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IBANDRONIC ACID 150 MG FILM-COATED TABLETS

Active substance: SODIUM IBANDRONATE MONOHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Ibandronic acid 150mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg ibandronic acid (as ibandronic
sodium monohydrate).
Excipients: each tablet contains 271 mg lactose.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
White, oblong biconvex film coated tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of osteoporosis in postmenopausal women at increased risk of
fracture (see section 5.1).
A reduction in the risk of vertebral fractures has been demonstrated, efficacy
on femoral neck fractures has not been established.

4.2

Posology and method of administration
Posology:
The recommended dose is one 150 mg film-coated tablet once a month. The
tablet should preferably be taken on the same date each month.

Ibandronic acid should be taken after an overnight fast (at least 6 hours) and 1
hour before the first food or drink (other than water) of the day (see section
4.5) or any other oral medicinal products or supplementation (including
calcium).
In case a dose is missed, patients should be instructed to take one ibandronic
acid 150 mg tablet the morning after the tablet is remembered, unless the time
to the next scheduled dose is within 7 days. Patients should then return to
taking their dose once a month on their originally scheduled date.
If the next scheduled dose is within 7 days, patients should wait until their next
dose and then continue taking one tablet once a month as originally scheduled.
Patients should not take two tablets within the same week.
Patients should receive supplemental calcium and / or vitamin D if dietary
intake is inadequate (see section 4.4 and section 4.5).
The optimal duration of bisphosphonate treatment for osteoporosis has not
been established. The need for continued treatment should be re-evaluated
periodically based on the benefits and potential risks of ibandronic acid on an
individual patient basis, particularly after 5 or more years of use.
Special Populations
Patients with renal impairment
No dose adjustment is necessary for patients with mild or moderate renal
impairment where creatinine clearance is equal or greater than 30 ml/min.
Ibandronic acid is not recommended for patients with a creatinine clearance
below 30 ml/min due to limited clinical experience (see section 4.4 and section
5.2).
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly Population
No dose adjustment is required (see section 5.2).
Paediatric Population
There is no relevant use of ibandronic acid in children, and ibandronic acid
was not studied in the paediatric population.
Method of Administration:
For oral use.
Tablets should be swallowed whole with a glass of plain water (180 to 240 ml)
while the patient is sitting or standing in an upright position. Patients should
not lie down for 1 hour after taking ibandronic acid.
Plain water is the only drink that should be taken with ibandronic acid. Please
note that some mineral waters may have a higher concentration of calcium and
therefore, should not be used.
Patients should not chew or suck the tablet, because of a potential for
oropharyngeal ulceration.

4.3

Contraindications
- Hypersensitivity to ibandronic acid or to any of the excipients.
- 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
Hypocalcaemia
Existing hypocalcaemia must be corrected before starting ibandronic acid
therapy. Other disturbances of bone and mineral metabolism should also be
effectively treated. Adequate intake of calcium and vitamin D is important in
all patients.
Gastrointestinal Disorders
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 ibandronic acid 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 hospitalisation,
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 to and be able
to comply with the dosing instructions (see section 4.2).
Physicians should be alert to any signs or symptoms signalling a possible
oesophageal reaction and patients should be instructed to discontinue
ibandronic acid 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.
Since Nonsteroidal Anti-Inflammatory Drugs and bisphosphonates are both
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.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported
with bisphosphonate therapy, primarily in patients receiving long-term
treatment for osteoporosis. These transverse or short oblique, fractures can
occur anywhere along the femur from just below the lesser trochanter to just
above the supracondylar flare. These fractures occur after minimal or no
trauma and some patients experience thigh or groin pain, often associated with
imaging features of stress fractures, weeks to months before presenting with a
completed femoral fracture. Fractures are often bilateral; therefore the
contralateral femur should be examined in bisphosphonate-treated patients
who have sustained a femoral shaft fracture. Poor healing of these fractures
has also been reported. Discontinuation of bisphosphonate therapy in patients
suspected to have an atypical femur fracture should be considered pending
evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any
thigh, hip or groin pain and any patient presenting with such symptoms should
be evaluated for an incomplete femur fracture.
Renal impairment
Due to limited clinical experience, ibandronic acid is not recommended for
patients with a creatinine clearance below 30 ml/min (see section 5.2).
The medicinal product contains lactose. Patients with rare hereditary problems
of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
4.5

Interaction with other medicinal products and other forms of interaction
Oral bioavailability of ibandronic acid is generally reduced in the presence of
food. In particular, products containing calcium and other multivalent cations
(such as aluminium, magnesium, iron), including milk, are likely to interfere

with absorption of ibandronic acid, which is consistent with findings in animal
studies. Therefore, patients should fast overnight (at least 6 hours) before
taking ibandronic acid and continue fasting for 1 hour following intake of
ibandronic acid (see section 4.2).
Calcium supplements, antacids and some oral medicinal products containing
multivalent cations (such as aluminium, magnesium, iron) are likely to
interfere with the absorption of ibandronic acid. Therefore, patients should not
take other oral medicinal products for at least 6 hours before taking ibandronic
acid and for 1 hour following intake of ibandronic acid.
Metabolic interactions are not considered likely, since ibandronic acid does
not inhibit the major human hepatic P450 isoenzymes and has been shown not
to induce the hepatic cytochrome P450 system in rats. Furthermore, plasma
protein binding is approximately 85% - 87% (determined in vitro at
therapeutic concentrations), and thus there is a low potential for interaction
with other medicinal products due to displacement. Ibandronic acid is
eliminated by renal excretion only and does not undergo any
biotransformation. The secretory pathway appears not to include known acidic
or basic transport systems involved in the excretion of other active substances.
In a two-year study in postmenopausal women with osteoporosis (BM 16549),
the incidence of upper gastrointestinal events in patients concomitantly taking
aspirin or NSAIDs was similar in patients taking ibandronic acid 2.5mg daily
or 150mg once monthly after one and two years.
Of over 1500 patients enrolled in study BM 16549 comparing monthly with
daily dosing regimens of ibandronic acid, 14% and 18% of patients used
histamine (H2) blockers or proton pump inhibitors after one and two years,
respectively. Among these patients, the incidence of upper gastrointestinal
events in the patients treated with ibandronic acid 150mg once monthly was
similar to that in patients treated with ibandronic acid 2.5mg daily.
In healthy male volunteers and postmenopausal women, intravenous
administration of ranitidine caused an increase in ibandronic acid
bioavailability of about 20%, probably as a result of reduced gastric acidity.
However, since this increase is within the normal variability of the
bioavailability of ibandronic acid, no dose adjustment is considered necessary
when ibandronic acid is administered with H2-antagonists or other active
substances which increase gastric pH.
Pharmacokinetic interaction studies in postmenopausal women have
demonstrated the absence of any interaction potential with tamoxifen or
hormone replacement therapy (oestrogen).
No interaction was observed when co-administered with melphalan/
prednisolone in patients with multiple myeloma.

4.6

Fertility, pregnancy and lactation
Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant
women. Studies in rats have shown some reproductive toxicity (see section
5.3). The potential risk for humans is unknown.
Ibandronic acid should not be used during pregnancy.
Lactation
It is not known whether ibandronic acid is excreted in human milk. Studies in
lactating rats have demonstrated the presence of low levels of ibandronic acid
in the milk following intravenous administration.
Ibandronic acid should not be used during lactation.
Fertility
There are no data on the effects of ibandronic acid from humans. In
reproductive studies in rats by the oral route, ibandronic acid decreased
fertility. In studies in rats using the intravenous route, ibandronic acid
decreased fertility at high daily doses (see section 5.3).
4.7

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

4.8

Undesirable effects
The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated
in 1251 patients treated in 4 placebo-controlled clinical studies, with the large
majority of patients coming from the pivotal three year fracture study
(MF4411). The overall safety profile of ibandronic acid 2.5 mg daily in all
these studies was similar to that of placebo.
In a two-year study in postmenopausal women with osteoporosis (BM 16549)
the overall safety of ibandronic acid 150 mg once monthly and ibandronic acid
2.5 mg daily was similar. The overall proportion of patients who experienced
an adverse reaction, was 22.7 % and 25.0 % for ibandronic acid 150 mg once
monthly after one and two years, respectively. The majority of adverse
reactions were mild to moderate in intensity. Most cases did not lead to
cessation of therapy.
The most commonly reported adverse reaction was arthralgia.
Adverse reactions considered by investigators to be causally related to
ibandronic acid are listed below by System Organ Class.
Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥
1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000) and
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 occurring in postmenopausal women
receiving ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg
daily in the phase III studies BM16549 and MF4411 and in postmarketing
experience.
System Organ Class
Immune system disorders
Nervous system disorders
Eye disorders
Gastrointestinal disorders

Skin and subcutaneous
tissues disorders
Musculoskeletal,
connective tissue and bone
disorders

General disorders and
administration site
conditions

Frequency
Rare
Common
Uncommon
Rare
Common

Adverse reactions
Hypersensitivity reaction
Headache
Dizziness
Ocular inflammation*†
Oesophagitis, Gastritis, Gastro
oesophageal reflex disease, Dyspepsia,
Diarrhoea, Abdominal pain, Nausea
Uncommon Oesophagitis including oesophageal
ulcerations or strictures and dysphagia,
Vomiting, Flatulence
Rare
Duodenitis
Common
Rash
Rare
Common

Angioedema, Face oedema, Urticaria
Arthralgia, Myalgia, Musculoskeletal
pain, Muscle cramp, Musculoskeletal
stiffness
Uncommon Back pain
Rare
Atypical subtrochanteric and diaphyseal
femoral fractures (bisphosphonate class
adverse reaction) †
Very rare
Osteonecrosis of jaw*†
Common
Influenza like illness*

Uncommon Fatigue
*See further information below
†Identified in postmarketing experience.
Gastrointestinal adverse events
Patients with a previous history of gastrointestinal disease including patients
with peptic ulcer without recent bleeding or hospitalisation, and patients with
dyspepsia or reflux controlled by medication were included in the once
monthly treatment study. For these patients, there was no difference in the
incidence of upper gastrointestinal adverse events with the 150 mg once
monthly regimen compared to the 2.5 mg daily regimen.
Influenza-like illness
Transient, influenza-like symptoms have been reported with ibandronic acid
150 mg once monthly, typically in association with the first dose. Such
symptoms were generally of short duration, mild or moderate in intensity, and
resolved during continuing treatment without requiring remedial measures.

Influenza-like illness includes events reported as acute phase reaction or
symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of
appetite, or bone pain.
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.
4.9

Overdose
No specific information is available on the treatment of over dosage with
ibandronic acid.
However, based on a knowledge of this class of compounds, oral over-dosage
may result in upper gastrointestinal adverse reactions (such as upset stomach,
dyspepsia, oesophagitis, gastritis, or ulcer) or hypocalcaemia. Milk or antacids
should be given to bind ibandronic acid, and any adverse reactions treated
symptomatically. Owing 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
Pharmacotherapeutic group: Drugs for treatment of bone diseases, Drugs
affecting bone structure and mineralization, Bisphosphonates, ATC code:
M05B A06
Mechanism of action
Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogencontaining group of bisphosphonates, which act selectively on bone tissue and
specifically inhibit osteoclast activity without directly affecting bone
formation. It does not interfere with osteoclast recruitment. Ibandronic acid
leads to progressive net gains in bone mass and a decreased incidence of

fractures through the reduction of elevated bone turnover towards
premenopausal levels in postmenopausal women.
Pharmacodynamic effects
The pharmacodynamic action of ibandronic acid is inhibition of bone
resorption. In vivo, ibandronic acid prevents experimentally induced bone
destruction caused by cessation of gonadal function, retinoids, tumours or
tumour extracts. In young (fast growing) rats, the endogenous bone resorption
is also inhibited, leading to increased normal bone mass compared with
untreated animals.
Animal models confirm that ibandronic acid is a highly potent inhibitor of
osteoclastic activity. In growing rats, there was no evidence of impaired
mineralization even at doses greater than 5,000 times the dose required for
osteoporosis treatment.
Both daily and intermittent (with prolonged dose-free intervals) long-term
administration in rats, dogs and monkeys was associated with formation of
new bone of normal quality and maintained or increased mechanical strength
even at doses in the toxic range. In humans, the efficacy of both daily and
intermittent administration with a dose-free interval of 9-10 weeks of
ibandronic acid was confirmed in a clinical trial (MF 4411), in which
ibandronic acid demonstrated anti-fracture efficacy.
In animal models ibandronic acid produced biochemical changes indicative of
dose-dependent inhibition of bone resorption, including suppression of urinary
biochemical markers of bone collagen degradation (such as deoxypyridinoline,
and cross-linked N-telopeptides of type I collagen (NTX)).
In a Phase 1 bioequivalence study conducted in 72 postmenopausal women
receiving 150 mg orally every 28 days for a total of four doses, inhibition in
serum CTX following the first dose was seen as early as 24 hours post-dose
(median inhibition 28 %), with median maximal inhibition (69 %) seen 6 days
later. Following the third and fourth dose, the median maximum inhibition 6
days post dose was 74 % with reduction to a median inhibition of 56 % seen
28 days following the fourth dose. With no further dosing, there is a loss of
suppression of biochemical markers of bone resorption.
Clinical efficacy
Independent risk factors, for example, low BMD, age, the existence of
previous fractures, a family history of fractures, high bone turnover and low
body mass index should be considered in order to identify women at increased
risk of osteoporotic fractures.
Ibandronic acid 150 mg once monthly
Bone mineral density (BMD)
Ibandronic acid 150 mg once monthly was shown to be at least as effective as
ibandronic acid 2.5 mg daily at increasing BMD in a two year, double-blind,
multicentre study (BM 16549) of postmenopausal women with osteoporosis
(lumbar spine BMD T score below -2.5 SD at baseline). This was
demonstrated in both the primary analysis at one year and in the confirmatory
analysis at two years endpoint (Table 2).

Table 2: Mean relative change from baseline of lumbar spine, total hip,
femoral neck and trochanter BMD after one year (primary analysis) and two
years of treatment (Per-Protocol Population) in study BM 16549.
One year data in study BM
16549
Mean
relative
changes
from
baseline %
[95% CI]
Lumbar
spine L2L4 BMD
Total hip
BMD
Femoral
neck
BMD
Trochanter
BMD

Two year data in study BM
16549

Ibandronic
acid 2.5 mg
daily
(N=318)

Ibandronic
acid 150 mg
once monthly
(N=320)

Ibandronic
acid 2.5 mg
daily
(N=294)

Ibandronic
acid 150 mg
once monthly
(N=291)

3.9 [3.4, 4.3]

4.9 [4.4, 5.3]

5.0 [4.4, 5.5]

6.6 [6.0, 7.1]

2.0 [1.7, 2.3]

3.1 [2.8, 3.4]

2.5 [2.1, 2.9]

4.2 [3.8, 4.5]

1.7 [1.3, 2.1]

2.2 [1.9, 2.6]

1.9 [1.4, 2.4]

3.1 [2.7, 3.6]

3.2 [2.8, 3.7]

4.6 [4.2, 5.1]

4.0 [3.5, 4.5]

6.2 [5.7, 6.7]

Furthermore, ibandronic acid 150 mg once monthly was proven superior to
ibandronic acid 2.5 mg daily for increases in lumbar spine BMD in a
prospectively planned analysis at one year, p=0.002, and at two years,
p<0.001.
At one year (primary analysis), 91.3 % (p=0.005) of patients receiving
ibandronic acid 150 mg once monthly had a lumbar spine BMD increase
above or equal to baseline (BMD responders), compared with 84.0 % of
patients receiving ibandronic acid 2.5 mg daily. At two years, 93.5 %
(p=0.004) and 86.4 % of patients receiving ibandronic acid 150 mg once
monthly or ibandronic acid 2.5 mg daily, respectively, were responders.
For total hip BMD, 90.0 % (p<0.001) of patients receiving ibandronic acid
150 mg once monthly and 76.7 % of patients receiving ibandronic acid 2.5 mg
daily had total hip BMD increases above or equal to baseline at one year. At
two years 93.4 % (p<0.001) of patients receiving ibandronic acid 150 mg once
monthly and 78.4 %, of patients receiving ibandronic acid 2.5 mg daily had
total hip BMD increases above or equal to baseline.
When a more stringent criterion is considered, which combines both lumbar
spine and total hip BMD, 83.9 % (p<0.001) and 65.7 % of patients receiving
ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily,
respectively, were responders at one year. At two years, 87.1 % (p<0.001) and
70.5 %,of patients met this criterion in the 150 mg monthly and 2.5 mg daily
arms respectively.
Biochemical markers of bone turn-over
Clinically meaningful reductions in serum CTX levels were observed at all
time points measured, i.e. months 3, 6, 12 and 24. After one year (primary

analysis) the median relative change from baseline was -76 % for ibandronic
acid 150 mg once monthly and -67 % for ibandronic acid 2.5 mg daily. At two
years the median relative change was -68 % and -62 %, in the 150 mg monthly
and 2.5 mg daily arms respectively.
At one year, 83.5 % (p= 0.006) of patients receiving ibandronic acid 150 mg
once monthly and 73.9 % of patients receiving ibandronic acid 2.5 mg daily
were identified as responders (defined as a decrease ≥50 % from baseline). At
two years 78.7 % (p=0.002) and 65.6 % of patients were identified as
responders in the 150 mg monthly and 2.5 mg daily arms respectively.
Based on the results of study BM 16549, ibandronic acid 150 mg once
monthly is expected to be at least as effective in preventing fractures as
ibandronic acid 2.5 mg daily.
Ibandronic acid 2.5 mg daily
In the initial three-year, randomised, double-blind, placebo-controlled, fracture
study (MF 4411), a statistically significant and medically relevant decrease in
the incidence of new radiographic morphometric and clinical vertebral
fractures was demonstrated (table 3). In this study, ibandronic acid was
evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an
exploratory regimen. Ibandronic acid was taken 60 minutes before the first
food or drink of the day (post-dose fasting period). The study enrolled women
aged 55 to 80 years, who were at least 5 years postmenopausal, who had a
BMD at lumbar spine of 2 to 5 SD below the premenopausal mean (T-score)
in at least one vertebra [L1-L4], and who had one to four prevalent vertebral
fractures. All patients received 500 mg calcium and 400 IU vitamin D daily.
Efficacy was evaluated in 2,928 patients. ibandronic acid 2.5 mg administered
daily, showed a statistically significant and medically relevant reduction in the
incidence of new vertebral fractures. This regimen reduced the occurrence of
new radiographic vertebral fractures by 62 % (p=0.0001) over the three year
duration of the study. A relative risk reduction of 61 % was observed after 2
years (p=0.0006). No statistically significant difference was attained after 1
year of treatment (p=0.056). The anti-fracture effect was consistent over the
duration of the study. There was no indication of a waning of the effect over
time.
The incidence of clinical vertebral fractures was also significantly reduced by
49 % (p=0.011). The strong effect on vertebral fractures was furthermore
reflected by a statistically significant reduction of height loss compared to
placebo (p<0.0001).
Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)
Placebo
(N=974)
Relative risk reduction
New morphometric vertebral
fractures
Incidence of new morphometric
vertebral fractures

Ibandronic acid
2.5 mg daily
(N=977)
62% (40.9, 75.1)

9.56% (7.5, 11.7)

4.68% (3.2, 6.2)

Relative risk reduction of
clinical vertebral fracture
Incidence of clinical vertebral
fracture
BMD – mean change relative to
baseline lumbar spine at year 3
BMD – mean change relative to
baseline total hip at year 3

1.26% (0.8, 1.7)

49% (14.03,
69.49)
2.75% (1.61,
3.89)
6.54% (6.1, 7.0)

-0.69% (-1.0, -0.4)

3.36% (3.0, 3.7)

5.33% (3.73, 6.92)

The treatment effect of ibandronic acid was further assessed in an analysis of
the subpopulation of patients who, at baseline, had a lumbar spine BMD Tscore below –2.5. The vertebral fracture risk reduction was very consistent
with that seen in the overall population.
Table 4: Results from 3 years fracture study MF 4411 (%, 95 % CI) for
patients with lumbar spine BMD T-score below –2.5 at baseline
Placebo
(N=587)
Relative Risk Reduction
New morphometric vertebral
fractures
Incidence of new morphometric
vertebral fractures
Relative risk reduction of
clinical vertebral fracture
Incidence of clinical vertebral
fracture
BMD – mean change relative to
baseline lumbar spine at year 3
BMD – mean change relative to
baseline total hip at year 3

Ibandronic acid
2.5 mg daily
(N=575)
59% (34.5, 74.3)

12.54% (9.53, 15.55)

1.13% (0.6, 1.7)

5.36% (3.31,
7.41)
50% (9.49,
71.91)
3.57% (1.89,
5.24)
7.01% (6.5, 7.6)

-0.70% (-1.1, -0.2)

3.59% (3.1, 4.1)

6.97% (4.67, 9.27)

In the overall patient population of the study MF4411, no reduction was
observed for non-vertebral fractures, however daily ibandronic acid appeared
to be effective in a high-risk subpopulation (femoral neck BMD T-score < 3.0), where a non-vertebral fracture risk reduction of 69% was observed.
Daily treatment with 2.5 mg resulted in progressive increases in BMD at
vertebral and nonvertebral sites of the skeleton.
Three-year lumbar spine BMD increase compared to placebo was 5.3 % and
6.5 % compared to baseline. Increases at the hip compared to baseline were
2.8 % at the femoral neck, 3.4 % at the total hip, and 5.5 % at the trochanter.
Biochemical markers of bone turnover (such as urinary CTX and serum
Osteocalcin) showed the expected pattern of suppression to premenopausal
levels and reached maximum suppression within a period of 3-6 months.

A clinically meaningful reduction of 50 % of biochemical markers of bone
resorption was observed as early as one month after start of treatment with
ibandronic acid 2.5 mg.
Following treatment discontinuation, there is a reversion to the pathological
pre-treatment rates of elevated bone resorption associated with
postmenopausal osteoporosis.
The histological analysis of bone biopsies after two and three years of
treatment of postmenopausal women showed bone of normal quality and no
indication of a mineralization defect.
Paediatric population
Bonviva was not studied in the paediatric population, therefore no efficacy or
safety data are available for this patient population.

5.2

Pharmacokinetic properties
The primary pharmacological effects of ibandronic acid on bone are not
directly related to actual plasma concentrations, as demonstrated by various
studies in animals and humans.
Absorption
The absorption of ibandronic acid in the upper gastrointestinal tract is rapid
after oral administration and plasma concentrations increase in a doseproportional manner up to 50 mg oral intake, with greater than doseproportional increases seen above this dose. 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
plain water). Bioavailability is reduced by about 90 % when ibandronic acid is
administered with a standard breakfast in comparison with bioavailability seen
in fasted subjects. There is no meaningful reduction in bioavailability provided
ibandronic acid is taken 60 minutes before the first food of the day. Both
bioavailability and BMD gains are reduced when food or beverage is taken
less than 60 minutes after ibandronic acid is ingested.
Distribution
After initial systemic exposure, ibandronic acid rapidly binds to bone or is
excreted into urine. In humans, the apparent terminal volume of distribution is
at least 90 l and the amount of dose reaching the bone is estimated to be 40-50
% of the circulating dose. Protein binding in human plasma is approximately
85 % - 87 % (determined in vitro at therapeutic concentrations), and thus there
is a low potential for interaction with other medicinal products due to
displacement.
Biotransformation
There is no evidence that ibandronic acid is metabolised in animals or humans.

Elimination
The absorbed fraction of ibandronic acid is removed from the circulation via
bone absorption (estimated to be 40-50 % in postmenopausal women) and the
remainder is eliminated unchanged by the kidney. The unabsorbed fraction of
ibandronic acid is eliminated unchanged in the faeces.
The range of observed apparent half-lives is broad, the apparent terminal halflife is generally in the range of 10-72 hours. As the values calculated are
largely a function of the duration of study, the dose used, and assay sensitivity,
the true terminal half-life is likely to be substantially longer, in common with
other bisphosphonates. Early plasma levels fall quickly reaching 10 % of 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 84160 ml/min. Renal clearance (about 60 mL/min in healthy postmenopausal
females) accounts for 50-60 % of total clearance and is related to creatinine
clearance. The difference between the apparent total and renal clearances is
considered to reflect the uptake by bone.
Pharmacokinetics in special clinical situations
Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in men
and women.
Race
There is no evidence for any clinically relevant inter-ethnic differences
between Asians and Caucasians in ibandronic acid disposition. There are few
data available on patients of African origin.
Patients with renal impairment
Renal clearance of ibandronic acid in patients with various degrees of renal
impairment is linearly related to creatinine clearance.
No dose adjustment is necessary for patients with mild or moderate renal
impairment (CLcr equal or greater than 30 ml/min), as shown in study BM
16549 where the majority of patients had mild to moderate renal impairment.
Subjects with severe renal failure (CLcr less than 30 ml/min) receiving daily
oral administration of 10 mg ibandronic acid for 21 days, had 2-3 fold higher
plasma concentrations than subjects with normal renal function and total
clearance of ibandronic acid was 44 ml/min. After intravenous administration
of 0.5 mg, total, renal, and non-renal clearances decreased by 67 %, 77 % and
50 %, respectively, in subjects with severe renal failure but there was no
reduction in tolerability associated with the increase in exposure. Due to the
limited clinical experience, ibandronic acid is not recommended in patients
with severe renal impairment (see section 4.2 and section 4.4). The
pharmacokinetics of ibandronic acid was not assessed in patients with endstage renal disease managed by other than hemodialysis. The
pharmacokinetics of ibandronic acid in these patients is unknown, and
ibandronic acid should not be used under these circumstances.
Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have
hepatic impairment. The liver has no significant role in the clearance of
ibandronic acid which is not metabolised but is cleared by renal excretion and
by uptake into bone. Therefore dose adjustment is not necessary in patients
with hepatic impairment.
Elderly Population
In a multivariate analysis, age was not found to be an independent factor of
any of the pharmacokinetic parameters studied. As renal function decreases
with age this is the only factor to take into consideration (see renal impairment
section).
Paediatric Population
There are no data on the use of ibandronic acid in these age groups.

5.3

Preclinical safety data
Toxic effects, e.g signs of renal damage, were observed in dogs only at
exposures considered sufficiently in excess of the maximum human exposure
indicating little relevance to clinical use.
Mutagenicity/Carcinogenicity:
No indication of carcinogenic potential was observed. Tests for genotoxicity
revealed no evidence of genetic activity for ibandronic acid.
Reproductive toxicity:
There was no evidence for a direct foetal toxic or teratogenic effect of
ibandronic acid in orally treated rats and rabbits and there were no adverse
effects on the development in F1 offspring in rats at an extrapolated exposure
of at least 35 times above human exposure. In reproductive studies in rats by
the oral route effects on fertility consisted of increased preimplantation losses
at dose levels of 1mg/kg/day and higher. In reproductive studies in rats by the
intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and
1mg/kg/day and decreased fertility in males at 1mg/kg/day and in females at
1.2mg/kg/day.Adverse effects of ibandronic acid in reproductive toxicity
studies in the rat were those observed with bisphosphonates as a class. They
include a decreased number of implantation sites, interference with natural
delivery (dystocia), and an increase in visceral variations (renal pelvis ureter
syndrome).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core:
Ludipress (Lactose, Povidone, Crospovidone)
Magnesium Stearate
Coating:
Opadry® II 85F18422 White:
Polyethylene glycol,
Titanium Dioxide,
Talc,
Polyvinyl alcohol.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
24 months

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
OPA/Aluminium/PVC/Aluminium or PVC/PVDC/Aluminium blisters, paper
folding box
Pack size: 1, 3 or 6 film-coated tablets
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Ltd
One Onslow Street,
Guildford
Surrey
GU1 4YS
UK
Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 17780/0528

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/07/2011

10

DATE OF REVISION OF THE TEXT
11/04/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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