ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Iasibon 1 mg concentrate for solution for infusion
2.
One ampoule with 1 ml concentrate for solution for infusion contains 1 mg ibandronic acid (as
ibandronic sodium monohydrate).
Excipients:
Each ampoule contains 0.15008 mmol of sodium (as sodium chloride and sodium acetate trihydrate)
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Clear, colourless solution.
4.
4.1
Iasibon is indicated 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
Iasibon therapy should only be initiated by physicians experienced in the treatment of cancer.
For intravenous administration.
For single use only. Only clear solution without particles should be used.
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. For infusion, the contents of the vial(s) should only be added to 100 ml isotonic
sodium chloride solution or 100 ml 5% glucose solution.
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 characterizing 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. Consideration should be given to the severity of the hypercalcaemia as well as the tumour
2
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 dosage. 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. For this
purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml
5% dextrose solution) and infused over two hours.
As the inadvertent intra-arterial administration of preparations not expressly recommended for this
purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure
that Iasibon concentrate for solution for infusion is administered intravenously.
Patients with hepatic impairment
No dosage adjustment is required (see section 5.2).
Patients with renal impairment
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is
necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal
impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with
breast cancer and metastatic bone disease the following dosing recommendations should be followed
(see section 5.2):
Creatinine Clearance
(ml/min)
Dosage / Infusion time
1
Infusion Volume
2
≥50 CLcr <80
6 mg / 15 minutes
100 ml
≥30
CLcr <50
4 mg / 1 hour
500 ml
<30
2 mg / 1 hour
500 ml
1
Administration every 3 to 4 week
2
0.9% sodium chloride solution or 5% glucose solution
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.
Elderly
No dose adjustment is required.
Children and adolescents
Iasibon is not recommended for patients below age 18 years due to insufficient data on safety and
3
efficacy.
4.3
Hypocalcaemia (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. Iasibon should
not be used in children.
4.4
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.
As no clinical data are available, dosage recommendations cannot be given for patients with severe
hepatic insufficiency.
Overhydration should be avoided in patients at risk of cardiac failure.
Hypocalcemia 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.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including
osteomyelitis) has been reported in patients with cancer receiving treatment regimens including
primarily intravenously administered bisphosphonates. Many of these patients were also receiving
chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with
osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with
bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy,
corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients
who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate
the condition. For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical
judgement of the treating physician should guide the management plan of each patient based on
individual benefit/risk assessment.
This medicinal product contains 0.15008 mmol sodium per dose. This should be taken into
consideration by patients on a controlled sodium diet.
4.5
Iasibon should not be mixed with calcium containing solutions
No interaction was observed when co-administered with melphalan/prednisolone in patients with
multiple myeloma.
Other interaction studies in postmenopausal women have demonstrated the absence of any interaction
4
potential with tamoxifen or hormone replacement therapy (oestrogen).
In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is
eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway
does not appear to include known acidic or basic transport systems involved in the excretion of
otheractive 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. Plasma protein binding is
low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active
substances.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can
lower serum calcium levels for prolonged periods. Attention should also be paid to the possible
existence of simultaneous hypomagnesaemia.
In clinical studies, Iasibon has been administered concomitantly with commonly used anticancer agents,
diuretics, antibiotics and analgesics without clinically apparent interactions occurring.
Interaction studies have only been performed in adults.
4.6
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.
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 lactation.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following
convention: very common ( ≥10%), common ( ≥1% and <10%), uncommon ( ≥0.1% and <1%), rare (
≥0.01% and <0.1%), and very rare ( ≤0.01%).
Treatment of Tumour Induced Hypercalcaemia
The safety profile for Iasibon in tumour-induced hypercalcaemia is derived from controlled clinical
trials in this indication and after the intravenous administration of Iasibon at the recommended doses.
Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu- like
syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no
specific treatment was required and the symptoms subsided after a couple of hours/days.
Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a
determination of causality).
Table 1 Number (percentage) of patients reporting adverse reactions in controlled clinical
trials in tumour-induced hypercalcaemia after treatment with Iasibon
System Organ Class / Adverse reaction
Frequency Number (%)
(n=352)
Metabolism and nutrition disorders
Common: Hypocalcaemia
10 (2.8)
5
Musculoskeletal and connective tissue
disorders
Common:
Bone Pain
6 (1.7)
Uncommon:
Myalgia
1 (0.3)
General disorders and administration site
conditions
Very common: Pyrexia
Uncommon:
Influenza-like illness
39 (11.1)
2 (0.6)
1 (0.3)
Rigors
Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled. Events were recorded
irrespective of a determination of causality.
Frequently, decreased renal calcium excretion is accompanied by a fall in serum phosphate levels not
requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
Other reactions reported at lower frequency are as follows:
Immune system disorders:
Very rare:
Hypersensitivity
Skin and subcutaneous tissue disorders:
Very rare:
Angioneurotic oedema
Respiratory, thoracic and mediastinal disorders:
Very rare:
Bronchospasm
Administration of other bisphosphonates has been associated with broncho-constriction in
acetylsalicylic acid-sensitive asthmatic patients.
Prevention of skeletal svents in patients with breast cancer and bone metastases
The safety profile of intravenous Iasibon in patients with breast cancer and bone metastases is derived
from a controlled clinical trial in this indication and after the intravenous administration of Iasibon at
the recommended dose.
Table 2 lists adverse reactions from the pivotal phase III study (152 patients treated with Iasibon 6 mg),
i.e. adverse events with a remote, possible, or probable relationship to study medication, occurring
commonly and more frequently in the active treatment group than in placebo.
Table 2 Adverse reactions occurring commonly and greater than placebo in patients with
metastatic bone disease due to breast cancer treated with Iasibon 6 mg administered
intravenously
Adverse Reaction
Placebo (n = 157) No.
(%)
Iasibon 6mg
(n = 152) No. (%)
Infections and Infestations:
Infection
1 (0.6)
2 (1.3)
Endocrine disorders:
Parathyroid disorder
1 (0.6)
2 (1.3)
6
Nervous System disorders:
Headache
Dizziness
Dysgeusia (taste perversion)
4 (2.5)
2 (1.3)
0 (0.0)
9 (5.9)
4 (2.6)
2 (1.3)
Eye disorders:
Cataract
1 (0.6)
2 (1.3)
Cardiac disorders:
Bundle branch block
1 (0.6)
2 (1.3)
Respiratory, thoracic and mediastinal
disorders:
Pharyngitis
Gastrointestinal disorders:
Diarrhoea Dyspepsia Vomiting
Gastrointestinal pain
Tooth disorder
1 (0.6)
5 (3.2)
2 (1.3)
2 (1.3)
0 (0.0)
8 (5.3)
6 (3.9)
5 (3.3)
4 (2.6)
3 (2.0)
Skin and subcutaneous tissue disorders:
Skin disorder
Ecchymosis
0 (0.0)
2 (1.3)
Musculoskeletal and connective tissue
disorders:
Myalgia
Arthralgia Joint disorder Osteoarthritis
6 (3.8)
1 (0.6)
0 (0.0)
8 (5.3)
2 (1.3)
2 (1.3)
General disorders:
Asthenia
Influenza-like illness Oedema peripheral
Thirst
8 (5.1)
2 (1.3)
2 (1.3)
0 (0.0)
10 (6.6)
8 (5.3)
3 (2.0)
2 (1.3)
Investigations:
Gamma-GT increased
Creatinine increased
1 (0.6)
1 (0.6)
4 (2.6)
3 (2.0)
Other adverse reactions reported at a lower frequency are as follows:
Uncommon:
Infection and infestation:
cystitis, vaginitis, oral candidiasis
Neoplasms benign and malignant (including cysts and polyps):
benign skin neoplasm
Blood and lymphatic system:
anaemia, blood dyscrasia
Metabolism and nutrition disorders:
hypophosphataemia
Psychiatric disorders:
sleep disorder, anxiety, affection lability
Nervous system disorders:
cerbrovascular disorder, nerve root lesion ,amnesia, migraine, neuralgia,
hypertonia, hyperaestesia, paraesthesia circumoral, parosmia.
Ear and labyrinth disorders:
deafness
Cardiac disorders:
myocardial ischaemia, cardiovascular disorder, palpitations
Vascular disorders:
hypertension, lymphoedema, varicose veins
Respiratory, thoracic and mediastinal disorders:
lung oedema, stridor
Gastrointestinal disorders:
gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis
Hepato-biliary disorders:
cholelithiasis
Skin and subcutaneous tissue disorders:
rash, alopecia
Renal and urinary disorders:
urinary retention, renal cyst
Reproductive system and breast
disorders:
pelvic pain
General disorders and administration site conditions:
hypothermia
7
Investigations:
blood alkaline phosphatase increase, weight decrease
Injury, poisoning and procedural complications
: injury, injection site pain
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).
4.9
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.
5.1
Pharmacodynamic properties
Pharmaco-therapeutic group: Bisphosphonate, ATC Code: M05B A 06
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
45
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 the treatment of tumour-induced hypercalcemia
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.
8
88
86
78
100%
76
64
80
62
63
60
54
44
40
6mg
20
4mg
ibandronic acid dose
High 90%
confidence
interval
2mg
Response
rate
Low 90%
confidence
interval
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 Iasibon 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 Iasibon (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
Iasibon 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 Iasibon 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 3.
9
Table 3
Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
All Skeletal Related Events (SREs)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
SMPR (per patient year)
1.48
1.19
p=0.004
Number of events (per
patient)
3.64
2.65
p=0.025
SRE relative risk
-
0.60
p=0.003
Secondary efficacy endpoints
A statistically significant improvement in bone pain score was shown for intravenous Iasibon 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 Iasibon treated patients compared with placebo. A tabular summary of these
secondary efficacy results is presented in table 4.
Table 4
Secondary efficacy results (breast cancer patients with metastatic bone disease)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
Bone pain *
0.21
-0.28
p<0.001
Analgesic use *
0.90
0.51
p=0.083
Quality of Life *
-45.4
-10.3
p=0.004
* Mean change from baseline to last assessment.
There was a marked depression of urinary markers of bone resorption (pyridinoline and
deoxypyridinoline) in patients treated with Iasibon that was statistically significant compared to
placebo.
In a study in 130 patients with metastatic breast cancer the safety of Iasibon 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.
5.2
Pharmacokinetic properties
After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose
proportional.
Distribution
10
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 drug-drug interaction due to displacement is
unlikely.
Metabolism
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.
Pharmacokinetics in Special Populations
Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race
There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in
ibandronic acid disposition. There are only very few data available on patients with African origin.
Patients with renal impairment
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine
clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min),
dose-adjusted mean AUC
0-24h
was increased by 110% compared to healthy volunteers. In clinical
pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes
infusion), mean AUC
0-24
increased by 14% and 86%, respectively, in subjects with mild (mean
estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment
compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C
max
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
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
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).
11
Children and adolescents
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. Adverse effects of ibandronic acid in reproductive toxicity studies
in the rat were those expected for this class of drug (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.
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
3 years.
After reconstitution: 24 hours.
6.4
Special precautions for storage
No special precautions for storage prior to reconstitution. After reconstitution: Store at 2°C - 8°C (in a
refrigerator).
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 - 8°C.
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 1 mg is supplied as pack containing 1 ampoule (2 ml type I glass ampoule).
6.6
Special precautions for disposal and other handling
12
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Pharmathen S.A.
Dervenakion 6
Pallini Attiki, 15351
Greece
8.
9.
Date of first Authorisation:
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
13
1.
I
asibon 2 mg concentrate for solution for infusion
2.
One ampoule with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as
ibandronic sodium monohydrate).
Excipients:
Each ampoule contains 0.30019 mmol of sodium (as sodium chloride and sodium acetate trihydrate)
F
or a full list of excipients, see section 6.1.
3.
C
oncentrate for solution for infusion. Clear, colourless solution.
4.
4.1
Iasibon is indicated 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
Iasibon therapy should only be initiated by physicians experienced in the treatment of cancer. For
intravenous administration.
For single use only. Only clear solution without particles should be used.
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. For infusion, the contents of the vial(s) should only be added to 100 ml isotonic
sodium chloride solution or 100 ml 5% glucose solution.
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 characterizing 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. 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 dosage. In patients with moderate
hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose.
14
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. For this
purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml
5% dextrose solution) and infused over two hours.
As the inadvertent intra-arterial administration of preparations not expressly recommended for this
purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure
that Iasibon concentrate for solution for infusion is administered intravenously.
Patients with hepatic impairment
No dosage adjustment is required (see section 5.2).
Patients with renal impairment
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is
necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal
impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with
breast cancer and metastatic bone disease the following dosing recommendations should be followed
(see Section 5.2):
Creatinine Clearance
(ml/min)
Dosage / Infusion time
1
Infusion Volume
2
≥50 CLcr <80
6 mg / 15 minutes
100 ml
≥30
CLcr <50
4 mg / 1 hour
500 ml
<30
2 mg / 1 hour
500 ml
1
Administration every 3 to 4 week
2
0.9% sodium chloride solution or 5% glucose solution
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.
Elderly
No dose adjustment is required.
Children and adolescents
Iasibon is not recommended for patients below age 18 years due to insufficient data on safety and
efficacy.
15
4.3
Hypocalcaemia (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. Iasibon should
not be used in children.
4.4
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.
As no clinical data are available, dosage recommendations cannot be given for patients with severe
hepatic insufficiency.
Overhydration should be avoided in patients at risk of cardiac failure.
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.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including
osteomyelitis) has been reported in patients with cancer receiving treatment regimens including
primarily intravenously administered bisphosphonates. Many of these patients were also receiving
chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with
osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with
bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy,
corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients
who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate
the condition. For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical
judgement of the treating physician should guide the management plan of each patient based on
individual benefit/risk assessment.
This medicinal product contains 0.30019 mmol sodium per dose. This should be taken into
consideration by patients on a controlled sodium diet.
4.5
Iasibon should not be mixed with calcium containing solutions
No interaction was observed when co-administered with melphalan/prednisolone in patients with
multiple myeloma.
Other interaction studies in postmenopausal women have demonstrated the absence of any interaction
potential with tamoxifen or hormone replacement therapy (oestrogen).
In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is
16
eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway
does not appear to include known acidic or basic transport systems involved in the excretion of
otheractive 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. Plasma protein binding is
low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active
substances.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can
lower serum calcium levels for prolonged periods. Attention should also be paid to the possible
existence of simultaneous hypomagnesaemia.
In clinical studies, Iasibon has been administered concomitantly with commonly used anticancer agents,
diuretics, antibiotics and analgesics without clinically apparent interactions occurring.
Interaction studies have only been performed in adults.
4.6
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.
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 lactation.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following
convention: very common ( ≥10%), common ( ≥1% and <10%), uncommon ( ≥0.1% and <1%), rare
( ≥0.01% and <0.1%), and very rare ( ≤0.01%).
Treatment of Tumour Induced Hypercalcaemia
The safety profile for Iasibon in tumour-induced hypercalcaemia is derived from controlled clinical
trials in this indication and after the intravenous administration of Iasibon at the recommended doses.
Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like
syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no
specific treatment was required and the symptoms subsided after a couple of hours/days.
Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a
determination of causality).
Table 1 Number (percentage) of Patients Reporting Adverse Reactions in Controlled
Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Iasibon
System Organ Class / Adverse reaction
Frequency Number
(%) (n=352)
Metabolism and nutrition disorders
Common:
Hypocalcaemia
10 (2.8)
17
Musculoskeletal and connective tissue disorders:
Common:
Bone Pain
6 (1.7)
1 (0.3)
Uncommon:
Myalgia
General disorders and administration site conditions:
Very common: Pyrexia
Uncommon:
Influenza-like illness
39 (11.1)
2 (0.6)
1 (0.3)
Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled. Events were recorded
irrespective of a determination of causality.
Frequently, decreased renal calcium excretion is accompanied by a fall in serum phosphate levels not
requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
Other reactions reported at lower frequency are as follows:
Immune system disorders:
Very rare:
Hypersensitivity
Skin and subcutaneous tissue disorders:
Very rare:
Angioneurotic oedema
Respiratory, thoracic and mediastinal disorders:
Very rare:
Bronchospasm
Administration of other bisphosphonates has been associated with broncho-constriction in
acetylsalicylic acid-sensitive asthmatic patients.
Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases
The safety profile of intravenous Iasibon in patients with breast cancer and bone metastases is derived
from a controlled clinical trial in this indication and after the intravenous administration of Iasibon at
the recommended dose.
Table 2 lists adverse reactions from the pivotal phase III study (152 patients treated with Iasibon 6mg),
i.e. adverse events with a remote, possible, or probable relationship to study medication, occurring
commonly and more frequently in the active treatment group than in placebo.
Table 2 Adverse Reactions Occurring Commonly and Greater than Placebo in Patients
with Metastatic Bone Disease due to Breast Cancer Treated with Iasibon 6 mg administered
intravenously
Adverse Reaction
Placebo (n = 157) No.
(%)
Iasibon 6mg
(n = 152) No. (%)
Infections and Infestations:
Infection
1 (0.6)
2 (1.3)
Endocrine disorders:
Parathyroid disorder
1 (0.6)
2 (1.3)
Nervous System disorders:
Headache
Dizziness
Dysgeusia (taste perversion)
4 (2.5)
2 (1.3)
0 (0.0)
9 (5.9)
4 (2.6)
2 (1.3)
Eye disorders:
Cataract
1 (0.6)
2 (1.3)
18
Rigors
Cardiac disorders:
Bundle branch block
1 (0.6)
2 (1.3)
Respiratory, thoracic and mediastinal
disorders:
Pharyngitis
Gastrointestinal disorders:
Diarrhoea Dyspepsia Vomiting
Gastrointestinal pain
Tooth disorder
1 (0.6)
5 (3.2)
2 (1.3)
2 (1.3)
0 (0.0)
8 (5.3)
6 (3.9)
5 (3.3)
4 (2.6)
3 (2.0)
Skin and subcutaneous tissue disorders:
Skin disorder
Ecchymosis
0 (0.0)
2 (1.3)
Musculoskeletal and connective tissue
disorders:
Myalgia
Arthralgia Joint disorder Osteoarthritis
6 (3.8)
1 (0.6)
0 (0.0)
8 (5.3)
2 (1.3)
2 (1.3)
General disorders:
Asthenia
Influenza-like illness Oedema peripheral
Thirst
8 (5.1)
2 (1.3)
2 (1.3)
0 (0.0)
10 (6.6)
8 (5.3)
3 (2.0)
2 (1.3)
Investigations:
Gamma-GT increased
Creatinine increased
1 (0.6)
1 (0.6)
4 (2.6)
3 (2.0)
Other adverse reactions reported at a lower frequency are as follows:
Uncommon:
Infection and infestation:
cystitis, vaginitis, oral candidiasis
Neoplasms benign and malignant (including cysts and polyps):
benign skin neoplasm
Blood and lymphatic system:
anaemia, blood dyscrasia
Metabolism and nutrition disorders:
hypophosphataemia
Psychiatric disorders:
sleep disorder, anxiety, affection lability
Nervous system disorders:
cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia,
hypertonia, hyperaestesia, paraesthesia circumoral, parosmia.
Ear and labyrinth disorders:
deafness
Cardiac disorders:
myocardial ischaemia, cardiovascular disorder, palpitations
Vascular disorders:
hypertension, lymphoedema, varicose veins
Respiratory, thoracic and mediastinal disorders:
lung oedema, stridor
Gastrointestinal disorders:
gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis
Hepato-biliary disorders:
cholelithiasis
Skin and subcutaneous tissue disorders:
rash, alopecia
Renal and urinary disorders:
urinary
retention, renal cyst
Reproductive system and breast disorders:
pelvic pain
General disorders and administration site conditions:
hypothermia
Investigations:
blood alkaline phosphatase increase, weight decrease
Injury, poisoning and procedural complications
: injury, injection site pain
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).
19
4.9
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.
5.1
Pharmacodynamic properties
Pharmaco-therapeutic group: Bisphosphonate, ATC Code: M05B A 06
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
45
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 the Treatment of Tumour-Induced Hypercalcemia
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.
20
88
86
78
100%
76
64
80
62
63
60
54
44
40
6mg
20
4mg
ibandronic acid dose
High 90%
confidence
interval
2mg
Response
rate
Low 90%
confidence
interval
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 Iasibon 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 Iasibon (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
-
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
Iasibon 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 Iasibon 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 3.
Table 3
Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
21
-
vertebral fractures
All Skeletal Related Events (SREs
)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
SMPR (per patient year)
1.48
1.19
p=0.004
Number of events (per
patient)
3.64
2.65
p=0.025
SRE relative risk
-
0.60
p=0.003
Secondary Efficacy Endpoints
A statistically significant improvement in bone pain score was shown for intravenous Iasibon 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 Iasibon treated patients compared with placebo. A tabular summary of these
secondary efficacy results is presented in Table 4.
Table 4
Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
Bone pain *
0.21
-0.28
p<0.001
Analgesic use *
0.90
0.51
p=0.083
Quality of Life *
-45.4
-10.3
p=0.004
* Mean change from baseline to last assessment.
There was a marked depression of urinary markers of bone resorption (pyridinoline and
deoxypyridinoline) in patients treated with Iasibon that was statistically significant compared to
placebo.
In a study in 130 patients with metastatic breast cancer the safety of Iasibon infused over 1 hour or 15
minutes was compared. No difference was observed in the indicators of renal function. The overall
adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the
known safety profile over longer infusion times and no new safety concerns were identified relating to
the use of a 15 minute infusion time.
A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of
<50ml/min.
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 drug-drug interaction due to displacement is
unlikely.
22
Metabolism
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.
Pharmacokinetics in Special Populations
Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race
There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in
ibandronic acid disposition. There are only very few data available on patients with African origin.
Patients with renal impairment
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine
clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr =21.2 mL/min), dose-
adjusted mean AUC
0-24h
was increased by 110% compared to healthy volunteers. In clinical
pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes
infusion), mean AUC
0-24
increased by 14% and 86%, respectively, in subjects with mild (mean
estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment
compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C
max
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
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
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).
Children and adolescents
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
23
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. Adverse effects of ibandronic acid in reproductive toxicity studies
in the rat were those expected for this class of drug (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.
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
3 years
After reconstitution: 24 hours.
6.4
Special precautions for storage
No special precautions for storage prior to reconstitution. After reconstitution: Store at 2 °C – 8 °C (in a
refrigerator).
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 - 8°C.
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 2mg is supplied as packs containing 1 ampoule( 4 ml type I glass ampoule).
6.6
Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
24
Pharmathen S.A.
Dervenakion 6
Pallini Attiki, 15351
Greece
8.
9.
Date of first Authorisation:
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
25
1.
Iasibon 6 mg Concentrate for solution for infusion
2.
One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid, (as ibandronic
sodium monohydrate)
Excipients:
Each vial contains 0.90054 mmol of sodium (as sodium chloride and sodium acetate trihydrate)
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion. Clear, colourless solution.
4.
4.1
Iasibon is indicated 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
Iasibon therapy should only be initiated by physicians experienced in the treatment of cancer. For
intravenous administration.
For single use only. Only clear solution without particles should be used.
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. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic
sodium chloride solution or 100 ml 5% glucose solution.
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 characterizing 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
(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. 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
26
calcium* ≥3 mmol/l or ≥12 mg/dl) 4 mg is an adequate single dosage. 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. For this
purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml
5% dextrose solution) and infused over two hours.
As the inadvertent intra-arterial administration of preparations not expressly recommended for this
purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure
that Iasibon concentrate for solution for infusion is administered intravenously.
Patients with hepatic impairment
No dosage adjustment is required (see section 5.2).
Patients with renal impairment
For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is
necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal
impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with
breast cancer and metastatic bone disease the following dosing recommendations should be followed
(see Section 5.2):
Creatinine Clearance
(ml/min)
Dosage / Infusion time
1
Infusion Volume
2
≥50 CLcr <80
6 mg / 15 minutes
100 ml
≥30
CLcr <50
4 mg / 1 hour
500 ml
<30
2 mg / 1 hour
500 ml
1
Administration every 3 to 4 week
2
0.9% sodium chloride solution or 5% glucose solution
A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.
27
Elderly
No dose adjustment is required.
Children and adolescents
Iasibon is not recommended for patients below age 18 years due to insufficient data on safety and
efficacy.
4.3
Hypocalcaemia (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates. Iasibon should
not be used in children.
4.4
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.
As no clinical data are available, dosage recommendations cannot be given for patients with severe
hepatic insufficiency.
Overhydration should be avoided in patients at risk of cardiac failure.
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.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including
osteomyelitis) has been reported in patients with cancer receiving treatment regimens including
primarily intravenously administered bisphosphonates. Many of these patients were also receiving
chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with
osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with
bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy,
corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who
develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the
condition. For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical
judgement of the treating physician should guide the management plan of each patient based on
individual benefit/risk assessment.
This medicinal product contains 0.90054 mmol sodium per dose. This should be taken into
consideration by patients on a controlled sodium diet.
4.5
Iasibon should not be mixed with calcium containing solutions.
28
No interaction was observed when co-administered with melphalan/prednisolone in patients with
multiple myeloma.
Other interaction studies in postmenopausal women have demonstrated the absence of any interaction
potential with tamoxifen or hormone replacement therapy (oestrogen).
In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is
eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway
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. Plasma protein binding is
low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active
substances.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can
lower serum calcium levels for prolonged periods. Attention should also be paid to the possible
existence of simultaneous hypomagnesaemia.
In clinical studies, Iasibon has been administered concomitantly with commonly used anticancer agents,
diuretics, antibiotics and analgesics without clinically apparent interactions occurring.
Interaction studies have only been performed in adults.
4.6
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.
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 lactation.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following
convention: very common ( ≥10%), common ( ≥1% and <10%), uncommon ( ≥0.1% and <1%), rare
(≥0.01% and <0.1%), and very rare ( ≤0.01%).
Treatment of Tumour Induced Hypercalcaemia
The safety profile for Iasibon in tumour-induced hypercalcaemia is derived from controlled clinical
trials in this indication and after the intravenous administration of Iasibon at the recommended doses.
Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like
syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no
specific treatment was required and the symptoms subsided after a couple of hours/days.
Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a
determination of causality).
Table 1 Number (percentage) of Patients Reporting Adverse Reactions in Controlled
Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Iasibon
29
System Organ Class / Adverse reaction
Frequency Number
(%) (n=352)
Metabolism and nutrition disorders
Common:
Hypocalcaemia
10 (2.8)
Musculoskeletal and connective tissue disorders:
Common:
Bone Pain
6 (1.7)
1 (0.3)
Uncommon:
Myalgia
General disorders and administration site conditions:
Very common: Pyrexia
Uncommon:
Influenza-like illness
39 (11.1)
2 (0.6)
1 (0.3)
Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled. Events were recorded
irrespective of a determination of causality.
Frequently, decreased renal calcium excretion is accompanied by a fall in serum phosphate levels not
requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
Other reactions reported at lower frequency are as follows:
Immune system disorders:
Very rare:
Hypersensitivity
Skin and subcutaneous tissue disorders:
Very rare:
Angioneurotic oedema
Respiratory, thoracic and mediastinal disorders:
Very rare:
Bronchospasm
Administration of other bisphosphonates has been associated with broncho-constriction in
acetylsalicylic acid-sensitive asthmatic patients.
Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases
The safety profile of intravenous Iasibon in patients with breast cancer and bone metastases is derived
from a controlled clinical trial in this indication and after the intravenous administration of Iasibon at
the recommended dose.
Table 2 lists adverse reactions from the pivotal phase III study (152 patients treated with Iasibon 6 mg),
i.e. adverse events with a remote, possible, or probable relationship to study medication, occurring
commonly and more frequently in the active treatment group than in placebo.
Table 2 Adverse Reactions Occurring Commonly and Greater than Placebo in Patients
with Metastatic Bone Disease due to Breast Cancer Treated with Iasibon 6 mg administered
intravenously
Adverse Reaction
Placebo (n = 157) No.
(%)
Iasibon 6mg
(n = 152) No. (%)
Infections and Infestations:
Infection
1 (0.6)
2 (1.3)
Endocrine disorders:
Parathyroid disorder
1 (0.6)
2 (1.3)
30
Rigors
Nervous System disorders:
Headache
Dizziness
Dysgeusia (taste perversion)
4 (2.5)
2 (1.3)
0 (0.0)
9 (5.9)
4 (2.6)
2 (1.3)
Eye disorders:
Cataract
1 (0.6)
2 (1.3)
Cardiac disorders:
Bundle branch block
1 (0.6)
2 (1.3)
Respiratory, thoracic and mediastinal
disorders:
Pharyngitis
Gastrointestinal disorders:
Diarrhoea Dyspepsia Vomiting
Gastrointestinal pain
Tooth disorder
1 (0.6)
5 (3.2)
2 (1.3)
2 (1.3)
0 (0.0)
8 (5.3)
6 (3.9)
5 (3.3)
4 (2.6)
3 (2.0)
Skin and subcutaneous tissue disorders:
Skin disorder
Ecchymosis
0 (0.0)
2 (1.3)
Musculoskeletal and connective tissue
disorders:
Myalgia
Arthralgia Joint disorder Osteoarthritis
6 (3.8)
1 (0.6)
0 (0.0)
8 (5.3)
2 (1.3)
2 (1.3)
General disorders:
Asthenia
Influenza-like illness Oedema peripheral
Thirst
8 (5.1)
2 (1.3)
2 (1.3)
0 (0.0)
10 (6.6)
8 (5.3)
3 (2.0)
2 (1.3)
Investigations:
Gamma-GT increased
Creatinine increased
1 (0.6)
1 (0.6)
4 (2.6)
3 (2.0)
Other adverse reactions reported at a lower frequency are as follows:
Uncommon:
Infection and infestation:
cystitis, vaginitis, oral candidiasis
Neoplasms benign and malignant (including cysts and polyps):
benign skin neoplasm
Blood and lymphatic system:
anaemia, blood dyscrasia
Metabolism and nutrition disorders:
hypophosphataemia
Psychiatric disorders:
sleep disorder, anxiety, affection lability
Nervous system disorders:
cerbrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia,
hypertonia, hyperaestesia, paraesthesia circumoral, parosmia.
Ear and labyrinth disorders:
deafness
Cardiac disorders:
myocardial ischaemia, cardiovascular disorder, palpitations
Vascular disorders:
hypertension, lymphoedema, varicose veins
Respiratory, thoracic and mediastinal disorders:
lung oedema, stridor
Gastrointestinal disorders:
gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis
Hepato-biliary disorders:
cholelithiasis
Skin and subcutaneous tissue disorders:
rash, alopecia
Renal and urinary disorders:
urinary
retention, renal cyst
Reproductive system and breast disorders:
pelvic pain
General disorders and administration site conditions:
hypothermia
Investigations:
blood alkaline phosphatase increase, weight decrease
Injury, poisoning and procedural complications
: injury, injection site pain
31
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).
4.9
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.
5.1
Pharmacodynamic properties
Pharmaco-therapeutic group: Bisphosphonate, ATC Code: M05B A 06
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
45
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 the Treatment of Tumour-Induced Hypercalcemia
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.
32
88
86
78
100%
76
64
80
62
63
60
54
44
40
6mg
20
4mg
ibandronic acid dose
High 90%
confidence
interval
2mg
Response
rate
Low 90%
confidence
interval
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 Iasibon 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 Iasibon (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
-
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
Iasibon 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 Iasibon 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 3.
33
-
surgery to bone for treatment of fractures
Table 3
Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
All Skeletal Related Events (SREs
)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
SMPR (per patient year)
1.48
1.19
p=0.004
Number of events (per
patient)
3.64
2.65
p=0.025
SRE relative risk
-
0.60
p=0.003
Secondary Efficacy Endpoints
A statistically significant improvement in bone pain score was shown for intravenous Iasibon 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 Iasibon treated patients compared with placebo. A tabular summary of these
secondary efficacy results is presented in Table 4.
Table 4
Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)
Placebo
n=158
Iasibon 6 mg
n=154
p-value
Bone pain *
0.21
-0.28
p<0.001
Analgesic use *
0.90
0.51
p=0.083
Quality of Life *
-45.4
-10.3
p=0.004
* Mean change from baseline to last assessment.
There was a marked depression of urinary markers of bone resorption (pyridinoline and
deoxypyridinoline) in patients treated with Iasibon that was statistically significant compared to
placebo.
In a study in 130 patients with metastatic breast cancer the safety of Iasibon infused over 1 hour or 15
minutes was compared. No difference was observed in the indicators of renal function. The overall
adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the
known safety profile over longer infusion times and no new safety concerns were identified relating to
the use of a 15 minute infusion time.
A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of
<50ml/min.
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 drug-drug interaction due to displacement is
unlikely.
34
Metabolism
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.
Pharmacokinetics in Special Populations
Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race
There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in
ibandronic acid disposition. There are only very few data available on patients with African origin.
Patients with renal impairment
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine
clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr =21.2 mL/min), dose-
adjusted mean AUC
0-24h
was increased by 110% compared to healthy volunteers. In clinical
pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes
infusion), mean AUC
0-24
increased by 14% and 86%, respectively, in subjects with mild (mean
estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment
compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C
max
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
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
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).
Children and adolescents
There are no data on the use of Iasibon in patients less than 18 years old
5.3
Preclinical safety data
35
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. Adverse effects of ibandronic acid in reproductive toxicity studies
in the rat were those expected for this class of drug (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.
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
3 years
After reconstitution: 24 hours.
6.4
Special precautions for storage
No special precautions for storage prior to reconstitution. After reconstitution: Store at 2 °C – 8 °C (in a
refrigerator).
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 - 8°C.
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 6mg is supplied as packs containing 1, 5 and 10 vials (9 ml type I glass vial).
6.6
Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
36
Pharmathen S.A.
Dervenakion 6
Pallini Attiki, 15351
Greece
8.
9.
Date of first Authorisation:
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
37
1.
FURTHER INFORMATION
What Iasibon contains
-
The active substance is ibandronic acid. Each film-coated tablet contains 50 mg of ibandronic
acid (as ibandronic sodium monohydrate).
The other ingredients are:
-
tablet core: povidone, microcrystalline cellulose, crospovidone, maize starch pregelatinised,
glycerol dibehenate, colloidal anhydrous silica.
-
tablet coat: titanium dioxide (E171), lactose monohydrate, hypromellose (E464), macrogol
4000
What Iasibon looks like and contents of the pack
The film-coated tablets are white, round biconvex tablets supplied in Polyamide/Al/PVC - Aluminum
foil blister. They are available in packs of 3, 6, 9, 28 and 84 tablets.
Not all pack sizes may be marketed
Marketing Authorisation Holder
Pharmathen S.A.
Dervenakion 6
Pallini 15351
Attiki
Greece
Manufacturer
Pharmathen S.A.
Dervenakion 6
Pallini 15351
Attiki
Greece
And
Pharmathen International S.A.
Industrial Park Sapes, Street block 5
69300 Sapes, Prefecture of Rodopi
85
Greece
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Pharmathen S.A.
Tél/Tel: +30 210 66 65 067
Luxembourg/Luxemburg
Portfarma ehf.
Tél/Tel: +354 534 4030
България
Alvogen Pharma Bulgaria Ltd
Teл.: +359 2 400 555 2
Magyarország
Pharmathen S.A.
Tel.: +30 210 66 65 067
Česká republika
Pharmathen S.A.
Tel: +30 210 66 65 067
Malta
Pharmathen S.A.
Tel: +30 210 66 65 067
Danmark
Pharmathen S.A.
Tlf: +30 210 66 65 067
Nederland
Pharmathen S.A.
Tel: +30 210 66 65 067
Deutschland
Pharmathen S.A.
Tel: +30 210 66 65 067
Norge
Pharmathen S.A.
Tlf: +30 210 66 65 067
Eesti (Estonia)
Portfarma ehf.
Tel: +354 534 4030
Österreich
Pharmathen S.A.
Tel: +30 210 66 65 067
Ελλάδα
Pharmathen S.A.
Τηλ: +30 210 66 65 067
Polska
Pharmathen S.A.
Tel.: +30 210 66 65 067
España
Pharmathen S.A.
Tel: +30 210 66 65 067
Portugal
Pharmathen S.A.
Tel: +30 210 66 65 067
France
Pharmathen S.A.
Tél: +30 210 66 65 067
România
Alvogen Pharma SRL Romania
Tel: +40 744 543249
Ireland
Aspire Pharma Ltd
Tel: +44 1730 234527
Slovenija
Pharmathen S.A.
Tel: +30 210 66 65 067
Ísland
Portfarma ehf.
Sími: +354 534 4030
Slovenská republika
Pharmathen S.A.
Tel: +30 210 66 65 067
Italia
Pharmathen S.A.
Tel: +30 210 66 65 067
Suomi/Finland
Pharmathen S.A.
Puh/Tel: +30 210 66 65 067
Κύπρος
P.T. Hagjigeorgiou Co Ltd
Τηλ: +357 25372425
Sverige
Pharmathen S.A.
Tel: +30 210 66 65 067
Latvija
United Kingdom
86
Portfarma ehf.
Tel: +354 534 4030
Aspire Pharma Ltd
Tel: +44 1730 234527
Lietuva
Portfarma ehf.
Tel: +354 534 4030
This leaflet was last approved in {
MM/YYYY
}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
87
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