helps to stop 
your bones from getting weaker.  
 
 
2. What you need to know before you receive Bondronat 
 
Do not receive Bondronat: 
• if you are allergic to ibandronic acid or any of the other ingredients of this medicine that are 

listed in section 6 
• if you have, or have ever had low levels of calcium in your blood 
 
Do not receive this medicine if any of the above apply to you. If you are not sure, talk to your doctor 
or pharmacist before having Bondronat. 
 
Warnings and precautions 
A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported very 
rarely in the post marketing setting in patients receiving Bondronat for cancer-related conditions.  ONJ 
can also occur after stopping treatment. 
 
It is important to try and prevent ONJ developing as it is a painful condition that can be difficult to 
treat. In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions 
you should take. 
 



 56 

Before receiving treatment, tell your doctor/nurse (health care professional) if: 
• you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

planned tooth extraction 
• you don’t receive routine dental care or have not had a dental check up for a long time 
• you are a smoker (as this may increase the risk of dental problems) 
• you have previously been treated with a bisphosphonate (used to treat or prevent bone 

disorders) 
• you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
• you have cancer.  
 
Your doctor may ask you to undergo a dental examination before starting treatment with Bondronat.  
 
While being treated, you should maintain good oral hygiene (including regular teeth brushing) and 
receive routine dental check-ups. If you wear dentures you should make sure these fit properly. If you 
are under dental treatment or will undergo dental surgery (e.g. tooth extractions), inform your doctor 
about your dental treatment and tell your dentist that you are being treated with Bondronat.  
 
Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth 
such as loose teeth, pain or swelling, non-healing of sores or discharge, as these could be signs of 
osteonecrosis of the jaw. 
 
Talk to your doctor, pharmacist or nurse before receiving Bondronat: 
• if you are allergic to any other bisphosphonates 
• if you have high or low levels of vitamin D, calcium or any other minerals 
• if you have kidney problems 
• if you have heart problems and the doctor recommended to limit your daily fluid intake 
 
Cases of serious, sometimes fatal allergic reaction have been reported in patients treated with 
intravenous ibandronic acid. 
If you experience one of the following symptoms, such as shortness of breath/difficulty breathing, 
tight feeling in throat, swelling of tongue, dizziness, feeling of loss of consciousness, redness or 
swelling of face, body rash, nausea and vomiting, you should immediately alert your doctor or nurse 
(see section 4). 

 
Children and adolescents 
Bondronat should not be used in children and adolescents below the age of 18 years. 
 
Other medicines and Bondronat 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Bondronat can affect the way some other medicines work. Also, some 
other medicines can affect the way Bondronat works. 
 
In particular, tell your doctor or pharmacist if you are receiving a type of antibiotic injection called 
‘aminoglycoside’ such as gentamicin. This is because aminoglycosides and Bondronat can both lower 
the amount of calcium in your blood.  
 
Pregnancy and breast-feeding 
Do not receive Bondronat if you are pregnant, planning to get pregnant or if you are breast-feeding. 
Ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
You can drive and use machines as it’s expected that Bondronat has no or negligible effect on your 
ability to drive and use machines. Talk to your doctor first if you want to drive, use machines or tools.  
 
Bondronat contains less than 1 mmol sodium (23 mg) per vial, i.e. ‘essentially sodium free’. 
 
 



 57 

3. How to receive Bondronat 
 
Receiving this medicine 
• Bondronat is normally given by a doctor or other medical staff who have experience with the 

treatment of cancer 
• it is given as an infusion into your vein 
 
Your doctor may do regular blood tests while you are receiving Bondronat. This is to check that you 
are being given the right amount of this medicine.  
 
How much to receive 
Your doctor will work out how much Bondronat you will be given depending on your illness.  
If you have breast cancer that has spread to your bones, then the recommended dose is 3 vials (6 mg) 
every 3-4 weeks, as an infusion in your vein over at least 15 minutes. 
 
If you have a raised calcium level in your blood due to a tumour then the recommended dose is a 
single administration of 1 vial (2 mg) or 2 vials (4 mg), depending on the severity of your illness. The 
medicine should be administered as an infusion in your vein over two hours. A repeated dose may be 
considered in case of insufficient response or if your illness reappears. 
 
Your doctor may adjust your dose and duration of intravenous infusion if you have kidney problems. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. 
 
Talk to a nurse or a doctor straight away if you notice any of the following serious side effects 
you may need urgent medical treatment: 
 
Rare (may affect up to 1 in 1,000 people) 
• persistent eye pain and inflammation 
• new pain, weakness or discomfort in your thigh, hip or groin. You may have early signs of a 

possible unusual fracture of the thigh bone 
 
Very rare (may affect up to 1 in 10,000 people) 
• pain or sore in your mouth or jaw. You may have early signs of severe jaw problems (necrosis 

(dead bone tissue) in the jaw bone) 
• Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These 

could be signs of bone damage in the ear. 
• itching, swelling of your face, lips, tongue and throat, with difficulty breathing. You may be 

having a serious, potentially life threatening allergic reaction (see section 2) 
• severe adverse skin reactions 
 
Not known (frequency cannot be estimated from the available data) 
• asthma attack 
 



 58 

Other possible side effects 
 
Common (may affect up to 1 in 10 people) 
• flu-like symptoms, including fever, shaking and shivering, feeling of discomfort, fatigue, bone 

pain and aching muscles and joints. These symptoms usually disappear within a couple of hours 
or days. Talk to a nurse or doctor if any effects become troublesome or last more than a couple 
of days 

• rise in body temperature 
• stomach and tummy pain, indigestion, being sick, vomiting or having diarrhoea (loose bowels) 
• low calcium or phosphate levels in your blood 
• changes in blood test results such as Gamma GT or creatinine  
• a heart rhythm problem called ‘bundle branch block’ 
• pain in your bone or muscles  
• headache, feeling dizzy or feeling weak 
• feeling thirsty, sore throat, changes in taste 
• swollen legs or feet 
• aching joints, arthritis, or other joint problems 
• problems with your parathyroid gland 
• bruising 
• infections  
• a problem with your eyes called ‘cataracts’  
• skin problems 
• tooth problems  
 
Uncommon (may affect less than 1 in 100 people) 
• shaking or shivering  
• your body temperature getting too low (‘hypothermia’) 
• a condition affecting the blood vessels in your brain called ‘cerebrovascular disorder’ (stroke  

or brain bleeding) 
• heart and circulatory problems (including palpitations, heart attack, hypertension (high blood 

pressure) and varicose veins)  
• changes in your blood cells (‘anaemia’) 
• a high level of alkaline phosphatase in your blood 
• fluid build up and swelling (‘lymphoedema’) 
• fluid in your lungs 
• stomach problems such as ‘gastroenteritis” or ‘gastritis’ 
• gallstones  
• being unable to pass water (urine), cystitis (bladder inflammation)  
• migraine 
• pain in your nerves, damaged nerve root  
• deafness  
• increased sensitivity of sound, taste or touch or changes in smell 
• difficulty swallowing 
• mouth ulcers, swollen lips (‘cheilitis’), oral thrush  
• itching or tingling skin around your mouth 
• pelvic pain, discharge, itching or pain in the vagina 
• a skin growth called a ‘benign skin neoplasm” 
• memory loss  
• sleep problems, feeling anxious, emotional instability, or mood swings  
• skin rash 
• hair loss 
• injury or pain at the injection site 
• weight loss  
• kidney cyst (fluid-filled sac in the kidney)  



 59 

 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet.You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Bondronat 
 
• Keep this medicine out of the sight and reach of children 
• Do not use this medicine after the expiry date which is stated on the folding box and on the 

label after EXP. The expiry date refers to the last day of that month 
• After dilution the infusion solution is stable for 24 hours at 2-8°C (in a refrigerator) 
• Do not use this medicine if you notice that the solution is not clear or contains particles 
 
 
6. Content of the pack and other information 
 
What Bondronat contains 
• The active substance is ibandronic acid. One vial with 2 ml of a concentrate for solution for 

infusion contains 2 mg ibandronic acid (as sodium monohydrate) 
• The other ingredients are sodium chloride, acetic acid, sodium acetate and water for injections 
 
What Bondronat looks like and contents of the pack 
Bondronat is a colourless, clear solution. Bondronat is supplied as packs containing 1 vial (2 ml type I 
glass vial with a bromobutyl rubber stopper). 
 
Marketing Authorisation Holder and Manufacturer 

Marketing Authorisation Holder 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
Manufacturer 
Waymade PLC 
Sovereign House, 
Miles Gray Road, 
Basildon, Essex,  
SS14 3FR 
United Kingdom 
 
Waymade PLC 
Josselin Road 
Burnt Mills Industrial Estate 
Basildon, SS13 1QF 
United Kingdom 
 
Atnahs Pharma Denmark ApS, 
Copenhagen Towers,  
Ørestads Boulevard 108, 5.tv 
DK-2300 København S,  
Denmark 
 
This leaflet was last revised in {MM/YYYY} 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 60 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/  

http://www.ema.europa.eu/


 61 

------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only 
 
Dosage: Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases 
The recommended dose for prevention of skeletal events in patients with breast cancer and bone 
metastases is 6 mg intravenously given every 3-4 weeks. The dose should be infused over at least 15 
minutes.  
 
Patients with renal impairment  
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is 
necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal 
impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with 
breast cancer and metastatic bone disease the following dosing recommendations should be followed: 
 
Creatinine Clearance 

(ml/min) Dosage Infusion Volume 
1 and Time 2 

≥50 CLcr<80 6 mg (6 ml of concentrate for solution for infusion) 100 ml over 15 minutes 

≥30 CLcr <50 4 mg (4 ml of concentrate for solution for infusion) 500 ml over 1 hour 

<30 2 mg (2 ml of concentrate for solution for infusion) 500 ml over 1 hour 
1  0.9% sodium chloride solution or 5% glucose solution 
2  Administration every 3 to 4 week 
 
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min. 
 
Dosage: Treatment of Tumour-induced Hypercalcaemia 
Bondronat is usually administered in a hospital setting. The dose is determined by the doctor 
considering the following factors. 
 
Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) 
sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the 
tumour type. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* 
≥3 mmol/l or ≥12 mg/dl) 4 mg will be an adequate single dosage. In patients with moderate 
hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. 
The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms 
of efficacy. 
 
* Note albumin-corrected serum calcium concentrations are calculated as follows: 
 
Albumin-corrected  
Serum calcium 
(mmol/l) 

= Serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8 

or 
Albumin-corrected  
Serum calcium (mg/dl) 

= Serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)] 

   
To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 
4. 

 
In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The 
median time to relapse (re-increase of serum albumin corrected serum calcium above 3 mmol/l) was 
18-19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg. 
 



 62 

Method and route of administration 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. 
 
For this purpose the contents of the vial are to be used as follows: 
 
• Prevention of Skeletal Events in patients with breast cancer and bone metastases - added to 

100 ml isotonic sodium chloride solution or 100 ml 5% dextrose solution and infused over at 
least 15 minutes. See also dosage section above for patients with renal impairment 

• Treatment of tumour-induced hypercalcaemia - added to 500 ml isotonic sodium chloride 
solution or 500 ml 5% dextrose solution and infused over 2 hours 

 
Note: 
In order to avoid potential incompatibilities, Bondronat concentrate for solution for infusion should 
only be mixed with isotonic sodium chloride solution or with 5% dextrose solution. Calcium 
containing solutions should not be mixed with Bondronat concentrate for solution for infusion. 
 
Diluted solutions are for single use. Only clear solutions without particles should be used. 
 
It is recommended that the product once diluted be used immediately (see point 5 of this leaflet “How 
to store Bondronat”). 
 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion.  
Care must be taken not to  administer Bondronat concentrate for solution for infusion via intra-arterial 
or paravenous administration, as this could lead to tissue damage. 
 
Frequency of administration 
For treatment of tumour induced hypercalcaemia, Bondronat concentrate for solution for infusion is 
generally given as a single infusion.  
 
For the prevention of skeletal events in patients with breast cancer and bone metastases, the Bondronat 
infusion is repeated at 3-4 week intervals. 
 
Duration of treatment 
A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. 
Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy. 
 
For patients with breast cancer and bone metastases, Bondronat infusion should be administered every 
3-4 weeks. In clinical trials, therapy has continued for up to 96 weeks. 
 
Overdose 
Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for 
infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical 
studies with high doses, kidney and liver function should be monitored. 
 
Clinically relevant hypocalcaemia (very low serum calcium levels) should be corrected by intravenous 
administration of calcium gluconate. 
 



 63 

Package leaflet: Information for the patient 
 

Bondronat 50 mg film-coated tablets 
ibandronic acid 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again 
• If you have any further questions, ask your doctor or pharmacist 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4 
 
What is in this leaflet:  
1. What Bondronat is and what it is used for 
2. What you need to know before you take Bondronat 
3. How to take Bondronat 
4. Possible side effects 
5 How to store Bondronat 
6.  Contents of the pack and other information 
 
 
1. What Bondronat is and what it is used for 
 
Bondronat contains the active substance ibandronic acid. This belongs to a group of medicines called 
bisphosphonates.  
 
Bondronat is used in adults and prescribed to you if you have breast cancer that has spread to your 
bones (called ‘bone metastases’).  
 
• It helps to prevent your bones from breaking (fractures)  
• It also helps to prevent other bone problems that may need surgery or radiotherapy  
 
Bondronat works by reducing the amount of calcium that is lost from your bones. This helps to stop 
your bones from getting weaker.  
 
 
2. What you need to know before you take Bondronat 
 
Do not take Bondronat: 
• if you are allergic to ibandronic acid or any of the other ingredients of this medicine that are 

listed in section 6 
• if you have problems with your food pipe/gullet (oesophagus) such as narrowing or difficulty 

swallowing 
• if you cannot stand or sit upright for at least one hour (60 minutes) at a time 
• if you have or ever had low calcium in your blood 
Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Bondronat. 
 
Warnings and precautions 
A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported very 
rarely in the post marketing setting in patients receiving Bondronat for cancer-related conditions.  ONJ 
can also occur after stopping treatment. 
 



 64 

It is important to try and prevent ONJ developing as it is a painful condition that can be difficult to 
treat. In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions 
you should take. 
 
Before receiving treatment, tell your doctor/nurse (health care professional) if: 
• you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

planned tooth extraction 
• you don’t receive routine dental care or have not had a dental check up for a long time 
• you are a smoker (as this may increase the risk of dental problems) 
• you have previously been treated with a bisphosphonate (used to treat or prevent bone 

disorders) 
• you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
• you have cancer.  
 
Your doctor may ask you to undergo a dental examination before starting treatment with Bondronat.  
 
While being treated, you should maintain good oral hygiene (including regular teeth brushing) and 
receive routine dental check-ups. If you wear dentures you should make sure these fit properly. If you 
are under dental treatment or will undergo dental surgery (e.g. tooth extractions), inform your doctor 
about your dental treatment and tell your dentist that you are being treated with Bondronat.  
 
Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth 
such as loose teeth, pain or swelling, non-healing of sores or discharge, as these could be signs of 
osteonecrosis of the jaw. 
 
Talk to your doctor or pharmacist before taking Bondronat: 
• if you are allergic to any other bisphosphonates 
• if you have any swallowing or digestion problems 
• if you have high or low blood levels of vitamin D or any other minerals 
• if you have kidney problems 
 
Irritation, inflammation or ulceration of the gullet/food pipe (oesophagus) often with symptoms of 
severe pain in the chest, severe pain after swallowing food and/or drink, severe nausea, or vomiting 
may occur, especially if you do not drink a full glass of water and/or if you lie down within an hour of 
taking Bondronat. If you develop these symptoms, stop taking Bondronat and tell your doctor straight 
away (see sections 3 and 4). 
 
Children and adolescents  
Bondronat should not be used in children and adolescents below the age of 18 years. 
 
Other medicines and Bondronat 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Bondronat can affect the way some other medicines work. Also some other 
medicines can affect the way Bondronat works. 

In particular, tell your doctor or pharmacist if you are taking any of the following medicines: 
• supplements containing calcium, magnesium, iron or aluminium 
• acetylsalicylic acid and non-steroidal anti-inflammatory medicines called “NSAIDs”, such as 

ibuprofen or naproxen. This is because NSAIDs, and Bondronat can both irritate your stomach 
and gut 

• a type of antibiotic injection called “aminoglycoside” such as gentamicin. This is because 
aminoglycosides and Bondronat can both lower the amount of calcium in your blood 

 
Taking medicines that reduce stomach acid such as cimetidine and ranitidine, may slightly increase the 
effects of Bondronat. 
 



 65 

Bondronat with food and drink 
Do not take Bondronat with food or any other drinks except water as Bondronat is less effective if it is 
taken with food or drink (see section 3).  

 
Take Bondronat at least 6 hours after you last had anything to eat, drink or any other medicines or 
supplements (e.g. products containing calcium (milk), aluminium, magnesium and iron) except water. 
After taking your tablet, wait at least 30 minutes. Then you can have your first food and drink, and 
take any medicines or supplements (see section 3). 
 
Pregnancy and breast feeding 
Do not take Bondronat if you are pregnant, planning to get pregnant or if you are breast-feeding. 
Ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
You can drive and use machines as it’s expected that Bondronat has no or negligible effect on your 
ability to drive and use machines. Talk to your doctor first if you want to drive, use machine or tools. 
 
Bondronat contains lactose  
If you have been told by your doctor that you cannot tolerate or digest some sugars (e.g. if you have a 
galactose intolerance, the Lapp lactase deficiency or have problems with glucose-galactose 
absorption), talk to your doctor before taking this medicine. 
 
 
3. How to take Bondronat 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
Take your tablet at least 6 hours after you last had anything to eat, drink or any other medicines or 
supplements except water. 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. 
 
Your doctor may do regular blood tests while you are taking Bondronat. This is to check that you are 
being given the right amount of medicine. 
 
Taking this medicine 
It is important that you take Bondronat at the right time and in the right way. This is because it can 
cause irritation, inflammation or ulcers in your food pipe/gullet (oesophagus).  
 
You can help stop this happening by doing the following: 
 
• Take your tablet as soon as you get up for the day before having your first food, drink, any 

medicine or supplements  
 
• Take your tablet with a full glass of water only (about 200 mL). Do not take your tablet with 

any drink other than water  
 
• Swallow the tablet whole. Do not chew, suck or crush the tablet. Do not let the tablet dissolve in 

your mouth 
 
• After taking your tablet, wait at least 30 minutes. Then you can have your first food and drink, 

and take any medicines or supplements 
 
• Stay upright (sitting or standing) while taking your tablet and for the next hour (60 minutes). 

Otherwise, some of the medicine could leak back into your food pipe/gullet 
(oesophagus) 

 



 66 

How much to take 
The usual dose of Bondronat is one tablet each day. If you have moderate kidney problems, your 
doctor may reduce your dose to one tablet every other day. If you have severe kidney problems, your 
doctor may reduce your dose to one tablet each week. 
 
If you take more Bondronat than you should 
If you take too many tablets talk to a doctor or go to hospital straight away. Drink a full glass of milk 
before you go. Do not make yourself sick. Do not lie down. 
 
If you forget to take Bondronat 
Do not take a double dose to make up for a forgotten dose. If you are taking a tablet each day, skip the 
missed dose completely. Then carry on as usual the next day. If you are taking a tablet every other day 
or once a week, ask your doctor or pharmacist for advice. 
 
If you stop taking Bondronat 
Keep taking Bondronat for as long as your doctor tells you. This is because the medicine will only 
work if it is taken all the time. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. 
 
Talk to a nurse or a doctor straight away if you notice any of the following serious side effects,  
you may need urgent medical treatment: 
 
Common (may affect up to 1 in 10 people):  
• feeling sick, heartburn and discomfort in swallowing (inflammation of your gullet/ food pipe) 
 
Uncommon (may affect less than 1 in 100 people): 
• severe stomach pain. This could be a sign of an ulcer of the first section of the bowel 

(duodenum) that is bleeding, or that your stomach is inflamed (gastritis) 
 
Rare (may affect up to 1 in 1,000 people) 
• persistent eye pain and inflammation 
• new pain, weakness or discomfort in your thigh, hip or groin. You may have early signs of a 

possible unusual fracture of the thigh bone 
 
Very rare (may affect up to 1 in 10,000 people) 
• pain or sore in your mouth or jaw. You may have early signs of severe jaw problems (necrosis 

(dead bone tissue) in the jaw bone) 
• Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These 

could be signs of bone damage in the ear. 
• itching, swelling of your face, lips, tongue and throat with difficulty breathing. You may be 

having a serious, potentially life threatening allergic reaction 
• severe adverse skin reactions 
 
Not known (frequency cannot be estimated from the available data) 
• asthma attack 
 



 67 

Other possible side effects 
 
Common (may affect up to 1 in 10 people):  
• tummy pain, indigestion 
• low calcium levels in your blood 
• weakness 
 
Uncommon (may affect less than 1 in 100 people): 
• chest pain 
• itching or tingling skin (paraesthesia) 
• flu-like symptoms, feeling generally unwell or in pain 
• dry mouth, strange taste in your mouth or difficulty swallowing 
• anaemia (bloodlessness) 
• high levels of urea or high levels of parathyroid hormone in your blood 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Bondronat 
 
• Keep this medicine out of the sight and reach of children• Do not use this medicine after the 

expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last 
day of that month 

• Store in the original package in order to protect from moisture  
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 
environment 

 
 
6. Contents of the pack and other information 
 
What Bondronat contains 
• The active substance is ibandronic acid. Each film-coated tablet contains 50 mg of ibandronic 

acid (as sodium monohydrate) 
 
The other ingredients are: 
• tablet core: lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified 

stearic acid, colloidal anhydrous silica 
• tablet coat: hypromellose, titanium dioxide (E 171), talc, macrogol 6,000 
 
What Bondronat looks like and contents of the pack 
The film-coated tablets are of oblong shape and white to off-white in colour, engraved L2/IT. They are 
available in packs of 28 and 84 tablets. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 68 

Manufacturer 
Waymade PLC 
Sovereign House, 
Miles Gray Road, 
Basildon, Essex,  
SS14 3FR 
United Kingdom 
 
Waymade PLC 
Josselin Road 
Burnt Mills Industrial Estate 
Basildon, SS13 1QF 
United Kingdom 
 
IL CSM Clinical Supplies Management GmbH 
Marie-Curie-Strasse 8 
Lörrach 
Baden-Württemberg 
79539, Germany 
 
Atnahs Pharma Denmark ApS, 
Copenhagen Towers,  
Ørestads Boulevard 108, 5.tv 
DK-2300 København S,  
Denmark 
 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 



 69 

Package leaflet: Information for the patient 
 

Bondronat 6 mg concentrate for solution for infusion 
ibandronic acid  

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again 
• If you have any further questions, ask your doctor, pharmacist or nurse 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4 
 
What is in this leaflet:  
1. What Bondronat is and what it is used for 
2. What you need to know before you receive Bondronat 
3. How to receive Bondronat 
4. Possible side effects 
5. How to store Bondronat 
6. Contents of the pack and other information 
 
 
1. What Bondronat is and what it is used for 
 
Bondronat contains the active substance ibandronic acid. This belongs to a group of medicines called 
bisphosphonates. 

 
Bondronat is used in adults and prescribed to you if you have breast cancer that has spread to your 
bones (called ‘bone metastases’)  
• It helps to prevent your bones from breaking (fractures) 
• It helps to prevent other bone problems that may need surgery or radiotherapy  
 
Bondronat can also be prescribed if you have a raised calcium level in your blood due to a tumour. 
 
Bondronat works by reducing the amount of calcium that is lost from your bones. This helps to stop 
your bones from getting weaker.  
 
 
2. What you need to know before you receive Bondronat 
 
Do not receive Bondronat: 
• if you are allergic to ibandronic acid or any of the other ingredients of this medicine that are 

listed in section 6 
• if you have, or have ever had low levels of calcium in your blood 
 
Do not receive this medicine if any of the above apply to you. If you are not sure, talk to your doctor 
or pharmacist before having Bondronat. 
 
Warnings and precautions 
A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported very 
rarely in the post marketing setting in patients receiving Bondronat for cancer-related conditions.  ONJ 
can also occur after stopping treatment. 
 
It is important to try and prevent ONJ developing as it is a painful condition that can be difficult to 
treat. In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions 
you should take. 
 



 70 

Before receiving treatment, tell your doctor/nurse (health care professional) if: 
• you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

planned tooth extraction 
• you don’t receive routine dental care or have not had a dental check up for a long time 
• you are a smoker (as this may increase the risk of dental problems) 
• you have previously been treated with a bisphosphonate (used to treat or prevent bone 

disorders) 
• you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
• you have cancer  
 
Your doctor may ask you to undergo a dental examination before starting treatment with Bondronat.  
 
While being treated, you should maintain good oral hygiene (including regular teeth brushing) and 
receive routine dental check-ups. If you wear dentures you should make sure these fit properly. If you 
are under dental treatment or will undergo dental surgery (e.g. tooth extractions), inform your doctor 
about your dental treatment and tell your dentist that you are being treated with Bondronat.  
 
Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth 
such as loose teeth, pain or swelling, non-healing of sores or discharge, as these could be signs of 
osteonecrosis of the jaw. 
 
Talk to your doctor, pharmacist or nurse before receiving Bondronat: 
• if you are allergic to any other bisphosphonates 
• if you have high or low levels of vitamin D, calcium or any other minerals 
• if you have kidney problems 
• If you have heart problems and the doctor recommended to limit your daily fluid intake 
 
Cases of serious, sometimes fatal allergic reaction have been reported in patients treated with 
intravenous ibandronic acid. 
If you experience one of the following symptoms, such as shortness of breath/difficulty breathing, 
tight feeling in throat, swelling of tongue, dizziness, feeling of loss of consciousness, redness or 
swelling of face, body rash, nausea and vomiting, you should immediately alert your doctor or nurse 
(see section 4). 

 
Children and adolescents 
Bondronat should not be used in children and adolescents below the age of 18 years. 
 
Other medicines and Bondronat 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Bondronat can affect the way some other medicines work. Also, some 
other medicines can affect the way Bondronat works. 
 
In particular, tell your doctor or pharmacist if you are receiving a type of antibiotic injection called 
‘aminoglycoside’ such as gentamicin. This is because aminoglycosides and Bondronat can both lower 
the amount of calcium in your blood.  
 
Pregnancy and breast-feeding 
Do not receive Bondronat if you are pregnant, planning to get pregnant or if you are breast-feeding. 
Ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
You can drive and use machines as it’s expected that Bondronat has no or negligible effect on your 
ability to drive and use machines. Talk to your doctor first if you want to drive, use machines or tools.  
 
Bondronat contains less than 1 mmol sodium (23 mg) per vial, i.e. ‘essentially sodium free’. 
 
 



 71 

3. How to receive Bondronat 
 
Receiving this medicine 
• Bondronat is normally given by a doctor or other medical staff who have experience with the 

treatment of cancer 
• It is given as an infusion into your vein 
 
Your doctor may do regular blood tests while you are receiving Bondronat. This is to check that you 
are being given the right amount of this medicine.  
 
How much to receive 
Your doctor will work out how much Bondronat you will be given depending on your illness.  
If you have breast cancer that has spread to your bones, then the recommended dose is 1 vial (6 mg) 
every 3-4 weeks, as an infusion in your vein over at least 15 minutes. 
 
If you have a raised calcium level in your blood due to a tumour,then the recommended dose is a 
single administration of  2 mg or 4 mg depending on the severity of your illness. The medicine should 
be administered as an infusion in your vein over two hours. A repeated dose may be considered in case 
of insufficient response or if your illness reappears. 
 
Your doctor may adjust your dose and duration of intravenous infusion if you have kidney problems. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. 
 
Talk to a nurse or a doctor straight away if you notice any of the following serious side effects 
you may need urgent medical treatment: 
 
Rare (may affect up to 1 in 1,000 people) 
• persistent eye pain and inflammation 
• new pain, weakness or discomfort in your thigh, hip or groin. You may have early signs of a 

possible unusual fracture of the thigh bone 
 
Very rare (may affect up to 1 in 10,000 people) 
• pain or sore in your mouth or jaw. You may have early signs of severe jaw problems (necrosis 

(dead bone tissue) in the jaw bone) 
• Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These 

could be signs of bone damage in the ear. 
• itching, swelling of your face, lips, tongue and throat, with difficulty breathing. You may be 

having a serious, potentially life threatening allergic reaction (see section 2) 
• severe adverse skin reactions 
 
Not known (frequency cannot be estimated from the available data) 
• asthma attack 
 



 72 

Other possible side effects 
 
Common (may affect  up to 1 in 10 people) 
• flu-like symptoms, including fever, shaking and shivering, feeling of discomfort, fatigue, bone 

pain and aching muscles and joints. These symptoms usually disappear within a couple of hours 
or days. Talk to a nurse or doctor if any effects become troublesome or last more than a couple 
of days 

• rise in body temperature 
• stomach and tummy pain, indigestion, being sick, vomiting or having diarrhoea (loose bowels) 
• low calcium or phosphate levels in your blood 
• changes in blood test results such as Gamma GT or creatinine  
• a heart rhythm problem called ‘bundle branch block’ 
• pain in your bone or muscles  
• headache, feeling dizzy or feeling weak 
• feeling thirsty, sore throat, changes in taste 
• swollen legs or feet 
• aching joints, arthritis, or other joint problems 
• problems with your parathyroid gland 
• bruising 
• infections  
• a problem with your eyes called ‘cataracts’  
• skin problems 
• tooth problems  
 
Uncommon (may affect less than 1 in 100 people) 
• shaking or shivering  
• your body temperature getting too low (‘hypothermia’) 
• a condition affecting the blood vessels in your brain called ‘cerebrovascular disorder’” (stroke 

or brain bleeding) 
• heart and circulatory problems (including palpitations, heart attack, hypertension (high blood 

pressure) and varicose veins)  
• changes in your blood cells (‘anaemia’) 
• a high level of alkaline phosphatase in your blood 
• fluid build up and swelling (‘lymphoedema’) 
• fluid in your lungs 
• stomach problems such as ‘gastroenteritis’ or ‘gastritis’ 
• gallstones  
• being unable to pass water (urine), cystitis (bladder inflammation)  
• migraine 
• pain in your nerves, damaged nerve root  
• deafness  
• increased sensitivity of sound, taste or touch or changes in smell 
• difficulty swallowing 
• mouth ulcers, swollen lips (‘cheilitis’), oral thrush   
• itching or tingling skin around your mouth 
• pelvic pain, discharge, itching or pain in the vagina 
• a skin growth called a ‘benign skin neoplasm’ 
• memory loss  
• sleep problems, feeling anxious, emotional instability, or mood swings  
• skin rash 
• hair loss 
• injury or pain at the injection site 
• weight loss  
• kidney cyst (fluid-filled sac in the kidney)  



 73 

 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Bondronat 
 
• Keep this medicine out of the sight and reach of children 
• Do not use this medicine after the expiry date which is stated on the folding box and on the 

label after EXP. The expiry date refers to the last day of that month 
• After dilution the infusion solution is stable for 24 hours at 2-8 °C (in a refrigerator) 
• Do not use this medicine if you notice that the solution is not clear or contains particles 
 
 
6. Content of the pack and other information 
 
What Bondronat contains 
• The active substance is ibandronic acid. One vial with 6 ml of a concentrate for solution for 

infusion contains 6 mg ibandronic acid (as sodium monohydrate) 
• The other ingredients are sodium chloride, acetic acid, sodium acetate and water for injections 
 
What Bondronat looks like and contents of the pack 
Bondronat is a colourless, clear solution. Bondronat is supplied as packs containing 1, 5 and 10 vials 
(6 ml type I glass vialwith a bromobutyl rubber stopper). Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 

Marketing Authorisation Holder 
Atnahs Pharma Netherlands B.V. 
Strawinskylaan 3127 
1077 ZX Amsterdam 
Netherlands 
 
Manufacturer 
Waymade PLC 
Sovereign House, 
Miles Gray Road, 
Basildon, Essex,  
SS14 3FR 
United Kingdom 
 
Waymade PLC 
Josselin Road 
Burnt Mills Industrial Estate 
Basildon, SS13 1QF 
United Kingdom  
 
Atnahs Pharma Denmark ApS, 
Copenhagen Towers,  
Ørestads Boulevard 108, 5.tv 
DK-2300 København S,  
Denmark 
 
This leaflet was last revised in {MM/YYYY} 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 74 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/  

http://www.ema.europa.eu/


 75 

------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only 
 
Dosage: Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases 
The recommended dose for prevention of skeletal events in patients with breast cancer and bone 
metastases is 6 mg intravenously given every 3-4 weeks. The dose should be infused over at least 15 
minutes.  
 
Patients with renal impairment  
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is 
necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal 
impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with 
breast cancer and metastatic bone disease the following dosing recommendations should be followed: 
 
Creatinine Clearance 

(ml/min) Dosage Infusion Volume 
1 and Time 2 

≥50 CLcr<80 6 mg (6 ml of concentrate for solution for infusion) 100 ml over 15 minutes 

≥30 CLcr <50 4 mg (4 ml of concentrate for solution for infusion) 500 ml over 1 hour 

<30 2 mg (2 ml of concentrate for solution for infusion) 500 ml over 1 hour 
1  0.9% sodium chloride solution or 5% glucose solution 
2  Administration every 3 to 4 week 
 
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min. 
 
Dosage: Treatment of Tumour-induced Hypercalcaemia 
Bondronat is usually administered in a hospital setting. The dose is determined by the doctor 
considering the following factors. 
 
Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) 
sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the 
tumour type. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* 
≥3 mmol/l or ≥12 mg/dl) 4 mg will be an adequate single dosage. In patients with moderate 
hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. 
The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms 
of efficacy. 
 
* Note albumin-corrected serum calcium concentrations are calculated as follows: 
 
Albumin-corrected  
Serum calcium 
(mmol/l) 

= Serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8 

or 
Albumin-corrected  
Serum calcium (mg/dl) 

= Serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)] 

   
To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 
4. 

 
In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The 
median time to relapse (re-increase of serum albumin corrected serum calcium above 3 mmol/l) was 
18-19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg. 
 



 76 

Method and route of administration 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. 
 
For this purpose the contents of the vial are to be used as follows: 
 
• Prevention of Skeletal Events in patients with breast cancer and bone metastases - added to 

100 ml isotonic sodium chloride solution or 100 ml 5% dextrose solution and infused over at 
least 15 minutes. See also dosage section above for patients with renal impairment 

• Treatment of tumour-induced hypercalcaemia - added to 500 ml isotonic sodium chloride 
solution or 500 ml 5% dextrose solution and infused over 2 hours 

 
Note: 
In order to avoid potential incompatibilities, Bondronat concentrate for solution for infusion should 
only be mixed with isotonic sodium chloride solution or with 5% dextrose solution. Calcium 
containing solutions should not be mixed with Bondronat concentrate for solution for infusion. 
 
Diluted solutions are for single use. Only clear solutions without particles should be used. 
 
It is recommended that the product once diluted be used immediately (see point 5 of this leaflet ‘How 
to store Bondronat’). 
 
Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. 
Care must be taken not to administer Bondronat concentrate for solution for infusion via intra-arterial 
or paravenous administration, as this could lead to tissue damage. 
 
Frequency of administration 
For treatment of tumour induced hypercalcaemia, Bondronat concentrate for solution for infusion is 
generally given as a single infusion.  
 
For the prevention of skeletal events in patients with breast cancer and bone metastases, the Bondronat 
infusion is repeated at 3-4 week intervals. 
 
Duration of treatment 
A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. 
Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy. 
 
For patients with breast cancer and bone metastases, Bondronat infusion should be administered every 
3-4 weeks. In clinical trials, therapy has continued for up to 96 weeks. 
 
Overdose 
Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for 
infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical 
studies with high doses, kidney and liver function should be monitored. 
 
Clinically relevant hypocalcaemia (very low serum calcium levels) should be corrected by intravenous 
administration of calcium gluconate. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET