SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ibandronic Acid 6 mg Concentrate for Solution for Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid, (as 6.75 mg ibandronic acid, monosodium salt, monohydrate).

Excipients: Sodium (less than 1 mmol per dose).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1    Therapeutic indications

Ibandronic Acid Noridem is indicated in adults for:

-    Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases

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

4.2    Posology and method of administration

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

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterising the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this patient group. Treatment of tumour-induced hypercalcaemia

Prior to treatment with Ibandronic Acid Noridem the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium¹ >3 mmol/l or >12 mg/dl) 4 mg is an adequate single dose. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

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

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

serum calcium (mmol/l)

Or

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

serum 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. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Ibandronic Acid Noridem concentrate for solution for infusion should be administered as an intravenous infusion over 2 hours.

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Patients with renal impairment

For patients with mild renal impairment (CLcr >50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr >30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see section 5.2):

1

Administration every 3 to 4 week

2

0.9% sodium chloride solution or 5% glucose solution

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

Elderly population (> 65 years)

No dose adjustment is required(see section 5.2).

Paediatric population

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

Method of administration For intravenous administration.

The content of the vial is to be used as follows:

•    Prevention of Skeletal Events - added to 100 ml isotonic sodium chloride solution or 100 ml 5% dextrose solution and infused over at least 15 minutes. See also dose section above for patients with renal impairment ¹

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be

effectively treated before starting Ibandronic Acid therapy for metastatic bone disease.

Anaphylactic reaction/shock

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

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

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

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.

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

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

Patients with renal impairment

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

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency (see section 4.2).

Patients with cardiac impairment

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

Patients with known hypersensitivity to other bisphosphonates

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

Excipients with known effect Ibandroni Acid is essentially sodium free.

4.5    Interaction with other medicinal products and other forms of interaction

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

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods.

Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women.

Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Ibandronic Acid Noridem 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 Noridem should not be used during breast-feeding.

Fertility

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

4.7    Effects on ability to drive and use machines

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Ibandronic Acid Noridem has no or negligible influence on the ability to drive and use machines.

4.8    Undesirable effects

Summary of the safety profile

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

Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is reported. In most cases no specific treatment is required and the symptoms subsided after a couple of hours/days.

In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache.

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with ibandronic acid 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with ibandronic acid 6 mg), and from post-marketing experience.

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse Reactions Reported for Intravenous Administration of ibandronic acid

System Organ Class	Common	Uncommon	Rare	Very rare	Not known
Infections and infestations	Infection	Cystitis, vaginitis, oral candidiasis
Neoplasms benign, malignant,		Benign skin neoplasm

and unspecified
Blood and lymphatic system disorders		Anaemia, blood dyscrasia
Immune system disorders				Hypersensiti vityf, bronchospas mf, angioedema f, anaphylactic reaction/sho ckf**	Asthma exacerbatio n
Endocrine disorders	Parathyroid disorder
Metabolism and nutrition disorders	Hypocalcae mia**	Hypophosphata emia
Psychiatric disorders		Sleep disorder, anxiety, affection lability
Nervous system disorders	Headache, dizziness, dysgeusia (taste perversion)	Cerebrovascula r disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia
Eye disorders	Cataract		Ocular inflammat ionf**
Ear and labyrinth disorders		Deafness
Cardiac disorders	Bundle branch block	Myocardial ischaemia, cardiovascular disorder, palpitations
Respiratory, thoracic, and mediastinal	Pharyngitis	Lung oedema, stridor

disorders
Gastrointestin al disorders	Diarrhoea, vomiting, dyspepsia, gastrointesti nal pain, tooth disorder	Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis
Hepatobiliary disorders		Cholelithiasis
Skin and subcutatneous tissue disorders	Skin disorder, ecchymosis	Rash, alopecia
Musculoskelet al and connective tissue disorders	Osteoarthriti s, myalgia, arthralgia, joint disorder,bon e pain		Atypical subtrocha nteric and diaphyseal femoral fractures!	Osteonecros is of jaw!** Osteonecros is of the external auditory canal (bisphospho nate class adverse reaction)
Renal and urinary disorders		Urinary retention, renal cyst
Reproductive system and breast disorders		Pelvic pain
General disorders and administratio n site conditions	Pyrexia, influenzalike illness, oedema peripheral, asthenia, thirst	Hypothermia
Investigations	Gamma-GT increased, creatinine increased	Blood alkaline phosphatase increase, weight decrease
Injury, poisoning and procedural complications		Injury, injection site pain

**See further information below. jldentified in post-marketing experience.

Description of selected adverse reactions

Hypocalcaemia

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

Influenza-like illness

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

Osteonecrosis of _ jaw

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.

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via For UK: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

For IE: Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 67625177836, Website: www.imb.ie, e-mail: imbpharmacovigilance@imb.ie.

4.9 Overdose

Up to now there is no experience of acute poisoning with Ibandronic Acid Noridem concentrate for solution for infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical studies with high doses, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by intravenous administration of calcium gluconate.

5.1 Pharmacodynamic properties

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

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of

45

endogenous bone resorption has also been documented by Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterised by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in the treatment of tumour-induced hypercalcaemia Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.

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

Ibandronic acid dose	% of Patients with Response	90% Confidence Interval
2 mg	54	44-63
4 mg	76	62-86
6 mg	78	64-88

For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The median time to relapse (return of albumin-corrected serum calcium above

3.0 mmol/l) was 18 to 26 days.

Clinical studies in the _ prevention of skeletal events in _ patients with breast cancer and bone metastases

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with Ibandronic Acid Noridem 6 mg administered intravenously was assessed in one randomized placebo controlled phase III trial with a duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or 6 mg Ibandronic Acid Noridem (154 patients). The results from this trial are summarised below.

Primary efficacy endpoints

The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

-    radiotherapy to bone for treatment of fractures/impending fractures

-    surgery to bone for treatment of fractures

-    vertebral fractures

-    non-vertebral fractures

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Ibandronic Acid Noridem 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 Noridem 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results are summarised in Table 2.

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

	All Skeletal Related Events (SREs)
	Placebo n=158	Ibandronic Acid Noridem 6 mg n=154	p-value
SMPR (per patient year)	1.48	1.19	p=0.004
Number of events (per patient)	3.64	2.65	p=0.025
SRE relative risk	-	0.60	p=0.003

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous Ibandronic Acid Noridem 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Ibandronic Acid Noridem treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 3.

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

	Placebo n=158	Ibandronic Acid Noridem 6 mg n=154	p-value
Bone pain *	0.21	-0.28	p<0.001
Analgesic use *	0.90	0.51	p=0.083
Quality of Life *	-45.4	-10.3	p=0.004

* Mean change from baseline to last assessment.

There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Ibandronic Acid Noridem that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Ibandronic Acid Noridem infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of <50ml/min.

Paediatric population (see section 4.2 and section 5.2)

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

5.2 Pharmacokinetic properties

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

Distribution

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

Biotransformation

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

Elimination

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

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

Pharmacokinetics in special populations

Gender

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

Race

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

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min), dose-adjusted mean AUC_{0 24h} was increased by

110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC_{0 24}

increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C was not increased in patients with mild renal impairment and increased by

12% in patients with moderate renal impairment. For patients with mild renal impairment (CLcr >50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr >30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (see section 4.2).

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since

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

Elderly (see section 4.2)

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor that should be considered (see renal impairment section).

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of Ibandronic Acid Noridem in patients less than 18 years old

5.3 Preclinical safety data

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

Mutagenicity/Carcinogenicity:

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

Reproductive toxicity:

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride,

Acetic acid (E260)

Sodium acetate (E262)

Water for injections.

6.2 Incompatibilities

To avoid potential incompatibilities Ibandronic Acid Noridem concentrate for solution for infusion should only be diluted with isotonic sodium chloride solution or 5% glucose solution.

Ibandronic Acid Noridem should not be mixed with calcium containing solutions.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been shown for 24 hours under refrigeration and 25°C when the product is diluted with either 0.9% sodium chloride or 5% glucose to a concentration of 0.012mg/ml.

After dilution: From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

6.4 Special precautions for storage

No special precautions for storage prior to reconstitution.

6.5    Nature and contents of container

Ibandronic Acid Noridem is supplied as packs containing 1, 5 and 10 vials (6 ml type 1 glass vials). The vials are closed with rubber stoppers complying with Ph.Eur.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.

For single use only

7 MARKETING AUTHORISATION HOLDER

Noridem Enterprises Ltd Evagorou & Makariou,

Mitsi Building 3

Office 115, 1065 Nicosia, Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 24598/0036

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/04/2013

10    DATE OF REVISION OF THE TEXT

14/04/2016

1

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

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

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

Care must be taken not to administer Ibandroni Acid Noridem concentrate for solution for infusion via intra-arterial or paravenous administration, as this could lead to tissue damage.

4.3 Contraindications

-    Hypersensitivity to the active substance or to any of the excipients listed in section

6.1

-    Hypocalcaemia

4.4 Special warnings and precautions for use