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Iasibon (ibandronic acid) – Summary of product characteristics - M05BA06

Updated on site: 07-Oct-2017

Medication nameIasibon
ATC CodeM05BA06
Substanceibandronic acid
ManufacturerPharmathen S.A.

1.NAME OF THE MEDICINAL PRODUCT

Iasibon 1 mg concentrate for solution for infusion

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

One ampoule with 1 ml concentrate for solution for infusion contains 1 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

Iasibon 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

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

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

Iasibon 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

Dosage

Infusion Volume 1 and Time 2

(ml/min)

 

 

 

 

 

 

 

≥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 Iasibon 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 ampoule 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.

Iasibon concentrate for solution for infusion should be administered as an intravenous infusion. Care must be taken not to administer Iasibon 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 Iasibon 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 Iasibon 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, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

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

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

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

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibon 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 Iasibon (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

Iasibon contains less than 1 mmol sodium (23 mg) per ampoule, 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, Iasibon 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. Iasibon 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 Iasibon 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, 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

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Infections and

 

Infection

Cystitis, vaginitis,

 

 

 

infestations

 

 

oral candidiasis

 

 

 

Neoplasms

 

 

Benign skin

 

 

 

benign,

 

 

neoplasm

 

 

 

malignant,

 

 

 

 

 

 

and

 

 

 

 

 

 

unspecified

 

 

 

 

 

 

Blood and

 

 

Anaemia, blood

 

 

 

lymphatic

 

 

dyscrasia

 

 

 

system

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Immune

 

 

 

 

Hypersensitivity

Asthma

system

 

 

 

 

†,

exacerbation

disorders

 

 

 

 

bronchospasm†,

 

 

 

 

 

 

angioedema†

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

 

 

 

 

 

anaphylactic

 

 

 

 

 

 

reaction/shock†

 

 

 

 

 

 

**

 

Endocrine

 

Parathyroid

 

 

 

 

disorders

 

disorder

 

 

 

 

Metabolism

 

Hypocalcae

Hypophosphatae

 

 

 

and nutrition

 

mia**

mia

 

 

 

disorders

 

 

 

 

 

 

Psychiatric

 

 

Sleep disorder,

 

 

 

disorders

 

 

anxiety, affection

 

 

 

 

 

 

lability

 

 

 

Nervous

 

Headache,

Cerebrovascular

 

 

 

system

 

dizziness,

disorder, nerve

 

 

 

disorders

 

dysgeusia

root lesion ,

 

 

 

 

 

(taste

amnesia,

 

 

 

 

 

perversion)

migraine,

 

 

 

 

 

 

neuralgia,

 

 

 

 

 

 

hypertonia,

 

 

 

 

 

 

hyperaestesia,

 

 

 

 

 

 

paraesthesia

 

 

 

 

 

 

circumoral,

 

 

 

 

 

 

parosmia

 

 

 

Eye disorders

 

Cataract

 

Ocular

 

 

 

 

 

 

inflammati

 

 

 

 

 

 

on†**

 

 

Ear and

 

 

Deafness

 

 

 

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

Bundle

Myocardial

 

 

 

disorders

 

branch

ischaemia,

 

 

 

 

 

block

cardiovascular

 

 

 

 

 

 

disorder,

 

 

 

 

 

 

palpitations

 

 

 

Respiratory,

 

Pharyngitis

Lung oedema,

 

 

 

thoracic, and

 

 

stridor

 

 

 

mediastinal

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Gastrointestin

 

Diarrhoea,

Gastroenteritis,

 

 

 

al disorders

 

vomiting,

gastritis, mouth

 

 

 

 

 

dyspepsia,

ulceration,

 

 

 

 

 

gastrointest

dysphagia,

 

 

 

 

 

inal pain,

cheilitis

 

 

 

 

 

tooth

 

 

 

 

 

 

disorder

 

 

 

 

Hepatobiliary

 

 

Cholelithiasis

 

 

 

disorders

 

 

 

 

 

 

Skin and

 

Skin

Rash, alopecia

 

Stevens-Johnson

 

subcutaneous

 

disorder,

 

 

Syndrome†,

 

tissue

 

ecchymosis

 

 

Erythema

 

disorders

 

 

 

 

Multiforme†,

 

 

 

 

 

 

Dermatitis

 

 

 

 

 

 

Bullous†

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Musculoskelet

 

Osteoarthrit

 

Atypical

Osteonecrosis of

 

al and

 

is, myalgia,

 

subtrochant

jaw†**,

 

connective

 

arthralgia,

 

eric and

osteonecrosis of

 

tissue

 

joint

 

diaphyseal

the external

 

disorders

 

disorder,

 

femoral

auditory canal

 

 

 

bone pain

 

fractures†

(bisphosphonate

 

 

 

 

 

 

class adverse

 

 

 

 

 

 

reaction)

 

Renal and

 

 

Urinary retention,

 

 

 

urinary

 

 

renal cyst

 

 

 

disorders

 

 

 

 

 

 

Reproductive

 

 

Pelvic pain

 

 

 

system and

 

 

 

 

 

 

breast

 

 

 

 

 

 

disorders

 

 

 

 

 

 

General

 

Pyrexia,

Hypothermia

 

 

 

disorders and

 

influenza-

 

 

 

 

administration

 

like

 

 

 

 

site conditions

 

illness**,

 

 

 

 

 

 

oedema

 

 

 

 

 

 

peripheral,

 

 

 

 

 

 

asthenia,

 

 

 

 

 

 

thirst

 

 

 

 

Investigations

 

Gamma-

Blood alkaline

 

 

 

 

 

GT

phosphatase

 

 

 

 

 

increased,

increase, weight

 

 

 

 

 

creatinine

decrease

 

 

 

 

 

increased

 

 

 

 

Injury,

 

 

Injury, injection

 

 

 

poisoning and

 

 

site pain

 

 

 

procedural

 

 

 

 

 

 

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

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

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with

ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

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

4.9Overdose

Up to now there is no experience of acute poisoning with Iasibon 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 Ibandronate6 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 Ibandronate (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 Ibandronate 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 Ibandronate 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

Ibandronate 6 mg

p-value

 

n=158

n=154

 

 

 

 

 

SMPR (per patient year)

1.48

1.19

p=0.004

 

 

 

 

Number of events (per

3.64

2.65

p=0.025

patient)

 

 

 

 

 

 

 

SRE relative risk

-

0.60

p=0.003

 

 

 

 

Secondary efficacy endpoints

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

Ibandronate 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 Ibandronate that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Ibandronate 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 Iasibon 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 Iasibon 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

6.1List of excipients

Sodium chloride

Acetic acid, glacial

Sodium acetate trihydrate

Water for injections

6.2Incompatibilities

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

Iasibon should not be mixed with calcium containing solutions.

6.3Shelf life

5 years.

After reconstitution: 24 hours.

6.4Special precautions for storage

This medicinal product does not require any special storage conditions prior to reconstitution.

After reconstitution: Store at 2°C - 8°C (in a refrigerator).

From a microbiological point of view, the product 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 to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.5Nature and contents of container

Iasibon 1 mg is supplied as pack containing 1 ampoule (2 ml type I glass ampoule).

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

Pharmathen S.A.

Dervenakion 6

Pallini Attiki, 15351

Greece

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/659/003

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 January 2011

Date of latest renewal: 30 September 2015

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

Iasibon 2 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ampoule 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

4.1 Therapeutic indications

Iasibon 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

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

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

Iasibon 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

Dosage

Infusion Volume 1 and Time 2

(ml/min)

 

 

 

 

 

 

 

≥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 Iasibon 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 ampoule 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.

Iasibon concentrate for solution for infusion should be administered as an intravenous infusion. Care must be taken to ensure that administer Iasibon 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 Iasibon 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 Iasibon 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, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

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

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

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

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibon 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 Iasibon . (see section 4.2).

Patients with hepatic impairment

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

Patients with cardiac impairment

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

Patients with known hypersensitivity to other bisphosphonates

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

Excipients with known effect

Iasibon contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially sodium free.

4.5 Interaction with other medicinal products and other forms of interaction

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (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

Pegnancy

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, Iasibon 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. Iasibon should not be used during breat-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 Iasibon 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, 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

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Infections and

 

Infection

Cystitis, vaginitis,

 

 

 

infestations

 

 

oral candidiasis

 

 

 

Neoplasms

 

 

Benign skin

 

 

 

benign,

 

 

neoplasm

 

 

 

malignant,

 

 

 

 

 

 

and

 

 

 

 

 

 

unspecified

 

 

 

 

 

 

Blood and

 

 

Anaemia, blood

 

 

 

lymphatic

 

 

dyscrasia

 

 

 

system

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Immune

 

 

 

 

Hypersensitivity†,

Asthma

system

 

 

 

 

bronchospasm†,

exacerbation

disorders

 

 

 

 

angioedema†

 

 

 

 

 

 

anaphylactic

 

 

 

 

 

 

reaction/shock†**

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Endocrine

 

Parathyroid

 

 

 

 

disorders

 

disorder

 

 

 

 

Metabolism

 

Hypocalcae

Hypophosphatae

 

 

 

and nutrition

 

mia**

mia

 

 

 

disorders

 

 

 

 

 

 

Psychiatric

 

 

Sleep disorder,

 

 

 

disorders

 

 

anxiety, affection

 

 

 

 

 

 

lability

 

 

 

Nervous

 

Headache,

Cerebrovascular

 

 

 

system

 

dizziness,

disorder, nerve

 

 

 

disorders

 

dysgeusia

root lesion ,

 

 

 

 

 

(taste

amnesia,

 

 

 

 

 

perversion)

migraine,

 

 

 

 

 

 

neuralgia,

 

 

 

 

 

 

hypertonia,

 

 

 

 

 

 

hyperaestesia,

 

 

 

 

 

 

paraesthesia

 

 

 

 

 

 

circumoral,

 

 

 

 

 

 

parosmia

 

 

 

Eye disorders

 

Cataract

 

Ocular

 

 

 

 

 

 

inflammat

 

 

 

 

 

 

ion†**

 

 

Ear and

 

 

Deafness

 

 

 

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

Bundle

Myocardial

 

 

 

disorders

 

branch block

ischaemia,

 

 

 

 

 

 

cardiovascular

 

 

 

 

 

 

disorder,

 

 

 

 

 

 

palpitations

 

 

 

Respiratory,

 

Pharyngitis

Lung oedema,

 

 

 

thoracic, and

 

 

stridor

 

 

 

mediastinal

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Gastrointestin

 

Diarrhoea,

Gastroenteritis,

 

 

 

al disorders

 

vomiting,

gastritis, mouth

 

 

 

 

 

dyspepsia,

ulceration,

 

 

 

 

 

gastrointestin

dysphagia,

 

 

 

 

 

al pain, tooth

cheilitis

 

 

 

 

 

disorder

 

 

 

 

Hepatobiliary

 

 

Cholelithiasis

 

 

 

disorders

 

 

 

 

 

 

Skin and

 

Skin

Rash, alopecia

 

Stevens-Johnson

 

subcutaneous

 

disorder,

 

 

Syndrome†,

 

tissue

 

ecchymosis

 

 

Erythema

 

disorders

 

 

 

 

Multiforme†,

 

 

 

 

 

 

Dermatitis

 

 

 

 

 

 

Bullous†

 

Musculoskelet

 

Osteoarthritis

 

Atypical

Osteonecrosis of

 

al and

 

, myalgia,

 

subtrocha

jaw†**,

 

connective

 

arthralgia,

 

nteric and

osteonecrosis of

 

tissue

 

joint

 

diaphysea

the external

 

disorders

 

disorder,

 

l femoral

auditory canal

 

 

 

bone pain

 

fractures†

(bisphosphonate

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

 

 

 

 

 

class adverse

 

 

 

 

 

 

reaction)

 

 

 

 

 

 

 

 

Renal and

 

 

Urinary retention,

 

 

 

urinary

 

 

renal cyst

 

 

 

disorders

 

 

 

 

 

 

Reproductive

 

 

Pelvic pain

 

 

 

system and

 

 

 

 

 

 

breast

 

 

 

 

 

 

disorders

 

 

 

 

 

 

General

 

Pyrexia,

Hypothermia

 

 

 

disorders and

 

influenza-

 

 

 

 

administration

 

like

 

 

 

 

site conditions

 

illness**,

 

 

 

 

 

 

oedema

 

 

 

 

 

 

peripheral,

 

 

 

 

 

 

asthenia,

 

 

 

 

 

 

thirst

 

 

 

 

Investigations

 

Gamma-GT

Blood alkaline

 

 

 

 

 

increased,

phosphatase

 

 

 

 

 

creatinine

increase, weight

 

 

 

 

 

increased

decrease

 

 

 

Injury,

 

 

Injury, injection

 

 

 

poisoning and

 

 

site pain

 

 

 

procedural

 

 

 

 

 

 

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

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

Ocular inflammation

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

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenousibandronic 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 Iasibon 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 Ibandronate 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 Ibandronate (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 Ibandronate 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 Ibandronate 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

Ibandronate 6 mg

p-value

 

n=158

n=154

 

 

 

 

 

SMPR (per patient year)

1.48

1.19

p=0.004

 

 

 

 

Number of events (per

3.64

2.65

p=0.025

patient)

 

 

 

 

 

 

 

SRE relative risk

-

0.60

p=0.003

 

 

 

 

Secondary efficacy endpoints

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

Ibandronate 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 Ibandronate that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Ibandronate 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 Iasibon 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 Iasibon 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

6.1 List of excipients

Sodium chloride

Acetic acid, glacial

Sodium acetate trihydrate

Water for injections

6.2 Incompatibilities

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

Iasibon should not be mixed with calcium containing solutions.

6.3 Shelf life

5 years.

After reconstitution: 24 hours.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions prior to reconstitution.

After reconstitution: Store at 2°C - 8°C (in a refrigerator).

From a microbiological point of view, the product 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 to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.5 Nature and contents of container

Iasibon 2 mg is supplied as pack containing 1 ampoule (4 ml type I glass ampoule).

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

Pharmathen S.A.

Dervenakion 6

Pallini Attiki, 15351

Greece

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/659/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 January 2011

Date of latest renewal: 30 September 2015

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

Iasibon 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

Iasibon 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

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

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

Iasibon 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

Dosage

Infusion Volume 1 and Time 2

(ml/min)

 

 

 

 

 

 

 

≥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 Iasibon 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.

Iasibon concentrate for solution for infusion should be administered as an intravenous infusion. Care must be taken not to administer Iasibon 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 Iasibon 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 Iasibon 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, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

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

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

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The

possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

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

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

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibon 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 Iasibon (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

Iasibon 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 to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

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

4.6 Fertility, pregnancy and lactation

Pegnancy

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, Iasibon 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. Iasibon 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 Iasibon 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, 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 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

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Infections and

 

Infection

Cystitis,

 

 

 

infestations

 

 

vaginitis, oral

 

 

 

 

 

 

candidiasis

 

 

 

Neoplasms

 

 

Benign skin

 

 

 

benign,

 

 

neoplasm

 

 

 

malignant,

 

 

 

 

 

 

and

 

 

 

 

 

 

unspecified

 

 

 

 

 

 

Blood and

 

 

Anaemia, blood

 

 

 

lymphatic

 

 

dyscrasia

 

 

 

system

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Immune

 

 

 

 

Hypersensitivity†,

Asthma

system

 

 

 

 

bronchospasm†,

exacerbation

disorders

 

 

 

 

angioedema†

 

 

 

 

 

 

anaphylactic

 

 

 

 

 

 

reaction/shock†**

 

Endocrine

 

Parathyroid

 

 

 

 

disorders

 

disorder

 

 

 

 

Metabolism

 

Hypocalcaemia*

Hypophosphatae

 

 

 

and nutrition

 

*

mia

 

 

 

disorders

 

 

 

 

 

 

Psychiatric

 

 

Sleep disorder,

 

 

 

disorders

 

 

anxiety,

 

 

 

 

 

 

affection lability

 

 

 

Nervous

 

Headache,

Cerebrovascular

 

 

 

system

 

dizziness,

disorder, nerve

 

 

 

disorders

 

dysgeusia (taste

root lesion ,

 

 

 

 

 

perversion)

amnesia,

 

 

 

 

 

 

migraine,

 

 

 

 

 

 

neuralgia,

 

 

 

 

 

 

hypertonia,

 

 

 

 

 

 

hyperaestesia,

 

 

 

 

 

 

paraesthesia

 

 

 

 

 

 

circumoral,

 

 

 

 

 

 

parosmia

 

 

 

Eye disorders

 

Cataract

 

Ocular

 

 

 

 

 

 

inflamma

 

 

 

 

 

 

tion†**

 

 

Ear and

 

 

Deafness

 

 

 

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

Bundle branch

Myocardial

 

 

 

disorders

 

block

ischaemia,

 

 

 

 

 

 

cardiovascular

 

 

 

 

 

 

disorder,

 

 

 

 

 

 

palpitations

 

 

 

Respiratory,

 

Pharyngitis

Lung oedema,

 

 

 

thoracic, and

 

 

stridor

 

 

 

mediastinal

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Gastrointestin

 

Diarrhoea,

Gastroenteritis,

 

 

 

al disorders

 

vomiting,

gastritis, mouth

 

 

 

 

 

dyspepsia,

ulceration,

 

 

 

 

 

gastrointestinal

dysphagia,

 

 

 

 

 

pain, tooth

cheilitis

 

 

 

 

 

disorder

 

 

 

 

Hepatobiliary

 

 

Cholelithiasis

 

 

 

disorders

 

 

 

 

 

 

Skin and

 

Skin disorder,

Rash, alopecia

 

Stevens-Johnson

 

subcutaneous

 

ecchymosis

 

 

Syndrome†,

 

tissue

 

 

 

 

Erythema

 

disorders

 

 

 

 

Multiforme†,

 

 

 

 

 

 

Dermatitis

 

 

 

 

 

 

Bullous†

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very rare

Not known

Class

common

 

 

 

 

 

Musculoskelet

 

Osteoarthritis,

 

Atypical

Osteonecrosis of

 

al and

 

myalgia,

 

subtrocha

jaw†**,

 

connective

 

arthralgia, joint

 

nteric and

osteonecrosis of

 

tissue

 

disorder, bone

 

diaphysea

the external

 

disorders

 

pain

 

l femoral

auditory canal

 

 

 

 

 

fractures†

(bisphosphonate

 

 

 

 

 

 

class adverse

 

 

 

 

 

 

reaction)

 

Renal and

 

 

Urinary

 

 

 

urinary

 

 

retention, renal

 

 

 

disorders

 

 

cyst

 

 

 

Reproductive

 

 

Pelvic pain

 

 

 

system and

 

 

 

 

 

 

breast

 

 

 

 

 

 

disorders

 

 

 

 

 

 

General

 

Pyrexia,

Hypothermia

 

 

 

disorders and

 

influenza-like

 

 

 

 

administration

 

illness**,

 

 

 

 

site conditions

 

oedema

 

 

 

 

 

 

peripheral,

 

 

 

 

 

 

asthenia, thirst

 

 

 

 

Investigations

 

Gamma-GT

Blood alkaline

 

 

 

 

 

increased,

phosphatase

 

 

 

 

 

creatinine

increase, weight

 

 

 

 

 

increased

decrease

 

 

 

Injury,

 

 

Injury, injection

 

 

 

poisoning and

 

 

site pain

 

 

 

procedural

 

 

 

 

 

 

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

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

Ocular inflammation

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

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

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

4.9 Overdose

Up to now there is no experience of acute poisoning with Iasibon 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 Ibandronate 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 Ibandronate (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 Ibandronate 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 Ibandronate 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

Ibandronate 6 mg

p-value

 

n=158

n=154

 

 

 

 

 

SMPR (per patient year)

1.48

1.19

p=0.004

 

 

 

 

Number of events (per

3.64

2.65

p=0.025

patient)

 

 

 

 

 

 

 

SRE relative risk

-

0.60

p=0.003

 

 

 

 

Secondary efficacy endpoints

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

Ibandronatebandro

p-value

 

n=158

nate 6 mg

 

 

 

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 Ibandronate that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Ibandronate 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 Iasibon 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 Iasibon in patients less than 18 years old.

5.3 Preclinical safety data

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

Mutagenicity/Carcinogenicity:

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

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route, effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive

studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of medicinal products (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Acetic acid, glacial

Sodium acetate trihydrate

Water for injections

6.2 Incompatibilities

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

Iasibon should not be mixed with calcium containing solutions.

6.3 Shelf life

5 years.

After reconstitution: 24 hours.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions prior to reconstitution.

After reconstitution: Store at 2°C - 8°C (in a refrigerator).

From a microbiological point of view, the product 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 to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.5 Nature and contents of container

Iasibon 6 mg is supplied as packs containing 1,5,10 vials (9 ml type I glass vial with a bromobutyl rubber stopper).

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

Pharmathen S.A.

Dervenakion 6

Pallini Attiki, 15351

Greece

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/659/005

EU/1/10/659/006

EU/1/10/659/007

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 January 2011

Date of latest renewal: 30 September 2015

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

Iasibon 50 mg film coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of ibandronic acid (as sodium monohydrate).

Excipients with known effect:

Contains 0.86 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablets.

White round biconvex tablets

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Iasibon is indicated in adults for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

4.2 Posology and method of administration

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

Posology

The recommended dose is one 50 mg film-coated tablet daily.

Special populations

Patients with hepatic impairment

No dose adjustment is required (see section 5.2 ).

Patients with renal impairment

No dose adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).

For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one

50 mg film-coated tablet every second day is recommended (see section 5.2).

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly population (> 65 years)

No dose adjustment is necessary (see section 5.2).

Paediatric population

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

Method of administration

For oral use.

Iasibon tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking Iasibon tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Water may be taken at any time during the course of Iasibon treatment (see section 4.5). Water with a high concentration of calcium should not be used. If there is concern regarding potentially high levels of calcium in the tap water (hard water), it is advised to use bottled water with a low mineral content.

-The tablets should be swallowed whole with a full glass of water (180 to 240 ml) while the patient is standing or sitting in an upright position.

-Patients should not lie down for 60 minutes after taking Iasibon.

-Patients should not chew, suck or crush the tablet because of a potential for oropharyngeal ulceration.

-Water is the only drink that should be taken with Iasibon.

4.3

Contraindications

-

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

-

Hypocalcaemia

-

Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

-

Inability to stand or sit upright for at least 60 minutes

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 Iasibon therapy. 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.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Iasibon is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Iasibon and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDS) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration.

Osteonecrosis of the jaw

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

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

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

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

Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

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

Renal function

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibon 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 Iasibon.

Rare hereditary problems

Iasibon tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Patients with known hypersensitivity to other bisphosphonates

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

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal product -Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Iasibon tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

Bioavailability was reduced by approximately 75% when Iasibon tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2).

Interactions with other medicinal products

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.

H2-antagonists or other medicinal products that increase gastric pH.

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when Iasibon is administered with H2-antagonists or medicinal products that

increase gastric pH.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).

Aminoglycosides

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, Iasibon 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. Iasibon 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 Iasibon 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 of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph

“Description of selected adverse reactions” and section 4.4).

Treatment was most frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.

Tabulated list of adverse reactions

Table 1 lists adverse reactions from 2 pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with ibandronic acid 50 mg administered orally), 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 Drug Reactions Reported for Oral Administration of Ibandronate

 

 

 

 

 

 

 

System

Very

Common

Uncommon

Rare

Very rare

Not known

Organ Class

common

 

 

 

 

 

 

 

 

 

 

 

 

Blood and

 

 

Anaemia

 

 

 

lymphatic

 

 

 

 

 

 

system

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

Immune

 

 

 

 

Hypersensitivity

Asthma

system

 

 

 

 

†,

exacerbation

disorders

 

 

 

 

bronchospasm†,

 

 

 

 

 

 

angioedema†,

 

 

 

 

 

 

Anaphylactic

 

 

 

 

 

 

reaction/shock†

 

 

 

 

 

 

**

 

Metabolism

 

Hypocalcaemia

 

 

 

 

and nutrition

 

**

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

Nervous

 

 

Paraesthesia,

 

 

 

system

 

 

dysgeusia

 

 

 

disorders

 

 

(taste

 

 

 

 

 

 

perversion)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

System

Very

 

Common

Uncommon

Rare

Very rare

Not known

Organ Class

common

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Eye disorders

 

 

 

 

Ocular

 

 

 

 

 

 

 

inflam

 

 

 

 

 

 

 

mation

 

 

 

 

 

 

 

†**

 

 

 

 

 

 

 

 

 

 

Gastrointesti

 

 

Oesophagitis,

Haemorrage,

 

 

 

nal disorders

 

 

abdominal pain,

duodenal

 

 

 

 

 

 

dyspepsia,

ulcer,

 

 

 

 

 

 

nausea

gastritis,

 

 

 

 

 

 

 

dysphagia,

 

 

 

 

 

 

 

dry mouth

 

 

 

 

 

 

 

 

 

 

 

Skin and

 

 

 

Pruritus

 

Stevens-Johnson

 

subcutaneous

 

 

 

 

 

Syndrome†,

 

tissue

 

 

 

 

 

Erythema

 

disorders

 

 

 

 

 

Multiforme†,

 

 

 

 

 

 

 

Dermatitis

 

 

 

 

 

 

 

Bullous†

 

 

 

 

 

 

 

 

 

Musculoskele

 

 

 

 

Atypic

Osteonecrosis of

 

tal and

 

 

 

 

al

jaw†**,

 

connective

 

 

 

 

subtro

osteonecrosis of

 

tissue

 

 

 

 

chante

the external

 

disorders

 

 

 

 

ric and

auditory canal

 

 

 

 

 

 

diaphy

(bisphosphonate

 

 

 

 

 

 

seal

class adverse

 

 

 

 

 

 

femor

reaction)

 

 

 

 

 

 

al

 

 

 

 

 

 

 

fractur

 

 

 

 

 

 

 

es†

 

 

 

 

 

 

 

 

 

 

Renal and

 

 

 

Azotaemia

 

 

 

urinary

 

 

 

(uraemia)

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General

 

 

Asthenia

Chest pain,

 

 

 

disorders and

 

 

 

influenza-

 

 

 

administratio

 

 

 

like illness,

 

 

 

n site

 

 

 

malaise, pain

 

 

 

conditions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Investigations

 

 

 

Blood

 

 

 

 

 

 

 

parathyroid

 

 

 

 

 

 

 

hormone

 

 

 

 

 

 

 

increased

 

 

 

 

 

 

 

 

 

 

 

**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.

Osteonecrosis of jaw

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

Ocular inflammation

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

Anaphylactic reaction/shock

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

Reporting of suspected adverse reactions

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

4.9 Overdose

No specific information is available on the treatment of overdosage with Iasibon. However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind Iasibon. Due to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

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 by45 Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

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

Bone resorption due to malignant disease is characterized 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 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 Ibandronate 50 mg tablets was assessed in two randomized placebo controlled phase III trials with a duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg Ibandronate (287 patients). The results from these trials are summarised below.

Primary efficacy endpoints

The primary endpoint of the trials 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 in any given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrated a significant advantage for Ibandronate 50 mg p.o. over placebo in the reduction in SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE for Ibandronate treated patients when compared with placebo (relative risk 0.62, 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

Ibandronate 50 mg

p-value

 

n=277

n=287

 

SMPR (per patient year)

1.15

0.99

p=0.041

 

 

 

 

SRE relative risk

-

0.62

p=0.003

 

 

 

 

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for Ibandronate 50 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in Quality of Life and WHO performance status was significantly less in Ibandronate treated patients compared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminal telopeptide released from Type I collagen) were significantly reduced in the Ibandronate group compared to placebo. This reduction in urinary CTx levels was significantly correlated with the primary efficacy endpoint SMPR (Kendall-tau-b (p<0.001)). A tabular summary of the secondary efficacy results is presented in Table 3.

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

 

Placebo n=277

Ibandronatebandronat

p-value

 

 

e 50 mg

 

 

 

n=287

 

 

Bone pain *

0.20

-0.10

p=0.001

 

 

 

 

Analgesic use *

0.85

0.60

p=0.019

 

 

 

 

Quality of Life *

-26.8

-8.3

p=0.032

 

 

 

 

WHO performance

0.54

0.33

p=0.008

score *

 

 

 

Urinary CTx **

10.95

-77.32

p=0.001

 

 

 

 

*Mean change from baseline to last assessment.

**Median change from baseline to last assessment

Paediatric population(see section 4.2 and section 5.2)

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

5.2 Pharmacokinetic properties

Absorption

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration. Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other than water). Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.

Bioavailability was reduced by approximately 75% when Iasibon tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2).

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 thusinteraction 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 absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.

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.

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 degree of renal impairment is related to creatinine clearance (CLcr). Subjects with severe renal impairment (CLcr ≤ 30 mL/min) receiving oral administration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function (CLcr ≥80 mL/min). Total clearance of ibandronic acid was reduced to 44 ml/min in the subjects with severe renal impairment compared with 129 mL/min in subjects with normal renal function.No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min). For patients with moderate renal impairment (CLcr ≥30 and

<50 mL/min) or severe renal impairment (CLcr <30 mL/min) 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 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 Iasibon 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 genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid in intravenously or orally 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

Tablet core:

Povidone

Cellulose, microcrystalline

Crospovidone

Maize starch pregelatinised

Glycerol dibehenate

Silica, anhydrous colloidal

Tablet coat:

Lactose monohydrate

Macrogol 4000

Hypromellose (E464)

Titanium dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Iasibon 50 mg film coated tablets are supplied in Polyamide/Al/PVC - Aluminum foil blister with 3, 6, 9, 28 or 84 tablets, packaged in a cardboard box.

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

Pharmathen S.A.

Dervenakion 6

15351 Pallini, Attiki

Greece

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/659/001

EU/1/10/659/002

EU/1/10/659/008

EU/1/10/659/009

EU/1/10/659/0010

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 January 2011

Date of latest renewal: 30 September 2015

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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