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Ibandronic acid Accord (ibandronic acid) – Summary of product characteristics - M05BA06

Updated on site: 07-Oct-2017

Medication nameIbandronic acid Accord
ATC CodeM05BA06
Substanceibandronic acid
ManufacturerAccord Healthcare Ltd

1.NAME OF THE MEDICINAL PRODUCT

Ibandronic acid Accord 2 mg concentrate for solution for infusion

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless solution.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Ibandronic acid 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.

4.2Posology and method of administration

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

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

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 the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ≥3 mmol/l or ≥12 mg/dl) 4 mg is an adequate single dose. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl)

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

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Patients with renal impairment

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

Creatinine Clearance (ml/min)

Dosage

Infusion Volume 1 and Time 2

≥50 CLcr <80

6 mg (6 ml of concentrate for

100 ml over 15 minutes

 

solution for infusion)

 

≥30 CLcr <50

4 mg (4 ml of concentrate for

500 ml over 1 hour

 

solution for infusion)

 

<30

2 mg (2 ml of concentrate for

500 ml over 1 hour

 

solution for infusion)

 

10.9% sodium chloride solution or 5% glucose solution

2Administration every 3 to 4 week

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

Elderly population (> 65 years)

No dose adjustment is required (see section 5.2).

Paediatric population

The safety and efficacy of ibandronic acid 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.

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

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

4.3

Contraindications

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

Hypocalcaemia

4.4

Special warnings and precautions for use

Patients with disturbances of bone and mineral metabolism

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

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

Anaphylactic reaction/shock

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

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

Osteonecrosis of the jaw

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

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

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with ibandronic acid in patients with concomitant risk factors.

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

-Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

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

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

Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease , invasive dental procedures e.g. tooth extractions

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with ibandronic acid. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to ibandronic acid administration.

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term 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, dose recommendations cannot be given for patients with severe hepatic insufficiency (see section 4.2).

Patients with cardiac impairment

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

Patients with known hypersensitivity to other bisphosphonates

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

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. ‘essentially sodium free’.

4.5Interaction 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.

4.6Fertility, 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 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 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).

4.7Effects 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 has no or negligible influence on the ability to drive and use machines.

4.8Undesirable effects

Summary of the safety profile

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

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

In most cases no specific treatment is required and the symptoms subside after a couple of hours/days. In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache.

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with 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

Common

Uncommon

Rare

Very rare

Not known

Class

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

Infection

Cystitis, vaginitis,

 

 

 

infestations

 

oral candidiasis

 

 

 

Neoplasms

 

 

Benign skin

 

 

 

benign,

 

 

neoplasm

 

 

 

malignant, and

 

 

 

 

 

unspecified

 

 

 

 

 

Blood and

 

 

Anaemia, blood

 

 

 

lymphatic system

 

dyscrasia

 

 

 

disorders

 

 

 

 

 

 

Immune system

 

 

 

Hypersensiti

Asthma

disorders

 

 

 

 

vity†,

exacerbation

 

 

 

 

 

bronchospas

 

 

 

 

 

 

m†,

 

 

 

 

 

 

angioedema†

 

 

 

 

 

 

anaphylacti

 

 

 

 

 

 

c

 

 

 

 

 

 

reaction/sh

 

 

 

 

 

 

ock†**

 

 

 

 

 

 

 

 

Endocrine

 

Parathyroid

 

 

 

 

disorders

 

disorder

 

 

 

 

Metabolism and

Hypocalcaemia*

Hypophosphataemia

 

 

 

nutrition

 

*

 

 

 

 

disorders

 

 

 

 

 

 

Psychiatric

 

 

Sleep disorder,

 

 

 

disorders

 

 

anxiety, affection

 

 

 

 

 

 

lability

 

 

 

Nervous system

Headache,

Cerebrovascular

 

 

 

disorders

 

dizziness,

disorder, nerve root

 

 

 

 

 

dysgeusia (taste

lesion , amnesia,

 

 

 

 

 

perversion)

migraine, neuralgia,

 

 

 

 

 

 

hypertonia,

 

 

 

 

 

 

hyperaestesia,

 

 

 

 

 

 

paraesthesia

 

 

 

 

 

 

circumoral, parosmia

 

 

 

 

 

 

 

 

 

Eye disorders

Cataract

 

Ocular

 

 

 

 

 

 

inflammation†**

 

 

Ear and

 

 

Deafness

 

 

 

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

Bundle branch

Myocardial

 

 

 

disorders

 

block

ischaemia,

 

 

 

 

 

 

cardiovascular

 

 

 

 

 

 

disorder, palpitations

 

 

 

 

 

 

 

 

 

Respiratory,

Pharyngitis

Lung oedema, stridor

 

 

 

thoracic, and

 

 

 

 

 

mediastinal

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Diarrhoea,

Gastroenteritis,

 

 

 

disorders

vomiting,

gastritis, mouth

 

 

 

 

dyspepsia,

ulceration,

 

 

 

 

gastrointestinal

dysphagia, cheilitis

 

 

 

 

pain, tooth

 

 

 

 

 

disorder

 

 

 

 

Hepatobiliary

 

Cholelithiasis

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Skin and

Skin disorder,

Rash, alopecia

 

Stevens-

 

subcutaneous

ecchymosis

 

 

Johnson

 

tissue disorders

 

 

 

Syndrome†

 

 

 

 

 

, Erythema

 

 

 

 

 

Multiforme

 

 

 

 

 

†,

 

 

 

 

 

Dermatitis

 

 

 

 

 

Bullous†

 

 

 

 

 

 

 

Musculoskeletal

Osteoarthritis,

 

Atypical

Osteonecro

 

and connective

myalgia,

 

subtrochanteric

sis of

 

tissue disorders

arthralgia, joint

 

and diaphyseal

jaw†**

 

 

disorder, bone

 

femoral

Osteonecro

 

 

pain

 

fractures†

sis of the

 

 

 

 

 

external

 

 

 

 

 

auditory

 

 

 

 

 

canal

 

 

 

 

 

(bisphosph

 

 

 

 

 

onate class

 

 

 

 

 

adverse

 

 

 

 

 

reaction)†

 

 

 

 

 

 

 

Renal and

 

Urinary retention,

 

 

 

urinary

 

renal cyst

 

 

 

Reproductive

 

Pelvic pain

 

 

 

system and

 

 

 

 

 

breast disorders

 

 

 

 

 

General

Pyrexia,Influenz

Hypothermia

 

 

 

disorders and

a-like illness**,

 

 

 

 

administration

oedema

 

 

 

 

site conditions

peripheral,

 

 

 

 

 

asthenia, thirst

 

 

 

 

 

 

 

 

 

 

Investigations

Gamma-GT

Blood alkaline

 

 

 

 

increased,

phosphatase increase,

 

 

 

 

creatinine

weight decrease

 

 

 

 

increased

 

 

 

 

Injury, poisoning

 

Injury, injection site

 

 

 

and procedural

 

pain

 

 

 

complications

 

 

 

 

 

**See further information below

 

 

 

 

†Identified in post-marketing experience.

Description of selected adverse reactions

Hypocalcaemia

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

Influenza-like illness

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

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.

Ocular inflammation

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

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

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

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

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

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

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

has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

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

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

Clinical studies in the treatment of tumour-induced hypercalcaemia

Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic

acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.

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

% of Patients with

90% Confidence

acid dose

Response

Interval

2 mg

44-63

 

 

 

4 mg

62-86

 

 

 

6 mg

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

Primary efficacy endpoints

The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a 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 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with ibandronic acid 6 mg 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

Ibandronic acid

p-value

 

n=158

6 mg n=154

 

 

SMPR (per patient year)

1.48

1.19

p=0.004

 

Number of events (per patient)

3.64

2.65

p=0.025

 

SRE relative risk

-

0.60

p=0.003

 

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous ibandronic acid 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 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

Ibandronic acid 6 mg

p-value

 

 

n=158

n=154

 

 

Bone pain *

 

0.21

-0.28

p<0.001

 

Analgesic use *

0.90

0.51

p=0.083

 

Quality of Life *

-45.4

-10.3

p=0.004

 

* Mean change from baseline to last assessment.

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

In a study in 130 patients with metastatic breast cancer the safety of ibandronic acid 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 <50 ml/min.

Paediatric population(see section 4.2 and section 5.2)

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

5.2Pharmacokinetic 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 AUC0-24h was increased by 110% compared to healthy volunteers. In clinical

pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean

estimated CLcr=68.1 ml/min) and moderate (mean estimated CLcr= 41.2 ml/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 ml/min). Mean Cmax was not increased in

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

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% 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 in patients less than 18 years old.

5.3Preclinical 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

6.1List of excipients

Sodium chloride

Sodium acetate trihydrate

Glacial acetic acid

Water for injections

6.2Incompatibilities

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

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

6.3Shelf life

2 years.

After dilution:

Chemical and physical in-use stability after dilution in 0.9 % sodium chloride or 5% glucose solution has been demonstrated for 36 hours at 25°C and 2 °C to 8 °C.

From a microbiological point of view, the solution for infusion should be used immediately. If 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 to 8°C unless dilution has taken place in controlled and validated aseptic condition.

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

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

6.5Nature and contents of container

6 ml, glass vial (type I) with fluorotec plus rubber stopper and aluminium seals with lavender flip-off cap. It is supplied as packs containing 1 vial.

6.6Special precautions for disposal

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

7.MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex HA1 4 HF

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/12/798/001

9.DATE OF FIRST AUTHORISATION

Date of first authorisation: 19 November 2012

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Ibandronic acid Accord 6 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Ibandronic acid is indicated in adults for

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

Treatment of tumour-induced hypercalcaemia with or without metastases.

4.2 Posology and method of administration

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

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

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 the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ≥3 mmol/l or ≥12 mg/dl) 4 mg is an adequate single dose. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl)

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

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Patients with renal impairment

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

Creatinine Clearance (ml/min)

Dosage

Infusion Volume1 and Time2

≥50 CLcr <80

6 mg (6 ml of concentrate for

100 ml over 15 minutes

 

solution for infusion)

 

≥30 CLcr <50

4 mg (4 ml of concentrate for

500 ml over 1 hour

 

solution for infusion)

 

<30

2 mg (2 ml of concentrate for

500 ml over 1 hour

 

solution for infusion)

 

10.9% sodium chloride solution or 5% glucose solution

2Administration every 3 to 4 week

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

Elderly population (> 65 years)

No dose adjustment is required (see section 5.2).

Paediatric population

The safety and efficacy of ibandronic acid 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

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

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

4.3

Contraindications

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

Hypocalcaemia.

4.4

Special warnings and precautions for use

Patients with disturbances of bone and mineral metabolism

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

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

Anaphylactic reaction/shock

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

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

Osteonecrosis of the jaw

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

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

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with ibandronic acid in patients with concomitant risk factors.

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

-Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

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

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

Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with ibandronic acid. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to ibandronic acid administration.

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

Osteonecrosis of the external auditory canal

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

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, dose recommendations cannot be given for patients with severe hepatic insufficiency (see section 4.2).

Patients with cardiac impairment

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

Patients with known hypersensitivity to other bisphosphonates

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

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, 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 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 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 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 has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

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

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

In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

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

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with 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 postmarketing 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

Common

Uncommon

Rare

Very rare

Not known

Class

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

Infection

Cystitis, vaginitis,

 

 

 

infestations

 

oral candidiasis

 

 

 

Neoplasms

 

 

Benign skin

 

 

 

benign,

 

 

neoplasm

 

 

 

malignant, and

 

 

 

 

 

unspecified

 

 

 

 

 

Blood and

 

 

Anaemia, blood

 

 

 

lymphatic system

 

dyscrasia

 

 

 

disorders

 

 

 

 

 

 

Immune system

 

 

 

Hypersensiti

Asthma

disorders

 

 

 

 

vity†,

exacerbation

 

 

 

 

 

bronchospas

 

 

 

 

 

 

m†,

 

 

 

 

 

 

angioedema†

 

 

 

 

 

 

,

 

 

 

 

 

 

anaphylacti

 

 

 

 

 

 

c

 

 

 

 

 

 

reaction/sh

 

 

 

 

 

 

ock†**

 

 

 

 

 

 

 

 

Endocrine

 

Parathyroid

 

 

 

 

disorders

 

disorder

 

 

 

 

Metabolism and

Hypocalcaemia**

Hypophosphataemia

 

 

 

nutrition

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Psychiatric

 

 

Sleep disorder,

 

 

 

disorders

 

 

anxiety, affection

 

 

 

 

 

 

lability

 

 

 

Nervous system

Headache,

Cerebrovascular

 

 

 

disorders

 

dizziness,

disorder, nerve root

 

 

 

 

 

dysgeusia (taste

lesion , amnesia,

 

 

 

 

 

perversion)

migraine, neuralgia,

 

 

 

 

 

 

hypertonia,

 

 

 

 

 

 

hyperaestesia,

 

 

 

 

 

 

paraesthesia

 

 

 

 

 

 

circumoral, parosmia

 

 

 

 

 

 

 

 

 

Eye disorders

Cataract

 

Ocular

 

 

 

 

 

 

inflammation†**

 

 

 

 

 

 

 

 

 

Ear and

 

 

Deafness

 

 

 

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

Bundle branch

Myocardial

 

 

 

disorders

 

block

ischaemia,

 

 

 

 

 

 

cardiovascular

 

 

 

 

 

 

disorder, palpitations

 

 

 

 

 

 

 

 

 

 

Respiratory,

Pharyngitis

Lung oedema, stridor

 

 

 

thoracic, and

 

 

 

 

 

mediastinal

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Diarrhoea,

Gastroenteritis,

 

 

 

disorders

vomiting,

gastritis, mouth

 

 

 

 

dyspepsia,

ulceration,

 

 

 

 

gastrointestinal

dysphagia, cheilitis

 

 

 

 

pain, tooth

 

 

 

 

 

disorder

 

 

 

 

Hepatobiliary

 

Cholelithiasis

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Skin and

Skin disorder,

Rash, alopecia

 

Stevens-

 

subcutaneous

ecchymosis

 

 

Johnson

 

tissue disorders

 

 

 

Syndrome†

 

 

 

 

 

, Erythema

 

 

 

 

 

Multiforme

 

 

 

 

 

†,

 

 

 

 

 

Dermatitis

 

 

 

 

 

Bullous†

 

Musculoskeletal

Osteoarthritis,

 

Atypical

Osteonecro

 

and connective

myalgia,

 

subtrochanteric

sis of

 

tissue disorders

arthralgia, joint

 

and diaphyseal

jaw†**

 

 

disorder, bone

 

femoral

Osteonecro

 

 

pain

 

fractures†

sis of the

 

 

 

 

 

external

 

 

 

 

 

auditory

 

 

 

 

 

canal

 

 

 

 

 

(bisphosph

 

 

 

 

 

onate class

 

 

 

 

 

adverse

 

 

 

 

 

reaction)†

 

 

 

 

 

 

 

Renal and

 

Urinary retention,

 

 

 

urinary

 

renal cyst

 

 

 

Reproductive

 

Pelvic pain

 

 

 

system and

 

 

 

 

 

breast disorders

 

 

 

 

 

General

Pyrexia,

Hypothermia

 

 

 

disorders and

Influenza-like

 

 

 

 

administration

illness, oedema

 

 

 

 

site conditions

peripheral,

 

 

 

 

Investigations

Gamma-GT

Blood alkaline

 

 

 

 

increased,

phosphatase increase,

 

 

 

 

creatinine

weight decrease

 

 

 

 

increased

 

 

 

 

Injury, poisoning

 

Injury, injection site

 

 

 

and procedural

 

pain

 

 

 

complications

 

 

 

 

 

**See further information below

 

 

 

 

†Identified in postmarketing experience.

Description of selected adverse reactions

Hypocalcaemia

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

Influenza-like illness

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

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.

Ocular inflammation

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

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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

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

has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

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

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

Clinical studies in the treatment of tumour-induced hypercalcaemia

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

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

% of Patients with

90% Confidence

acid dose

Response

Interval

2 mg

44-63

 

 

 

4 mg

62-86

 

 

 

6 mg

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 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 (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 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with ibandronic acid 6 mg 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

Ibandronic acid

p-value

 

n=158

6 mg n=154

 

 

SMPR (per patient year)

1.48

1.19

p=0.004

 

Number of events (per patient)

3.64

2.65

p=0.025

 

SRE relative risk

-

0.60

p=0.003

 

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous ibandronic acid 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 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

Ibandronic acid 6 mg

p-value

 

 

n=158

n=154

 

 

Bone pain *

 

0.21

-0.28

p<0.001

 

Analgesic use *

0.90

0.51

p=0.083

 

Quality of Life *

-45.4

-10.3

p=0.004

 

* Mean change from baseline to last assessment.

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

In a study in 130 patients with metastatic breast cancer the safety of ibandronic acid 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 <50 ml/min.

Paediatric population (see section 4.2 and section 5.2)

The safety and efficacy of ibandronic acid in children and adolescents below the age of 18 years 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 AUC0-24h was increased by 110% compared to healthy volunteers. In clinical

pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean

estimated CLcr=68.1 ml/min) and moderate (mean estimated CLcr= 41.2 ml/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 ml/min). Mean Cmax was not increased in

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

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% 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 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

Sodium acetate trihydrate

Glacial acetic acid

Water for injections

6.2 Incompatibilities

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

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

6.3 Shelf life

2 years.

After dilution:

Chemical and physical in-use stability after dilution in 0.9 % sodium chloride or 5% glucose solution has been demonstrated for 36 hours at 25°C and 2 °C to 8 °C.

From a microbiological point of view, the solution for infusion should be used immediately. If 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 to 8°C unless dilution has taken place in controlled and validated aseptic condition.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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

6.5 Nature and contents of container

6 ml, glass vial (type I) with fluorotec plus rubber stopper and aluminium seals with pink flip-off cap. It is supplied as packs containing 1, 5 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex HA1 4 HF

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/12/798/002

EU/1/12/798/003

EU/1/12/798/004

9. DATE OF FIRST AUTHORISATION

Date of first authorisation: 19 November 2012

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1. NAME OF THE MEDICINAL PRODUCT

Ibandronic acid Accord 3 mg solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 1 mg per ml.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection (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

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

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

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

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

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Elderly population (>65 years)

No dose adjustment is required (see section 5.2).

Paediatric population

There is no relevant use of ibandronic acid in children below 18 years, and ibandronic acid was not studied in this population (see section 5.1 and 5.2).

Method of administration

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

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

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

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.

Anaphylactic reaction/shock

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

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

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 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min

(see section 4.2 and section 5.2).

Patients with cardiac impairment

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

Osteonecrosis of the jaw

Osteonecrosis of the jaw(ONJ) has been reported very rarely in the post marketing setting in patients receiving ibandronic acid for osteoporosis (see section 4.8).

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

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with ibandronic acid in patients with concomitant risk factors.

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

-Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

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

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

-Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with ibandronic acid.While on treatment invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to ibandronic acid administration.

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

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

Ibandronic acid injection 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Ibandronic acid is only for use in postmenopausal women and must not be taken by women of child bearing potential.

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 breastfeeding.

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

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that ibandronic acid 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).

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

Tabulated list of adverse reactions

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 treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three-year fracture study (MF 4411).

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. 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

System Organ

Common

Uncommon

Rare

Very rare

Class

 

 

 

 

 

 

 

 

 

Immune system

 

Asthma

Hypersensitivity

Anaphylactic

disorders

 

exacerbation

reaction

reaction/shock*†

 

 

 

 

 

Nervous system

Headache

 

 

 

disorders

 

 

 

 

 

 

 

 

 

Eye disorders

 

 

Ocular

 

 

 

 

inflammation*†

 

 

 

 

 

 

Vascular

 

Phlebitis/

 

 

disorders

 

thrombophlebitis

 

 

 

 

 

 

 

Gastrointestinal

Gastritis, Dyspepsia,

 

 

 

disorders

Diarrhoea,

 

 

 

 

Abdominal pain,

 

 

 

 

Nausea, Constipation

 

 

 

 

 

 

 

 

Skin and

Rash

 

Angioedema,

Stevens-Johnson

subcutaneous

 

 

Facial

Syndrome†,

tissues disorders

 

 

swelling/oedema,

Erythema

 

 

 

Urticaria

Multiforme†,

 

 

 

 

Dermatitis

 

 

 

 

Bullous†

 

 

 

 

 

Musculoskeletal

Arthralgia, Myalgia,

Bone pain

Atypical

Osteonecrosis of

and , connective

Musculoskeletal

 

subtrochanteric

jaw*†

tissue disorders

pain, Back pain

 

and diaphyseal

Osteonecrosis of

 

 

 

femoral

the external

 

 

 

fractures†

auditory canal

 

 

 

 

(bisphosphonate

 

 

 

 

class adverse

 

 

 

 

reaction)†

 

 

 

 

 

General

Influenza like

Injection site

 

 

disorders and

illness*, Fatigue

reactions,

 

 

administration

 

Asthenia

 

 

site conditions

 

 

 

 

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

Description of selected adverse reactions

Influenza-like illness

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.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting ibandronic acid.

Ocular inflammation

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

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

No specific information is available on the treatment of overdosage with ibandronic acid injection.

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: Medicinal products for treatment of bone diseases, bisphosphonates, ATC code: M05BA06

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 pre-treatment 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 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

ibandronic acid

ibandronic acid 3

ibandronic acid

ibandronic acid

changes from

2.5 mg daily

mg injection

2.5 mg daily

3 mg injection

baseline %

(N=377)

every 3 months

(N=334)

every 3 months

[95% CI]

 

(N=365)

 

(N=334)

 

 

 

 

 

Lumbar spine

3.8 [3.4, 4.2]

4.8 [4.5, 5.2]

4.8 [4.3, 5.4]

6.3 [5.7, 6.8]

L2-L4 BMD

 

 

 

 

 

 

 

 

 

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

1.6 [1.2, 2.0]

2.3 [1.9, 2.7]

2.2 [1.8, 2.7]

2.8 [2.3, 3.3]

BMD

 

 

 

 

 

 

 

 

 

Trochanter

3.0 [2.6, 3.4]

3.8 [3.2, 4.4]

3.5 [3.0, 4.0]

4.9 [4.1, 5.7]

BMD

 

 

 

 

 

 

 

 

 

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 anti-fracture 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

ibandronic acid 2.5 mg daily

 

(N=974)

(N=977)

Relative risk reduction

 

62% (40.9, 75.1)

New morphometric vertebral

 

 

 

fractures

 

 

 

 

 

 

 

Incidence of new

9.56% (7.5, 11.7)

4.68%

(3.2, 6.2)

morphometric vertebral

 

 

 

fractures

 

 

 

 

 

 

Relative risk reduction of

 

49% (14.03, 69.49)

clinical vertebral fracture

 

 

 

 

 

 

 

Incidence of clinical vertebral

5.33% (3.73, 6.92)

2.75%

(1.61, 3.89)

fracture

 

 

 

 

 

 

 

BMD – mean change relative

1.26% (0.8, 1.7)

6.54%

(6.1, 7.0)

to baseline lumbar spine at

 

 

 

year 3

 

 

 

 

 

 

 

BMD – mean change relative

-0.69%

3.36%

 

to 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 of patients who, at baseline, had a lumbar spine BMD T-score below –2.5 (table 4). 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

ibandronic acid 2.5 mg daily

 

(N=587)

(N=575)

Relative Risk Reduction

 

59% (34.5, 74.3)

New morphometric vertebral

 

 

 

fractures

 

 

 

 

 

 

 

Incidence of new

12.54% (9.53, 15.55)

5.36%

(3.31, 7.41)

morphometric vertebral

 

 

 

fractures

 

 

 

 

 

 

Relative risk reduction of

 

50% (9.49, 71.91)

clinical vertebral fracture

 

 

 

 

 

 

 

Incidence of clinical vertebral

6.97% (4.67, 9.27)

3.57%

(1.89, 5.24)

fracture

 

 

 

 

 

 

 

BMD – mean change relative

1.13% (0.6, 1.7)

7.01%

(6.5, 7.6)

to baseline lumbar spine at

 

 

 

year 3

 

 

 

 

 

 

 

BMD – mean change relative

-0.70% (-1.1, -0.2)

3.59%

(3.1, 4.1)

to baseline total hip at year 3

 

 

 

 

 

 

 

 

 

 

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 (see section 4.2 and section 5.2).

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 half-life 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.

The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.(see section 4.5). 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 clinical situations

Gender

Pharmacokinetics of ibandronic acid are similar in men and women.

Race

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 dose 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 (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, which is not metabolised but is cleared by renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patients with hepatic impairment.

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

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of 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

Sodium chloride

Acetic acid, glacial

Sodium acetate trihydrate

Water for injections

6.2 Incompatibilities

Ibandronic acid solution for injection must not be mixed with calcium-containing solutions or other intravenously administered medicinal products.

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 made of colourless glass, the grey plunger rubber stopper and tip cap, 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.

6.6 Special precautions for disposal

Where the medicinal 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 professional.

7. MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex HA1 4HF

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/12/798/005

EU/1/12/798/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 November 2012

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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