SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ibandronic Acid Hexal 3 mg/ 3 ml solution for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe of 3 ml solution contains 3 mg ibandronic acid (as 3.375 mg ibandronic acid, monosodium salt, monohydrate).

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

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection Clear, colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 fractures has not been established.

4.2 Posology and Method of Administration

Posology

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, injections should 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 need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Ibandronic Acid on an individual patient basis, particularly after 5 or more years of use.

Special populations

Patients with renal impairment

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

Ibandronic Acid injection is not recommended for use in patients who have a serum creatinine above 200 frmol/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 and section 5.2)

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

Elderly Population

No dosage adjustment is required (see section 5.2).

Paediatric population

There is no relevant use in children, and ibandronic acid was not studied in the paediatric population.

Method of administration For intravenous use.

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

4.3 Contraindications

-    Hypocalcaemia (see section 4.4)

-    Hypersensitivity to the active substance or to any of the excipients

4.4 Special warnings and precautions for use

Administration failures

Care must be taken not to administer Ibandronic Acid injection via intra-arterial or paravenous administration as this could lead to tissue damage.

Hypocalcaemia Ibandronic Acid, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values.

Existing hypocalcaemia must be corrected before starting Ibandronic Acid injection therapy. Other disturbances of bone and mineral metabolism should also be effectively treated before starting Ibandronic Acid injection therapy.

All patients must receive adequate supplemental calcium and vitamin D.

Atypical fractures of the femur

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

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

Renal impairment

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

Due to limited clinical experience, Ibandronic Acid injection is not recommended for patients with a serum creatinine above 200 pmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min (see section 4.2 and section 5.2).

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.

Osteonecrosis of the jaw

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

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

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

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. 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 system in rats. Furthermore, plasma protein binding is approximately 85 % - 87 % (determined in vitro at therapeutic ibandronic acid concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation. The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.

Pharmacokinetic interaction studies in postmenopausal women have demonstrated the

absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

4.6 Fertility, Pregnancy and Lactation

Pregnancy

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

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three-year fracture study (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo.

In the pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overall safety of intravenous injection of ibandronic acid 3 mg every 3 months and oral ibandronic acid 2.5 mg daily were shown to be similar. The overall proportion of patients who experienced an adverse reaction was 26.0 % and 28.6 % for ibandronic acid 3 mg injection every 3 months after one year and two years,

respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases of adverse reactions did not lead to cessation of therapy.

The most commonly reported adverse reaction was influenza like illness.

Adverse reactions considered by investigators to be causally related to Ibandronic Acid are listed below by System Organ Class.

Frequencies are defined as common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (<1/10,000. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions occurring in postmenopausal women receiving ibandronic acid 3mg injection every 3 months or ibandronic acid 2.5mg daily in the phase III studies BM16550 and MF 4411 and in postmarketing experience.

System Organ Class	Common	Uncommon	Rare	Very rare
Immune system disorders			Hypersensitivity reaction
Nervous system disorders	Headache
Eye disorders			Ocular inflammation*!
Vascular disorders		Phlebitis/ thrombophlebitis
Gastrointestinal disorders	Gastritis, Dyspepsia, Diarrhoea, Abdominal pain, Nausea, Constipation
Skin and subcutaneous tissues disorders	Rash		Angioedema, Facial swelling/oedema, Urticaria
Musculoskeletal, connective tissue and bone disorders	Arthralgia, Myalgia, Musculoskeletal pain, Back pain	Bone pain	Atypical subtrochanteric and diaphyseal femoral fractures! (bisphosphonate class adverse reaction)	Osteonecrosis of jaw*!
General disorders and administration site conditions	Influenza like illness*, Fatigue	Injection site reactions, Asthenia

*See further information below fIdentified in postmarketing experience.

Transient, influenza-like symptoms have been reported in patients receiving intravenous injection of ibandronic acid 3 mg every 3 months, typically in association with the first dose.

Influenza-like illness includes events reported as acute phase reaction or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures.

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

Ocular inflammation

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

4.9 Overdose

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

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bisphosphonates, ATC code: M05B A06

Mechanism of action

Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.

Pharmacodynamic effects

The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid 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 also inhibited, leading to increased normal bone mass compared with untreated animals.

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

Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs and monkeys was associated with formation of new bone of normal quality and maintained or increased mechanical strength even at doses in the toxic range. In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9 - 10 weeks of ibandronic acid was confirmed 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-dependent inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen degradation (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 as intravenous doses of ibandronic acid in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption.

Ibandronic acid intravenous injection decreased levels of serum C-telopeptide of the alpha chain of Type I collagen (CTX) within 3 - 7 days of starting treatment and decreased levels of osteocalcin within 3 months.

Following treatment discontinuation, there is a reversion to the pathological pretreatment rates of elevated bone resorption associated with postmenopausal osteoporosis.

The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women with doses of oral ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to 1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect. An expected decrease in bone turnover, normal quality of bone and absence of defects in mineralization were also seen after two years of treatment with ibandronic acid 3 mg injection.

Clinical efficacy

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

Ibandronic acid 3 mg/ 3ml injection every 3 months

Bone mineral density (BMD)

Ibandronic acid 3 mg intravenous injection, administered every 3 months, was shown to be at least as effective 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 primary analysis 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 years demonstrated the non-inferiority of 3 mg every 3 months injection dosing regimen compared to 2.5 mg oral daily dosing regimen, in terms of mean increases in BMD at lumbar spine, total hip, femoral neck and 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 from baseline % [95% CI]	Ibandronic acid 2.5 mg daily (N=377)	Ibandronic acid 3 mg injection every 3 months (N=365)	Ibandronic acid 2.5 mg daily (N=334)	Ibandronic acid 3 mg injection every 3 months (N=334)
Lumbar spine L2-L4 BMD	3.8 [3.4, 4.2]	4.8 [4.5, 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, 4.4]	3.5 [3.0, 4.0]	4.9 [4.1, 5.7]

Furthermore, ibandronic acid 3 mg injection every 3 months was proven superior to oral    ibandronic    acid

2.5 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 or maintained their BMD after 1 year of treatment (i.e. were responders) compared with 84.9 % of patients receiving oral 2.5 mg daily (p=0.002). After 2 years of treatment, 92.8 % of patients receiving 3 mg injections and 84.7 % of patient receiving 2.5 mg oral therapy had increased or maintained lumbar spine BMD

(p=0.001).

For total hip BMD, 82.3 % of patients receiving 3 mg injection every 3 months were responders at one year, compared with 75.1 % of patients receiving 2.5 mg daily orally (p=0.02). After 2 years of treatment, 85.6 % of patients receiving 3 mg injections and 77.0 % of patient receiving 2.5 mg oral therapy 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 spine and total hip was 76.2 % in the 3 mg injection every 3 months arm and 67.2 % in the 2.5 mg daily orally arm (p=0.007). At two years, 80.1 % and 68.8 % of patients met this criterion in the 3 mg every 3 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. At 12 months median relative changes from baseline were -58.6 % for the intravenous injection of 3 mg every 3 months regimen and -62.6 % for oral

2.5 mg daily regimen. In addition, 64.8 % of patients receiving 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 CTX reduction was maintained over the 2 years, with more than half of the patients identified as responders in both treatment groups.

Based on the results of study BM 16550, ibandronic acid 3 mg intravenous injection, administered every 3 months is expected to be at least as effective in preventing fractures as the oral regimen of ibandronic acid 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), a statistically significant and medically relevant decrease in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronic acid 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 fasting period). 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 at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. Ibandronic acid 2.5 mg administered daily, showed a statistically significant and medically relevant reduction in the incidence of new vertebral fractures. This regimen reduced the occurrence of new radiographic vertebral fractures by 62 % (p=0.0001) over the three year duration of the study. A relative risk reduction of 61 % was observed after 2 years (p=0.0006). No statistically significant difference was attained after 1 year of treatment (p=0.056). The antifracture effect was consistent over the duration of 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 statistically significant reduction of height loss compared to placebo

(p<0.0001).

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

	Placebo (N=974)	Ibandronic acid 2.5 mg daily (N=977)
Relative risk reduction New morphometric vertebral Fractures		62% (40.9, 75.1)
Incidence of new morphometric vertebral fractures	9.56% (7.5, 11.7)	4.68% (3.2, 6.2)
Relative risk reduction of clinical vertebral fracture		49% (14.03, 69.49)
Incidence of clinical vertebral fracture	5.33% (3.73, 6.92)	2.75% (1.61, 3.89)
BMD - mean change relative to baseline lumbar spine at year 3	1.26% (0.8, 1.7)	6.54% (6.1, 7.0)
BMD - mean change relative to baseline total hip at year 3	-0.69% (-1.0, -0.4)	3.36% (3.0, 3.7)

The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation of patients who, at baseline, had a lumbar spine BMD T-score below -

2.5 (table 5). The vertebral fracture 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 (N=587)	Ibandronic acid 2.5 mg daily (N=575)
Relative risk reduction		59% (34.5, 74.3)

New morphometric vertebral Fractures
Incidence of new morphometric vertebral fractures	12.54% (9.53, 15.55)	5.36% (3.31, 7.41)
Relative risk reduction of clinical vertebral fracture		50% (9.49, 71.91)
Incidence of clinical vertebral fracture	6.97% (4.67, 9.27)	3.57% (1.89, 5.24)
BMD - mean change relative to baseline lumbar spine at year 3	1.13% (0.6, 1.7)	7.01% (6.5, 7.6)
BMD - mean change relative to baseline total hip at year 3	-0.70% (-1.1, -0.2)	3.59% (3.1, 4.1)

In the overall patient population of the study MF4411, no reduction was observed for non-vertebral fractures, however daily ibandronic acid appeared to be effective in a high-risk subpopulation (femoral neck 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 at vertebral and nonvertebral sites of the skeleton.

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

Biochemical markers of bone turnover (such as urinary CTX and serum Osteocalcin) showed the expected pattern of suppression to premenopausal levels and reached maximum suppression within a period 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 as early as one month after starting treatment with ibandronic acid 2.5 mg.

Paediatric population

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

5.2 Pharmacokinetic properties

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

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

Absorption Not applicable

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

Biotransformation

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

Elimination

Ibandronic acid is removed from the circulation via bone absorption (estimated to be 40 - 50 % in postmenopausal 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 the range of 10 - 72 hours. As the values calculated are largely a function of the duration of study, the dose used, and assay sensitivity, the true terminal halflife is likely to be substantially longer, in common with other bisphosphonates. Early plasma levels fall quickly, reaching 10 % of the 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.

Pharmacokinetics in special clinical situations

Gender

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.

Patients with renal impairment

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

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

Subjects with severe renal impairment (CLcr less than 30 ml/min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2 - 3 fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous administration 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 in tolerability associated with the increase in exposure. Due to the limited clinical experience, ibandronic acid is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4). The pharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in a small number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronic acid 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

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

Elderly Population

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, renal function is the only factor to take into consideration (see renal impairment section).

Paediatric Population

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

5.3 Preclinical safety data

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

Mutagenicity/Carcinogenicity:

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

Reproductive toxicity:

Specific studies for the 3-monthly dosing regimen have not been performed. In studies with daily i.v. dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in rats and rabbits. Body weight gain was decreased in F1 offspring in rats. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Other adverse reactions to ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include a decreased number of implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid, monohydrate Sodium chloride

Sodium hydroxide for pH adjustment Hydrochloric acid for pH adjustment Water for injections

6.2 Incompatibilities

Ibandronic Acid solution for injection must not be mixed with calcium-containing solutions.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Pre-filled syringes (3 ml) made of colourless type I glass closed with rubber plunger made of chlorobutyl and tip cap made of isoprene/bromobutyl rubber, containing 3 ml of solution for injection.

Packs of 1, 2, 4 or 5 pre-filled syringes with or without injection needles or with injection needles and alcohol swabs for skin cleansing.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Any unused solution for injection, syringe and injection needle should be disposed of in accordance with 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 other medicinal sharps:

Needles and syringes should never be reused.

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

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 your healthcare provider

7 MARKETING AUTHORISATION HOLDER

HEXAL AG Industriestrasse 25,

83607 Holzkrichen

Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 10880/0158

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/01/2011

10    DATE OF REVISION OF THE TEXT

24/07/2012