BONVIVA 3mg / 3ml injection solution in pre-filled syringe medication leaflet

Bonviva 3 mg solution for injection

One pre-filled syringe of 3 ml solution contains 3 mg ibandronic acid (as sodium monohydrate).

The concentration of ibandronic acid in the solution for injection is 1mg per ml.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution.

Treatment of osteoporosis in postmenopausal women at increased risk of fracture (see section 5.1).

A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral neck fractureshas not been established.

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

The recommended dose of ibandronic acid is 3 mg, administered as an intravenous injection over 15 -30 seconds, every three months.

Patients must receive supplemental calcium and vitamin D (see section 4.4 and section 4.5),

If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injectionsshould be scheduled every 3 months from the date of the last injection.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The needfor continued treatment should be re-evaluated periodically based on the benefits and potential risks of

Bonviva on an individual patient basis, particularly after 5 or more years of use.

Bonviva injection is not recommended for use in patients who have a serum creatinine above200 μmol/l (2.3 mg/dl) or who have a creatinine clearance (measured or estimated) below 30 ml/min,because of limited clinical data available from studies including such patients (see section 4.4 andsection 5.2).

No dose adjustment is necessary for patients with mild or moderate renal impairment where serumcreatinine is equal or below 200 μmol/l (2.3 mg/dl) or where creatinine clearance (measured orestimated) is equal or greater than 30 ml/min.

No dose adjustment is required (see section 5.2).

Elderly population (>65 years)

No dose adjustment is required (see section 5.2).

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

For intravenous use over 15 - 30 seconds, every three months.

Strict adherence to the intravenous administration route is required (see section 4.4).

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

- Hypocalcaemia

Administration failures

Care must be taken not to administer Bonviva injection via intra-arterial or paravenous administrationas this could lead to tissue damage.

Bonviva, like other bisphosphonates administered intravenously, may cause a transient decrease inserum calcium values.

Existing hypocalcaemia must be corrected before starting Bonviva injection therapy. Otherdisturbances of bone and mineral metabolism should also be effectively treated before starting

Bonviva injection therapy.

All patients must receive adequate supplemental calcium and vitamin D.

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 Bonvivaintravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactionsoccur, immediately discontinue the injection and initiate appropriate treatment.

Patients with concomitant diseases, or who use medicinal products which have potential forundesirable effects on the kidney, should be reviewed regularly in line with good medical practiceduring treatment.

Due to limited clinical experience, Bonviva injection is not recommended for patients with a serumcreatinine above 200 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min (see section4.2 and section 5.2).

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

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

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

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

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

- Potency of the medicinal product that inhibit bone resorption (higher risk for highly 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,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 ofsores or discharge during treatment with Bonviva. While on treatment, invasive dental proceduresshould be performed only after careful consideration and be avoided in close proximity to Bonvivaadministration.

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 Bonviva treatment should be considered until the condition resolves and contributingrisk 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 auditorycanal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. Thepossibility of 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 from 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 ofbisphosphonate therapy in patients suspected to have an atypical femur fracture should be consideredpending 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).

Bonviva is essentially sodium free.

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the majorhuman hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does notundergo any biotransformation.

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

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats haveshown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Bonviva 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. Bonviva should not be used during breastfeeding.

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

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

In table 1 a complete list of known adverse reactions is presented.

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treatedin 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotalthree-year fracture study (MF 4411).

In the pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overallsafety of intravenous injection of Bonviva 3 mg every 3 months and oral ibandronic acid 2.5 mg dailywere shown to be similar. The overall proportion of patients who experienced an adverse reaction was26.0 % and 28.6 % for Bonviva 3 mg injection every 3 months after one year and two years,respectively. Most cases of adverse reactions did not lead to cessation of therapy.

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 occurring in postmenopausal women receiving Bonviva 3 mg injectionevery 3 months or ibandronic acid 2.5 mg daily in the phase III studies BM16550 and MF 4411, and inpost-marketing experience.

System Organ Common Uncommon Rare Very rare Not

Class known

Immune system Asthma Hypersensitivity Anaphylacticdisorders exacerbation reaction reaction/shock*†

Metabolism and hypocalcaemianutritiondisorders

Nervous system Headachedisorders

Eye disorders Ocularinflammation*†

Vascular Phlebitis/disorders thrombophlebitis

Gastrointestinal Gastritis,disorders Dyspepsia,

Diarrhoea,

Abdominalpain, Nausea,

Skin and Rash Angioedema, Stevens-Johnsonsubcutaneous Facial Syndrome†,tissues swelling/oedema, Erythemadisorders Urticaria Multiforme†,

Dermatitis

Bullous†

Musculoskeletal Arthralgia, Bone pain Atypical Osteonecrosis of Atypicaland connective Myalgia, subtrochanteric jaw*† fracturestissue disorders Musculoskeletal and diaphyseal Osteonecrosis of of longpain, Back pain femoral the external bonesfractures† auditory canal other(bisphosphonate than theclass adverse femurreaction)†

General Influenza like Injection sitedisorders and illness*, reactions,administration Fatigue Astheniasite conditions

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

Influenza-like illness

Influenza-like illness includes events reported as acute phase reaction or symptoms, includingmyalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.

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, consistent evidence from epidemiological studies suggestsan increased 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 withibandronic 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 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.

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

Based on knowledge of this class of compounds, intravenous overdosage may result in hypocalcaemia,hypophosphataemia, and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium,phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate,potassium or sodium phosphate, and magnesium sulfate, respectively.

Pharmacotherapeutic group: Medicinal products for treatment of bone diseases, bisphosphonates, ATCcode: M05BA06

Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group ofbisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activitywithout directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronicacid leads to progressive net gains in bone mass and a decreased incidence of fractures through thereduction of elevated bone turnover towards premenopausal levels in postmenopausal women.

The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronicacid prevents bone destruction experimentally induced by cessation of gonadal function, retinoids,tumours or tumour extracts. In young (fast growing) rats, the endogenous bone resorption is alsoinhibited, leading to increased normal bone mass compared with untreated animals.

Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. Ingrowing rats, there was no evidence of impaired mineralisation even at doses greater than 5,000 timesthe dose required for osteoporosis treatment.

Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogsand monkeys was associated with formation of new bone of normal quality and maintained orincreased mechanical strength even at doses in the toxic range. In humans, the efficacy of both dailyand intermittent administration with a dose-free interval of 9 - 10 weeks of ibandronic acid wasconfirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.

In animal models ibandronic acid produced biochemical changes indicative of dose-dependentinhibition of bone resorption, including suppression of urinary biochemical markers of bone collagendegradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).

Both daily, intermittent (with a dose-free interval of 9 - 10 weeks per quarter) oral doses as well asintravenous doses of ibandronic acid in postmenopausal women produced biochemical changesindicative of dose-dependent inhibition of bone resorption.

Bonviva intravenous injection decreased levels of serum C-telopeptide of the alpha chain of Type Icollagen (CTX) within 3 - 7 days of starting treatment and decreased levels of osteocalcin within3 months.

Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates ofelevated bone resorption associated with postmenopausal osteoporosis.

The histological analysis of bone biopsies after two and three years of treatment of postmenopausalwomen with doses of oral ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect. Anexpected decrease in bone turnover, normal quality of bone and absence of defects in mineralizationwere also seen after two years of treatment with Bonviva 3 mg injection.

Independent risk factors, for example, low BMD, age, the existence of previous fractures, a familyhistory of fractures, high bone turnover and low body mass index should be considered in order toidentify women at increased risk of osteoporotic fractures.

Bonviva 3 mg injection every 3 months

Bone mineral density (BMD)

Bonviva 3 mg intravenous injection, administered every 3 months, was shown to be at least aseffective as oral ibandronic acid 2.5 mg daily in a 2-year, randomised, double-blind, multicentre, non-inferiority study (BM16550) of postmenopausal women (1386 women aged 55 - 80) with osteoporosis(lumbar spine BMD T-score below -2.5 SD at baseline). This was demonstrated in both the primaryanalysis at one year and in the confirmatory analysis at two years endpoint (Table 2).

The primary analysis of data from study BM16550 at one year and the confirmatory analysis at 2 yearsdemonstrated the non-inferiority of 3 mg every 3 months injection dosing regimen compared to 2.5 mgoral daily dosing regimen, in terms of mean increases in BMD at lumbar spine, total hip, femoral neckand trochanter (Table 2).

Table 2: Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter

BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study

BM 16550.

One year data in study BM 16550 Two year data in study

BM 16550

Mean relative changes ibandronic acid Bonviva 3 mg ibandronic Bonviva 3 mgfrom baseline % [95% CI] 2.5 mg daily injection every acid 2.5 mg injection every3 months daily 3 months(N=377) (N=365) (N=334)(N=334)

Lumbar spine L2-L4 BMD 3.8 [3.4, 4.2] 4.8 [4.5, pct. 5.2] 4.8 [4.3, 5.4] 6.3 [5.7, 6.8]

Total hip BMD 1.8 [1.5, 2.1] 2.4 [2.0, 2.7] 2.2 [1.8, 2.6] 3.1 [2.6, 3.6]

Femoral neck BMD 1.6 [1.2, 2.0] 2.3 [1.9, 2.7] 2.2 [1.8, 2.7] 2.8 [2.3, 3.3]

Trochanter BMD 3.0 [2.6, 3.4] 3.8 [3.2, pct. 4.4] 3.5 [3.0, 4.0] 4.9 [4.1, 5.7]

Furthermore, Bonviva 3 mg injection every 3 months was proven superior to oral ibandronic acid2.5 mg daily for increases in lumbar spine BMD in a prospectively planned analysis at one year,p<0.001, and at two years, p<0.001.

For lumbar spine BMD, 92.1 % of patients receiving 3 mg injection every 3 months increased ormaintained their BMD after 1 year of treatment (i.e. were responders) compared with 84.9 % ofpatients receiving oral 2.5 mg daily (p=0.002). After 2 years of treatment, 92.8 % of patients receiving3 mg injections and 84.7 % of patient receiving 2.5 mg oral therapy had increased or maintainedlumbar spine BMD (p=0.001).

For total hip BMD, 82.3 % of patients receiving 3 mg injection every 3 months were responders at oneyear, compared with 75.1 % of patients receiving 2.5 mg daily orally (p=0.02). After 2 years oftreatment, 85.6 % of patients receiving 3 mg injections and 77.0 % of patient receiving 2.5 mg oraltherapy had increased or maintained total hip BMD (p=0.004).

The proportion of patients who increased or maintained their BMD at one year at both lumbar spineand total hip was 76.2 % in the 3 mg injection every 3 months arm and 67.2 % in the 2.5 mg dailyorally arm (p=0.007). At two years, 80.1 % and 68.8 % of patients met this criterion in the 3 mg every3 months injection arm and the 2.5 mg daily arm (p=0.001).

Biochemical markers of bone turn-over

Clinically meaningful reductions in serum CTX levels were observed at all time points measured. At12 months median relative changes from baseline were -58.6 % for the intravenous injection of 3 mgevery 3 months regimen and -62.6 % for oral 2.5 mg daily regimen. In addition, 64.8 % of patientsreceiving 3 mg every 3 months injection were identified as responders (defined as a decrease ≥50 %from baseline), compared with 64.9 % of patients receiving 2.5 mg daily orally. Serum CTXreduction was maintained over the 2 years, with more than half of the patients identified as respondersin both treatment groups.

Based on the results of study BM 16550, Bonviva 3 mg intravenous injection, administered every 3months is expected to be at least as effective in preventing fractures as the oral regimen of ibandronicacid 2.5 mg daily.

Ibandronic acid 2.5 mg daily tablets

In the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), astatistically significant and medically relevant decrease in the incidence of new radiographicmorphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronicacid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an exploratory regimen.

Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fastingperiod). The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal,who had a BMD at the lumbar spine of -2 to -5 SD below the premenopausal mean (T-score) in atleast one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. Ibandronic acid2.5 mg administered daily, showed a statistically significant and medically relevant reduction in theincidence of new vertebral fractures. This regimen reduced the occurrence of new radiographicvertebral fractures by 62 % (p=0.0001) over the three year duration of the study. A relative riskreduction of 61 % was observed after 2 years (p=0.0006). No statistically significant difference wasattained after 1 year of treatment (p=0.056). The anti-fracture effect was consistent over the durationof the study. There was no indication of a waning of the effect over time.

The incidence of clinical vertebral fractures was also significantly reduced by 49 % after 3 years(p=0.011). The strong effect on vertebral fractures was furthermore reflected by a statisticallysignificant reduction of height loss compared to placebo (p<0.0001).

Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)

Placebo ibandronic acid 2.5 mg daily(N=974) (N=977)

Relative risk reduction 62% (40.9, 75.1)

New morphometric vertebralfractures

Incidence of new morphometric 9.56% (7.5, 11.7) 4.68% (3.2, 6.2)vertebral fractures

Relative risk reduction of clinical 49%vertebral fracture (14.03, 69.49)

Incidence of clinical vertebral 5.33% (3.73, 6.92) 2.75%fracture (1.61, 3.89)

BMD - mean change relative to 1.26% (0.8, 1.7) 6.54% (6.1, 7.0)baseline lumbar spine at year 3

BMD - mean change relative to -0.69% 3.36%baseline total hip at year 3 (-1.0, -0.4) (3.0, 3.7)

The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation ofpatients who, at baseline, had a lumbar spine BMD T-score below -2.5 (table 4). The vertebralfracture risk reduction was very consistent with that seen in the overall population.

Table 4: Results from 3 years fracture study MF 4411 (%, 95 % CI) for patients with lumbar spine

BMD T-score below -2.5 at baseline

Placebo ibandronic acid 2.5 mg daily(N=587) (N=575)

Relative Risk Reduction 59% (34.5, 74.3)

New morphometric vertebralfractures

Incidence of new morphometric 12.54% (9.53, 15.55) 5.36% (3.31, 7.41)vertebral fractures

Relative risk reduction of clinical 50% (9.49, 71.91)vertebral fracture

Incidence of clinical vertebral 6.97% (4.67, 9.27) 3.57% (1.89, pct. 5.24)fracture

BMD - mean change relative to 1.13% (0.6, 1.7) 7.01% (6.5, 7.6)baseline lumbar spine at year 3

BMD - mean change relative to -0.70% (-1.1, -0.2) 3.59% (3.1, 4.1)baseline total hip at year 3

In the overall patient population of the study MF4411, no reduction was observed for non-vertebralfractures, however daily ibandronic acid appeared to be effective in a high-risk subpopulation (femoralneck BMD T-score < -3.0), where a non-vertebral fracture risk reduction of 69% was observed.

Daily oral treatment with ibandronic acid 2.5 mg tablets resulted in progressive increases in BMD atvertebral and nonvertebral sites of the skeleton.

Three-year lumbar spine BMD increase compared to placebo was 5.3 % and 6.5 % compared tobaseline. Increases at the hip compared to baseline were 2.8 % at the femoral neck, 3.4 % at the totalhip, and 5.5 % at the trochanter.

Biochemical markers of bone turnover (such as urinary CTX and serum Osteocalcin) showed theexpected pattern of suppression to premenopausal levels and reached maximum suppression within aperiod of 3 - 6 months of using 2.5 mg ibandronic acid daily.

A clinically meaningful reduction of 50 % of biochemical markers of bone resorption was observed asearly as one month after starting treatment with ibandronic acid 2.5 mg.

Paediatric population (see section 4.2 and section 5.2).

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

The primary pharmacological effects of ibandronic acid on bone are not directly related to actualplasma concentrations, as demonstrated by various studies in animals and humans.

Plasma concentrations of ibandronic acid increase in a dose-proportional manner after intravenousadministration of 0.5 mg to 6 mg.

Not applicable

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 85 % - 87 % (determined in vitro at therapeutic ibandronic acid concentrations), andthus there is a low potential for interaction with other medicinal products due to displacement.

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

Ibandronic acid is removed from the circulation via bone absorption (estimated to be 40 - 50 % inpostmenopausal women) and the remainder is eliminated unchanged by the kidney.

The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in therange of 10 - 72 hours. As the values calculated are largely a function of the duration of study, thedose used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, incommon with other bisphosphonates. Early plasma levels fall quickly, reaching 10 % of the peakvalues 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. Renalclearance (about 60 ml/min in healthy postmenopausal females) accounts for 50 - 60 % of totalclearance, and is related to creatinine clearance. The difference between the apparent total and renalclearances is considered to reflect the uptake by bone.

The secretory pathway appears not to include known acidic or basic transport systems involved in theexcretion of other active substances.(see section 4.5). In addition, ibandronic acid does not inhibit themajor human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system inrats.

Pharmacokinetics in special clinical situations

Pharmacokinetics of ibandronic acid are similar in men and women.

There is no evidence for any clinically relevant inter-ethnic differences between Asians and

Caucasians in ibandronic acid disposition. There is limited data available on patients of African origin.

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearlyrelated to creatinine clearance (CLcr).

No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal orabove 30 ml/min).

Subjects with severe renal impairment (CLcr less than 30 ml/min) receiving daily oral administrationof 10 mg ibandronic acid for 21 days, had 2 - 3 fold higher plasma concentrations than subjects withnormal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenousadministration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearances decreased by 67 %,77 % and 50 %, respectively, in subjects with severe renal failure, but there was no reduction intolerability associated with the increase in exposure. Due to the limited clinical experience, Bonviva isnot recommended in patients with severe renal impairment (see section 4.2 and section 4.4). Thepharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in asmall number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronicacid in the patients not undergoing haemodialysis is unknown. Due to the limited data available,ibandronic acid should not be used in all patients with end-stage renal disease.

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, which is not metabolised but is clearedby renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patientswith hepatic impairment.

Elderly population (see section 4.2)

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

Paediatric population (see section 4.2 and section 5.1)

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

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

Mutagenicity/Carcinogenicity:

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

Specific studies for the 3-monthly dosing regimen have not been performed. In studies with daily i.v.

dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acidin rats and rabbits. Body weight gain was decreased in F1 offspring in rats. In reproductive studies inrats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic aciddecreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1mg/kg/day and in females at 1.2 mg/kg/day. Other adverse reactions to ibandronic acid in reproductivetoxicity studies in the rat were those observed with bisphosphonates as a class. They include adecreased number of implantation sites, interference with natural delivery (dystocia), and an increasein visceral variations (renal pelvis ureter syndrome).

Sodium chloride

Glacial acetic acid

Sodium acetate trihydrate

Water for injections

Bonviva solution for injection must not be mixed with calcium-containing solutions or otherintravenously administered medicinal products.

2 years.

This medicinal product does not require any special storage conditions.

Pre-filled syringes (5 ml) made of colourless type I glass, the grey rubber plunger stopper and tip capare made of fluororesin-laminated butyl rubber, containing 3 ml of solution for injection.

Packs of 1 pre-filled syringe and 1 injection needle or 4 pre-filled syringes and 4 injection needles.

Not all pack sizes may be marketed.

Where the medicinal product is administered into an existing intravenous infusion line, the infusateshould be restricted to either isotonic saline or 50 mg/ml (5 %) glucose solution. This also applies tosolutions used to flush butterfly and other devices.

Any unused solution for injection, syringe and injection needle should be disposed of in accordancewith local requirements. The release of pharmaceuticals in the environment should be minimized.

The following points should be strictly adhered to regarding the use and disposal of syringes and othermedicinal sharps:

* Needles and syringes should never be reused.

* Place all used needles and syringes into a sharps container (puncture-proof disposablecontainer).

* Keep this container out of the reach of children.

* Placing used sharps containers in the household waste should be avoided.

* Dispose of the full container according to local requirements or as instructed by yourhealthcare professional.

Atnahs Pharma Netherlands B.V.

Copenhagen Towers,

Ørestads Boulevard 108, 5.tv

DK-2300 København S

Denmark

EU/1/03/265/005

EU/1/03/265/006

Date of first authorisation: 23 February 2004

Date of latest renewal: 18 December 2013

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

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