ACID IBANDRONIC ACCORD 6mg perfusive solution concentrate medication leaflet

Ibandronic acid Accord 2 mg concentrate for solution for infusion

Ibandronic acid Accord 6 mg concentrate for solution for infusion

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as sodiummonohydrate).

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as sodiummonohydrate).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless solution.

Ibandronic acid is indicated in adults for− Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapyor surgery) in patients with breast cancer and bone metastases.

− Treatment of tumour-induced hypercalcaemia with or without metastases.

Patients treated with ibandronic acid should be given the package leaflet and the patient reminder card.

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

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 bonemetastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over atleast 15 minutes.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mildrenal impairment. There are no data available characterising the use of a shorter infusion time inpatients 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 patientgroup.

Treatment of tumour-induced hypercalcaemia

Prior to treatment with ibandronic acid the patient should be adequately rehydrated with 9 mg/ml(0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemiaas well as the tumour type. In general patients with osteolytic bone metastases require lower doses thanpatients 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. Inpatients 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 addany further benefit in terms of efficacy.

* Note albumin-corrected serum calcium concentrations are calculated as follows:

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

Or

Albumin-corrected serum = serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)]calcium (mg/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. Themedian time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was18-19 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.

Ibandronic acid concentrate for solution for infusion should be administered as an intravenous infusionover 2 hours.

No dose adjustment is required (see section 5.2).

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 andmetastatic 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 100 ml over 15 minutessolution for infusion)≥30 CLcr <50 4 mg (4 ml of concentrate for 500 ml over 1 hoursolution for infusion)<30 2 mg (2 ml of concentrate for 500 ml over 1 hoursolution for infusion)1 0.9% sodium chloride solution or 5% glucose solution2 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).

The safety and efficacy of ibandronic acid in children and adolescents below the age of 18 years havenot been established. No data are available (see section 5.1 and section 5.2).

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 ml5% dextrose solution and infused over at least 15 minutes. See also dose section above forpatients with renal impairment.

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

For single use only. Only clear solution without particles should be used.

Ibandronic acid concentrate for solution for infusion should be administered as an intravenous infusion.

Care must be taken not to administer ibandronic acid concentrate for solution for infusion viaintra-arterial or paravenous administration, as this could lead to tissue damage.

− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1− Hypocalcaemia

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treatedbefore starting ibandronic acid therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receivesupplemental 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 treatedwith intravenous ibandronic acid.

Appropriate medical support and monitoring measures should be readily available when Ibandronicacid intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergicreactions occur, immediately discontinue the injection and initiate appropriate treatment.

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patientsreceiving ibandronic acid for oncology indications (see section 4.8).

The start of treatmentor of a new course of treatment should be delayed in patients with unhealed opensoft tissue lesions in the mouth.

A dental examination with preventive dentistry and an individual benefit-risk assessment isrecommended prior to treatment with ibandronic acid 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 potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy

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

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

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease , invasivedental 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 ofsores or discharge during treatment with ibandronic acid. While on treatment, invasive dentalprocedures should be performed only after careful consideration and be avoided in close proximity toibandronic acid administration.

The management plan of the patients who develop ONJ should be set up in close collaborationbetween the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporaryinterruption of ibandronic acid treatment should be considered until the condition resolves andcontributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique fractures can occur anywhere along the femur f rom just below the lesser trochanter to justabove the supracondylar flare. These fractures occur after minimal or no trauma and some patientsexperience thigh or groin pain, often associated with imaging features of stress fractures, weeks tomonths before presenting with a completed femoral fracture. Fractures are often bilateral; therefore thecontralateral femur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported.

Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fractureshould 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture (seesection 4.8).

Atypical fractures of other long bones

Atypical fractures of other long bones, such as the ulna and tibia have also been reported in patientsreceiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal,or no trauma and some patients experience prodromal pain prior to presenting with a completedfracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated withthe long-term use of walking aids (see section 4.8).

Clinical studies have not shown any evidence of deterioration in renal function with long termibandronic acid therapy. Nevertheless, according to clinical assessment of the individual patient, it isrecommended that renal function, serum calcium, phosphate and magnesium should be monitored inpatients treated with ibandronic acid (see section 4.2).

As no clinical data are available, dose recommendations cannot be given for patients with severehepatic 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.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentiallysodium free.

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major humanhepatic 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 anybiotransformation.

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

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

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats havedemonstrated the presence of low levels of ibandronic acid in the milk following intravenousadministration. Ibandronic acid should not be used during breast-feeding.

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

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it isexpected that ibandronic acid has no or negligible influence on the ability to drive and use machines.

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of thefemur, osteonecrosis for the jaw, and ocular inflammation (see paragraph “description of selectedadverse reactions” and section 4.4).

Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in bodytemperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) isreported.

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 ismost frequently associated with asthenia followed by rise in body temperature and headache.

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour inducedhypercalcaemia: 311 patients treated with ibandronic acid 2 mg or 4 mg; Prevention of skeletal eventsin patients with breast cancer and bone metastases: 152 patients treated with ibandronic acid 6 mg), andfrom 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse Reactions Reported for Intravenous Administration of Ibandronic Acid

System Organ Common Uncommon Rare Very rare Not known

Class

Infections and Infection Cystitis, vaginitis,infestations oral candidiasis

Neoplasms Benign skinbenign, neoplasmmalignant, andunspecified

Blood and Anaemia, bloodlymphatic system dyscrasiadisorders

Immune system Hypersensitivity†, Asthmadisorders bronchospasm†, exacerbationangioedema†anaphylacticreaction/shock†

**

Endocrine Parathyroiddisorders disorder

Metabolism and Hypocalcaemia* Hypophosphataemianutrition *disorders

Psychiatric Sleep disorder,disorders anxiety, affectionlability

Nervous system Headache, Cerebrovasculardisorders dizziness, disorder, nerve rootdysgeusia (taste lesion, amnesia,perversion) migraine, neuralgia,hypertonia,hyperaestesia,paraesthesiacircumoral, parosmia

Eye disorders Cataract Ocularinflammation†**

Ear and Deafnesslabyrinthdisorders

Cardiac Bundle branch Myocardialdisorders block ischaemia,cardiovasculardisorder, palpitations

Respiratory, Pharyngitis Lung oedema, stridorthoracic, andmediastinaldisorders

Gastrointestinal Diarrhoea, Gastroenteritis,disorders vomiting, gastritis, mouthdyspepsia, ulceration,gastrointestinal dysphagia, cheilitispain, toothdisorder

Hepatobiliary Cholelithiasisdisorders

Skin and Skin disorder, Rash, alopecia Stevens-subcutaneous ecchymosis Johnsontissue disorders Syndrome†,

Erythema

Multiforme†,

Dermatitis

Bullous†

Musculoskeletal Osteoarthritis, Atypical Osteonecrosis of Atypicaland connective myalgia, subtrochante jaw†** fractures oftissue disorders arthralgia, joint ric and Osteonecrosis of long bonesdisorder, bone diaphyseal the external other thanpain femoral auditory canal the femurfractures† (bisphosphonateclass adversereaction)†

Renal and Urinary retention,urinary renal cystdisorders

Reproductive Pelvic painsystem andbreast disorders

General Pyrexia,Influenz Hypothermiadisorders and a-like illness**,administration oedemasite conditions peripheral,asthenia, thirst

Investigations Gamma-GT Blood alkalineincreased, phosphatase increase,creatinine weight decreaseincreased

Injury, poisoning Injury, injection siteand procedural paincomplications

**See further information below†Identified in post-marketing experience.

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels notrequiring 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. Inmost 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 withmedicinal 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.

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, evidence from epidemiological studies suggests anincreased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-termbisphosphonate therapy for postmenopausal osteoporosis, particularly beyond three to five years ofuse. The absolute risk of atypical subtrochanteric and diaphyseal long bone fractures (bisphosphonateclass adverse reaction) remains very low.

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronicacid. 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 treatedwith intravenous ibandronic acid.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Up to now there is no experience of acute poisoning with ibandronic acid concentrate for solution forinfusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinicalstudies with high doses, kidney and liver function should be monitored. Clinically relevanthypocalcaemia should be corrected by intravenous administration of calcium gluconate.

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 ofgonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorptionhas also been documented by Ca kinetic studies and by the release of radioactive tetracyclinepreviously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid didnot have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterised by excessive bone resorption that is notbalanced 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 ibandronicacid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, ischaracterised by a decrease in serum calcium and urinary calcium excretion.

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

Ibandronic % of Patients with 90% Confidenceacid dose Response Interval2 mg 54 44-634 mg 76 62-866 mg 78 64-88

For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. Themedian time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was18 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 dosedependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dosedependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with ibandronic acid 6mg administered intravenously was assessed in one randomized placebo controlled phase III trial withduration of 96 weeks. Female patients with breast cancer and radiologically confirmed bonemetastases were randomised to receive placebo (158 patients) or 6 mg ibandronic acid (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 compositeendpoint 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 asingle 12 week period could be potentially related. Multiple events were therefore counted only oncefor the purposes of the analysis. Data from this study demonstrated a significant advantage forintravenous ibandronic acid 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 ibandronic acid 6 mg andthere was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacyresults are summarised in Table 2.

Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

All Skeletal Related Events (SREs)

Placebo Ibandronic acid p-valuen=158 6 mg n=154

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 ibandronic acid6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entirestudy and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of

Life was significantly less in ibandronic acid treated patients compared with placebo. A tabularsummary of these secondary efficacy results is presented in Table 3.

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

Placebo Ibandronic acid 6 mg p-valuen=158 n=154

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 anddeoxypyridinoline) in patients treated with ibandronic acid that was statistically significant compared toplacebo.

In a study in 130 patients with metastatic breast cancer the safety of ibandronic acid infused over 1 houror 15 minutes was compared. No difference was observed in the indicators of renal function. Theoverall adverse event profile of ibandronic acid following the 15 minute infusion was consistent withthe known safety profile over longer infusion times and no new safety concerns were identified relatingto 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<50 ml/min.

Paediatric population (see section 4.2 and section 5.2)

The safety and efficacy of ibandronic acid in children and adolescents below the age of 18 years havenot been established. No data are available.

After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are doseproportional.

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

There is no evidence that ibandronic acid is metabolized in animals or humans.

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but theapparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fallquickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administrationrespectively. No systemic accumulation was observed when ibandronic acid was administeredintravenously 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. Renalclearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearanceand is related to creatinine clearance. The difference between the apparent total and renal clearances isconsidered to reflect the uptake by bone.

The secretory pathway of renal elimination does not appear to include known acidic or basic transportsystems involved in the excretion of other active substances. In addition, ibandronic acid does notinhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450system in rats.

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

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

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinineclearance (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 clinicalpharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutesinfusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (meanestimated CLcr=68.1 ml/min) and moderate (mean estimated CLcr= 41.2 ml/min) renal impairmentcompared to healthy volunteers (mean estimated CLcr=120 ml/min). Mean Cmax was not increased inpatients 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 isnecessary. For patients with moderate renal impairment (CLcr ≥30 and <50 ml/min) or severe renalimpairment (CLcr <30 ml/min) being treated for the prevention of skeletal events in patients with breastcancer 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. Theliver has no significant role in the clearance of ibandronic acid since it is not metabolized but is clearedby renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patientswith hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% attherapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinicallysignificant 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 pharmacokineticparameters studied. As renal function decreases with age, this is the only factor that should beconsidered (see renal impairment section).

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of ibandronic acid in patients less than 18 years old.

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximumhuman exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidneywas 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 ofeffects on genetic activity for ibandronic acid.

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid inintravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects onfertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. Inreproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at dosesof 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were thoseexpected for this class of medicinal products (bisphosphonates). They include a decreased number ofimplantation sites, interference with natural delivery (dystocia), an increase in visceral variations(renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

Sodium chloride

Sodium acetate trihydrate

Glacial acetic acid

Water for injections

To avoid potential incompatibilities Ibandronic acid concentrate for solution for infusion should only bediluted with isotonic sodium chloride solution or 5% glucose solution.

Ibandronic acid concentrate for solution for infusion should not be mixed with calcium containingsolutions.

3 years.

Chemical and physical in-use stability after dilution in 9 mg/ml (0.9 %) sodium chloride solution or5% glucose solution has been demonstrated for 36 hours at 25°C and 2°C to 8°C.

From a microbiological point of view, the solution for infusion should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2° C to 8°C unless dilution has taken place incontrolled and validated aseptic condition.

This medicinal product does not require any special storage conditions.

For storage conditions of the diluted medicinal product, see section 6.3.

6 ml, glass vial (type I) with ethylene tetrafluoroethylene rubber stopper and aluminium seals withlavender flip-off cap. It is supplied as packs containing 1 vial with 2 ml of concentrate.6 ml, glass vial (type I) with ethylene tetrafluoroethylene rubber stopper and aluminium seals withpink flip-off cap. It is supplied as packs containing 1, 5 or 10 vials with 6 ml of concentrate.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/12/798/001

EU/1/12/798/002

EU/1/12/798/003

EU/1/12/798/004

Date of first authorisation: 19 November 2012

Date of latest renewal: 18 September 2017

Detailed information on this medicinal product is available on the website of the European Medicines

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