ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Bondenza 150 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg ibandronic acid (as ibandronic sodium monohydrate).
Excipients:
Contains 162.75 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
White to off white film-coated tablets, of oblong shape marked “BNVA” on one side, and “150” on
the other side.
4.
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.
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.
Bondenza 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 Bondenza 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).
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.
Bondenza 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).
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 Bondenza in children, and Bondenza 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
Bondenza.
Plain water is the only drink that should be taken with Bondenza. 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.
-
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
Hypocalcaemia
Existing hypocalcaemia must be corrected before starting Bondenza 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 Bondenza 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 Bondenza 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.
3
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.
Renal impairment
Due to limited clinical experience, Bondenza is not recommended for patients with a creatinine
clearance below 30 ml/min (see section 5.2).
Galactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.
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 Bondenza, which is consistent with findings
in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Bondenza
and continue fasting for 1 hour following intake of Bondenza (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 Bondenza. Therefore,
patients should not take other oral medicinal products for at least 6 hours before taking Bondenza and
for 1 hour following intake of Bondenza.
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 2.5 mg daily or 150 mg 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 Bondenza 150 mg once monthly was similar to that in patients
treated with ibandronic acid 2.5 mg daily.
4
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 Bondenza 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.
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.
Bondenza should not be used during pregnancy.
Breast-feeding
It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have
demonstrated the presence of low levels of ibandronic acid in the milk following intravenous
administration.
Bondenza should not be used during lactation.
No studies on the effects on the ability to drive and use machines have been performed.
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
Bondenza 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 Bondenza 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 Bondenza are listed below by
System Organ Class.
Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare
(≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
5
Table 1: Adverse drug reactions occurring in postmenopausal women receiving Bondenza 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
Common
Uncommon
Rare
Very rare
Immune system
disorders
Hypersensitivity
reaction
Nervous system
disorders
Headache
Dizziness
Eye disorders
Ocular
inflammation
*†
Gastrointestinal
disorders
*
Oesophagitis,
Gastritis, Gastro
oesophageal reflux
disease, Dyspepsia,
Diarrhoea,
Abdominal pain,
Nausea
Oesophagitis
including
oesophageal
ulcerations or
strictures and
dysphagia,
Vomiting,
Flatulence
Duodenitis
Skin and subcutaneous
tissues disorders
Rash
Angioedema,
Face oedema,
Urticaria
Musculoskeletal,
connective tissue and
bone disorders
Arthralgia, Myalgia,
Musculoskeletal pain,
Muscle cramp,
Musculoskeletal
stiffness
Back pain
Osteonecrosis of
jaw
*†
General disorders and
administration site
conditions
Influenza like illness
*
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 Bondenza 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).
6
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.
No specific information is available on the treatment of over dosage with Bondenza.
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 Bondenza, 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05-
BA06
Mechanism of action
Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of
bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity
without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic
acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the
reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.
Pharmacodynamic effects
The pharmacodynamic action of ibandronic acid is inhibition of bone resorption.
In vivo
, ibandronic
acid prevents 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.
7
Bondenza 150 mg once monthly
Bone mineral density (BMD)
Bondenza 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
Two year data in study
BM 16549
Mean relative changes
from baseline % [95% CI]
ibandronic acid
2.5 mg daily
(N=318)
Bondenza
150 mg once
monthly
(N=320)
ibandronic acid
2.5 mg daily
(N=294)
Bondenza
150 mg once
monthly
(N=291)
Lumbar spine L2-L4 BMD 3.9 [3.4, 4.3]
4.9 [4.4, 5.3]
5.0 [4.4, 5.5]
6.6 [6.0, 7.1]
Total hip BMD
2.0 [1.7, 2.3]
3.1 [2.8, 3.4]
2.5 [2.1, 2.9]
4.2 [3.8, 4.5]
Femoral neck BMD
1.7 [1.3, 2.1]
2.2 [1.9, 2.6]
1.9 [1.4, 2.4]
3.1 [2.7, 3.6]
Trochanter BMD
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, Bondenza 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 Bondenza 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 Bondenza 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 Bondenza 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 Bondenza 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 Bondenza 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 Bondenza 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.
8
At one year, 83.5 % (p= 0.006) of patients receiving Bondenza 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, Bondenza 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)
ibandronic acid 2.5 mg daily
(N=977)
Relative Risk Reduction
New morphometric vertebral
fractures
62 % (40.9, 75.1)
Incidence of new morphometric
vertebral fractures
9.56 % (7.5, 11.7)
4.68 % (3.2,6.2)
Relative risk reduction of clinical
vertebral fracture
49 %
(14.03, 69.49)
Incidence of clinical vertebral
fracture
5.33 %
(3.73, 6.92)
2.75 %
(1.61, 3.89)
BMD – mean change relative to
baseline lumbar spine at year 3
1.26 % (0.8, 1.7)
6.54 % (6.1, 7.0)
BMD – mean change relative to
baseline total hip at year 3
-0.69 %
(-1.0, -0.4)
3.36 %
(3.0, 3.7)
The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation of
patients who at baseline had a lumbar spine BMD T-score below –2.5. The vertebral fracture risk
reduction was very consistent with that seen in the overall population.
9
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)
ibandronic acid 2.5 mg daily
(N=575)
Relative Risk Reduction
New morphometric vertebral
fractures
59 % (34.5, 74.3)
Incidence of new morphometric
vertebral fractures
12.54 % (9.53, 15.55)
5.36 % (3.31, 7.41)
Relative risk reduction of clinical
vertebral fracture
50 % (9.49, 71.91)
Incidence of clinical vertebral
fracture
6.97 % (4.67, 9.27)
3.57 % (1.89, 5.24)
BMD – mean change relative to
baseline lumbar spine at year 3
1.13 % (0.6, 1.7)
7.01 % (6.5, 7.6)
BMD – mean change relative to
baseline total hip at year 3
-0.70 % (-1.1, -0.2)
3.59 % (3.1, 4.1)
In the overall patient population of the study MF4411, no reduction was observed for non-vertebral
fractures, however daily ibandronate 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
Bondenza 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 dose-proportional manner up to 50 mg oral intake, with
greater than dose-proportional 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
10
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 half-life is generally in the
range of 10-72 hours. As the values calculated are largely a function of the duration of study, the dose
used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in common
with other bisphosphonates. Early plasma levels fall quickly reaching 10 % of peak values within 3
and 8 hours after intravenous or oral administration respectively.
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal
clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50-60 % of total
clearance and is related to creatinine clearance. The difference between the apparent total and renal
clearances is considered to reflect the uptake by bone.
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, Bondenza 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 end-stage 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
11
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 Bondenza 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 F
1
offspring in rats at an
extrapolated exposure of at least 35 times above human exposure. 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.
6.1 List of excipients
Tablet core
Lactose monohydrate
Povidone
Cellulose, microcrystalline
Crospovidone
Stearic acid
Silica, colloidal anhydrous
Tablet coat
Hypromellose
Titanium dioxide (E 171)
Talc
Macrogol 6,000
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
12
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Bondenza 150 mg film-coated tablets are supplied in blisters (PVC/PVDC, sealed with aluminium
foil) containing 1 or 3 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.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/03/266/003
EU/1/03/266/004
9.
23.02.2004/20.02.2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
13
1.
Bondenza 3 mg solution for injection
2.
One pre-filled syringe of 3 ml solution contains 3 mg ibandronic acid (as 3.375 mg ibandronic acid,
monosodium salt, monohydrate).
The concentration of ibandronic acid in the solution for injection is 1mg per ml.
Excipients: Sodium (less than 1 mmol per dose).
For a full list of excipients, see section 6.1.
3.
Solution for injection.
Clear, colourless solution.
4.
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.
Posology
The recommended dose of ibandronic acid is 3 mg, administered as an intravenous injection over 15 -
30 seconds, every three months.
Patients must receive supplemental calcium and vitamin D (see section 4.4 and section 4.5)
If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injections
should be scheduled every 3 months from the date of the last injection.
Special populations
Patients with renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment where serum
creatinine is equal or below 200 μmol/l (2.3 mg/dl) or where creatinine clearance (measured or
estimated) is equal or greater than 30 ml/min.
Bondenza injection is not recommended for use in patients who have a serum creatinine above
200 μmol/l (2.3 mg/dl) or who have a creatinine clearance (measured or estimated) below 30 ml/min,
because of limited clinical data available from studies including such patients (see section 4.4 and
section 5.2)
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly population
No dose adjustment is required (see section 5.2).
14
Paediatric population
There is no relevant use of Bondenza in children, and Bondenza was not studied in the paediatric
population .
Method of administration
For intravenous use.
Strict adherence to the intravenous administration route is required (see section 4.4).
-
Hypersensitivity to ibandronic acid or to any of the excipients.
-
Hypocalcaemia
Administration failures
Care must be taken not to administer Bondenza injection via intra-arterial or paravenous
administration as this could lead to tissue damage.
Hypocalcaemia
Bondenza, like other bisphosphonates administered intravenously, may cause a transient decrease in
serum calcium values.
Existing hypocalcaemia must be corrected before starting Bondenza injection therapy. Other
disturbances of bone and mineral metabolism should also be effectively treated before starting
Bondenza injection therapy.
All patients must receive adequate supplemental calcium and vitamin D.
Renal impairment
Patients with concomitant diseases, or who use medicinal products which have potential for
undesirable effects on the kidney, should be reviewed regularly in line with good medical practice
during treatment.
Due to limited clinical experience, Bondenza injection is not recommended for patients with a serum
creatinine above 200 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min (see section
4.2 and section 5.2).
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.
15
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 ibandronic acid 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.
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.
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.
Bondenza should not be used during pregnancy.
Breast-feeding
It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have
demonstrated the presence of low levels of ibandronic acid in the milk following intravenous
administration. Bondenza should not be used during lactation.
No studies on the effects on the ability to drive and use machines have been performed.
The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated
in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal
three-year fracture study (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all
these studies was similar to that of placebo.
In the pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overall
safety of intravenous injection of Bondenza 3 mg every 3 months and oral ibandronic acid 2.5 mg
daily were shown to be similar. The overall proportion of patients who experienced an adverse
reaction was 26.0 % and 28.6 % for Bondenza 3 mg injection every 3 months after one year and two
years, respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases
of adverse reactions did not lead to cessation of therapy.
The most commonly reported adverse reaction was influenza like illness.
Adverse reactions considered by investigators to be causally related to Bondenza are listed below by
System Organ Class.
Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare
(≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
16
Table 1: Adverse drug reactions occurring in postmenopausal women receiving Bondenza 3 mg
injection every 3 months or ibandronic acid 2.5 mg daily in the phase III studies BM16550 and MF
4411, and in postmarketing experience.
System Organ
Class
Common
Uncommon
Rare
Very rare
Immune system
disorders
Hypersensitivity
reaction
Nervous system
disorders
Headache
Eye disorders
Ocular
inflammation*
†
Vascular
disorders
Phlebitis/
thrombophlebitis
Gastrointestinal
disorders
Gastritis, Dyspepsia,
Diarrhoea, Abdominal
pain, Nausea,
Constipation
Skin and
subcutaneous
tissues disorders
Rash
Angioedema,
Facial
swelling/oedema,
Urticaria
Musculoskeletal,
connective tissue
and bone
disorders
Arthralgia, Myalgia,
Musculoskeletal pain,
Back pain
Bone pain
Osteonecrosis
of jaw*
†
General disorders
and
administration
site conditions
Influenza like illness*,
Fatigue
Injection site
reactions, Asthenia
*See further information below
†Identified in postmarketing experience.
Influenza-like illness
Transient, influenza-like symptoms have been reported in patients receiving intravenous injection of
Bondenza 3 mg every 3 months, typically in association with the first dose.
Influenza-like illness includes events reported as acute phase reaction or symptoms, including
myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain. Such symptoms were
generally of short duration, mild or moderate in intensity, and resolved during continuing treatment
without requiring remedial measures.
Osteonecrosis of the 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.
No specific information is available on the treatment of overdosage with Bondenza.
17
Based on knowledge of this class of compounds, intravenous overdosage may result in hypocalcaemia,
hypophosphataemia, and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium,
phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate,
potassium or sodium phosphate, and magnesium sulfate, respectively.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code:
M05BA06
Mechanism of action
Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of
bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity
without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic
acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the
reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.
Pharmacodynamic effects
The pharmacodynamic action of ibandronic acid is inhibition of bone resorption.
In vivo
, ibandronic
acid prevents bone destruction experimentally induced by cessation of gonadal function, retinoids,
tumours or tumour extracts. In young (fast growing) rats, the endogenous bone resorption is also
inhibited, leading to increased normal bone mass compared with untreated animals.
Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. In
growing rats, there was no evidence of impaired mineralisation even at doses greater than 5,000 times
the dose required for osteoporosis treatment.
Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs
and monkeys was associated with formation of new bone of normal quality and maintained or
increased mechanical strength even at doses in the toxic range. In humans, the efficacy of both daily
and intermittent administration with a dose-free interval of 9 - 10 weeks of ibandronic acid was
confirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.
In animal models ibandronic acid produced biochemical changes indicative of dose-dependent
inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen
degradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).
Both daily, intermittent (with a dose-free interval of 9 - 10 weeks per quarter) oral doses as well as
intravenous doses of ibandronic acid in postmenopausal women produced biochemical changes
indicative of dose-dependent inhibition of bone resorption.
Bondenza intravenous injection decreased levels of serum C-telopeptide of the alpha chain of Type I
collagen (CTX) within 3 - 7 days of starting treatment and decreased levels of osteocalcin within
3 months
.
Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates of
elevated bone resorption associated with postmenopausal osteoporosis.
The histological analysis of bone biopsies after two and three years of treatment of postmenopausal
women with doses of oral ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to
1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect. An
expected decrease in bone turnover, normal quality of bone and absence of defects in mineralization
were also seen after two years of treatment with Bondenza 3 mg injection.
18
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.
Bondenza 3 mg injection every 3 months
Bone mineral density (BMD)
Bondenza 3 mg intravenous injection, administered every 3 months, was shown to be at least as
effective as oral ibandronic acid 2.5 mg daily in a 2-year, randomised, double-blind, multicentre, non-
inferiority study (BM16550) of postmenopausal women (1386 women aged 55 - 80) with osteoporosis
(lumbar spine BMD T-score below -2.5 SD at baseline). This was demonstrated in both the primary
analysis at one year and in the confirmatory analysis at two years endpoint (Table 2).
The primary analysis of data from study BM16550 at one year and the confirmatory analysis at 2 years
demonstrated the non-inferiority of 3 mg every 3 months injection dosing regimen compared to 2.5 mg
oral daily dosing regimen, in terms of mean increases in BMD at lumbar spine, total hip, femoral neck
and trochanter (Table 2).
Table 2: Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter
BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study
BM 16550.
One year data in study BM 16550
Two year data in study
BM 16550
Mean relative changes
from baseline % [95% CI]
ibandronic acid
2.5 mg daily
Bondenza
3 mg injection
every 3 months
(N=365)
ibandronic
acid 2.5 mg
daily
Bondenza
3 mg injection
every 3
months
(N=334)
(N=377)
(N=334)
Lumbar spine L2-L4 BMD
3.8 [3.4, 4.2]
4.8 [4.5, 5.2]
4.8 [4.3, 5.4]
6.3 [5.7, 6.8]
Total hip BMD
1.8 [1.5, 2.1]
2.4 [2.0, 2.7]
2.2 [1.8, 2.6]
3.1 [2.6, 3.6]
Femoral neck BMD
1.6 [1.2, 2.0]
2.3 [1.9, 2.7]
2.2 [1.8, 2.7]
2.8 [2.3, 3.3]
Trochanter BMD
3.0 [2.6, 3.4]
3.8 [3.2, 4.4]
3.5 [3.0, 4.0]
4.9 [4.1, 5.7]
Furthermore, Bondenza 3 mg injection every 3 months was proven superior to oral ibandronic acid
2.5 mg daily for increases in lumbar spine BMD in a prospectively planned analysis at one year,
p<0.001, and at two years, p<0.001.
For lumbar spine BMD, 92.1 % of patients receiving 3 mg injection every 3 months increased or
maintained their BMD after 1 year of treatment (i.e. were responders) compared with 84.9 % of
patients receiving oral 2.5 mg daily (p=0.002). After 2 years of treatment, 92.8 % of patients receiving
3 mg injections and 84.7 % of patient receiving 2.5 mg oral therapy had increased or maintained
lumbar spine BMD (p=0.001).
For total hip BMD, 82.3 % of patients receiving 3 mg injection every 3 months were responders at one
year, compared with 75.1 % of patients receiving 2.5 mg daily orally (p=0.02). After 2 years of
treatment, 85.6 % of patients receiving 3 mg injections and 77.0 % of patient receiving 2.5 mg oral
therapy had increased or maintained total hip BMD (p=0.004).
The proportion of patients who increased or maintained their BMD at one year at both lumbar spine
and total hip was 76.2 % in the 3 mg injection every 3 months arm and 67.2 % in the 2.5 mg daily
19
orally arm (p=0.007). At two years, 80.1 % and 68.8 % of patients met this criterion in the 3 mg every
3 months injection arm and the 2.5 mg daily arm (p=0.001).
Biochemical markers of bone turn-over
Clinically meaningful reductions in serum CTX levels were observed at all time points measured. At
12 months median relative changes from baseline were –58.6 % for the intravenous injection of 3 mg
every 3 months regimen and –62.6 % for oral 2.5 mg daily regimen. In addition, 64.8 % of patients
receiving 3 mg every 3 months injection were identified as responders (defined as a decrease ≥50 %
from baseline), compared with 64.9 % of patients receiving 2.5 mg daily orally. Serum CTX
reduction was maintained over the 2 years, with more than half of the patients identified as responders
in both treatment groups.
Based on the results of study BM 16550, Bondenza 3 mg intravenous injection, administered every 3
months is expected to be at least as effective in preventing fractures as the oral regimen of ibandronic
acid 2.5 mg daily.
Ibandronic acid 2.5 mg daily tablets
In the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), a
statistically significant and medically relevant decrease in the incidence of new radiographic
morphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronic
acid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an exploratory regimen.
Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fasting
period). The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal,
who had a BMD at the lumbar spine of -2 to -5 SD below the premenopausal mean (T-score) in at
least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received
500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. Ibandronic acid
2.5 mg administered daily, showed a statistically significant and medically relevant reduction in the
incidence of new vertebral fractures. This regimen reduced the occurrence of new radiographic
vertebral fractures by 62 % (p=0.0001) over the three year duration of the study. A relative risk
reduction of 61 % was observed after 2 years (p=0.0006). No statistically significant difference was
attained after 1 year of treatment (p=0.056). The anti-fracture effect was consistent over the duration
of the study. There was no indication of a waning of the effect over time
.
The incidence of clinical vertebral fractures was also significantly reduced by 49 % after 3 years
(p=0.011). The strong effect on vertebral fractures was furthermore reflected by a statistically
significant reduction of height loss compared to placebo (p<0.0001).
Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)
Placebo
(N=974)
ibandronic acid 2.5 mg daily
(N=977)
Relative risk reduction
New morphometric vertebral
fractures
62% (40.9, 75.1)
Incidence of new morphometric
vertebral fractures
9.56% (7.5, 11.7)
4.68% (3.2, 6.2)
Relative risk reduction of clinical
vertebral fracture
49%
(14.03, 69.49)
Incidence of clinical vertebral
fracture
5.33% (3.73, 6.92)
2.75%
(1.61, 3.89)
BMD – mean change relative to
baseline lumbar spine at year 3
1.26% (0.8, 1.7)
6.54% (6.1, 7.0)
BMD – mean change relative to
baseline total hip at year 3
-0.69%
(-1.0, -0.4)
3.36%
(3.0, 3.7)
20
The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation of
patients who, at baseline, had a lumbar spine BMD T-score below –2.5 (table 4). The vertebral
fracture risk reduction was very consistent with that seen in the overall population.
Table 4: Results from 3 years fracture study MF 4411 (%, 95 % CI) for patients with lumbar spine
BMD T-score below –2.5 at baseline
Placebo
(N=587)
ibandronic acid 2.5 mg daily
(N=575)
Relative Risk Reduction
New morphometric vertebral
fractures
59% (34.5, 74.3)
Incidence of new morphometric
vertebral fractures
12.54% (9.53, 15.55)
5.36% (3.31, 7.41)
Relative risk reduction of clinical
vertebral fracture
50% (9.49, 71.91)
Incidence of clinical vertebral
fracture
6.97% (4.67, 9.27)
3.57% (1.89, 5.24)
BMD – mean change relative to
baseline lumbar spine at year 3
1.13% (0.6, 1.7)
7.01% (6.5, 7.6)
BMD – mean change relative to
baseline total hip at year 3
-0.70% (-1.1, -0.2)
3.59% (3.1, 4.1)
In the overall patient population of the study MF4411, no reduction was observed for non-vertebral
fractures, however daily ibandronate appeared to be effective in a high-risk subpopulation (femoral
neck BMD T-score < -3.0), where a non-vertebral fracture risk reduction of 69% was observed.
Daily oral treatment with ibandronic acid 2.5 mg tablets resulted in progressive increases in BMD at
vertebral and nonvertebral sites of the skeleton.
Three-year lumbar spine BMD increase compared to placebo was 5.3 % and 6.5 % compared to
baseline. Increases at the hip compared to baseline were 2.8 % at the femoral neck, 3.4 % at the total
hip, and 5.5 % at the trochanter.
Biochemical markers of bone turnover (such as urinary CTX and serum Osteocalcin) showed the
expected pattern of suppression to premenopausal levels and reached maximum suppression within a
period of 3 - 6 months of using 2.5 mg ibandronic acid daily.
A clinically meaningful reduction of 50 % of biochemical markers of bone resorption was observed as
early as one month after starting treatment with ibandronic acid 2.5 mg.
Paediatric population
Bondenza was not studied in the paediatric population, therefore no efficacy or safety data are
available for this patient population.
5.2 Pharmacokinetic properties
The primary pharmacological effects of ibandronic acid on bone are not directly related to actual
plasma concentrations, as demonstrated by various studies in animals and humans.
Plasma concentrations of ibandronic acid increase in a dose-proportional manner after intravenous
administration of 0.5 mg to 6 mg.
Absorption
Not applicable
21
Distribution
After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In
humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching
the bone is estimated to be 40 – 50 % of the circulating dose. Protein binding in human plasma is
approximately 85 % - 87 % (determined
in vitro
at therapeutic ibandronic acid concentrations), and
thus there is a low potential for interaction with other medicinal products due to displacement.
Biotransformation
There is no evidence that ibandronic acid is metabolised in animals or humans.
Elimination
Ibandronic acid is removed from the circulation via bone absorption (estimated to be 40 – 50 % in
postmenopausal women) and the remainder is eliminated unchanged by the kidney.
The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in the
range of 10 - 72 hours. As the values calculated are largely a function of the duration of study, the
dose used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in
common with other bisphosphonates. Early plasma levels fall quickly, reaching 10 % of the peak
values within 3 and 8 hours after intravenous or oral administration, respectively.
Total clearance of ibandronic acid is low with average values in the range 84 - 160 ml/min. Renal
clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50 – 60 % of total
clearance, and is related to creatinine clearance. The difference between the apparent total and renal
clearances is considered to reflect the uptake by bone.
Pharmacokinetics in special clinical situations
Gender
Pharmacokinetics of ibandronic acid are similar in men and women.
Race
There is no evidence for any clinically relevant inter-ethnic differences between Asians and
Caucasians in ibandronic acid disposition. There is limited data available on patients of African origin.
Patients with renal impairment
Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly
related to creatinine clearance (CLcr).
No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or
above 30 ml/min).
Subjects with severe renal impairment (CLcr less than 30 ml/min) receiving daily oral administration
of 10 mg ibandronic acid for 21 days, had 2 - 3 fold higher plasma concentrations than subjects with
normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous
administration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearances decreased by 67 %,
77 % and 50 %, respectively, in subjects with severe renal failure, but there was no reduction in
tolerability associated with the increase in exposure. Due to the limited clinical experience, Bondenza
is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4). The
pharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in a
small number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronic
acid in the patients not undergoing haemodialysis is unknown. Due to the limited data available,
ibandronic acid should not be used in all patients with end-stage renal disease.
Patients with hepatic impairment
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
22
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, renal function is the only
factor to take into consideration (see renal impairment section).
Paediatric population
There are no data on the use of Bondenza in these age groups.
5.3 Preclinical safety data
Toxic effects, e.g. signs of renal damage, were observed in dogs only at exposures considered
sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Mutagenicity/Carcinogenicity:
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of
genetic activity for ibandronic acid.
Reproductive toxicity:
Specific studies for the 3-monthly dosing regimen have not been performed. In studies with daily i.v.
dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid
in rats and rabbits. Body weight gain was decreased in F
1
offspring in rats. Other adverse reactions to
ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as
a class. They include a decreased number of implantation sites, interference with natural delivery
(dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).
6.
6.1 List of excipients
Sodium chloride
Glacial acetic acid
Sodium acetate trihydrate
Water for injections
6.2 Incompatibilities
Bondenza solution for injection must not be mixed with calcium-containing solutions or other
intravenously administered medicinal products.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Pre-filled syringes (5 ml) made of colourless type I glass, the grey rubber plunger stopper and tip cap
are made of fluororesin-laminated butyl rubber, containing 3 ml of solution for injection.
Packs of 1 pre-filled syringe and 1 injection needle or 4 pre-filled syringes and 4 injection needles.
23
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Where the product is administered into an existing intravenous infusion line, the infusate should be
restricted to either isotonic saline or 50 mg/ml (5 %) glucose solution. This also applies to solutions
used to flush butterfly and other devices.
Any unused solution for injection, syringe and injection needle should be disposed of in accordance
with local requirements. The release of pharmaceuticals in the environment should be minimized.
The following points should be strictly adhered to regarding the use and disposal of syringes and other
medicinal sharps:
• Needles and syringes should never be reused.
• Place all used needles and syringes into a sharps container (puncture-proof disposable
container).
• Keep this container out of the reach of children.
• Placing used sharps containers in the household waste should be avoided.
• Dispose of the full container according to local requirements or as instructed by your
healthcare provider.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/03/266/005
EU/1/03/266/006
9.
23.02.2004/20.02.2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
24
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
25
A
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Film-coated tablet:
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
Solution for injection in pre-filled syringe:
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in the Risk Management Plan (RMP) version 2.0 presented in
Module 1.8.2 of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
26
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Bondenza 150 mg film-coated tablets
Ibandronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg ibandronic acid (as ibandronic sodium monohydrate).
3.
LIST OF EXCIPIENTS
The tablets also contains lactose. See the package leaflet for further information.
4.
Film-coated tablets
1 film-coated tablet
3 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Once monthly tablet
Oral use
Month 1 __/__/__ 3 film-coated tablets
Month 2 __/__/__ 3 film-coated tablets
Month 3 __/__/__ 3 film-coated tablets
Note down the date you take your tablet
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
30
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/03/266/003 1 film-coated tablet
EU/1/03/266/004 3 film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Bondenza 150 mg
31
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister foil
1.
Bondenza 150 mg film-coated tablets
Ibandronic acid
2.
Roche Registration Ltd.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Bondenza 3 mg solution for injection
Ibandronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One pre-filled syringe of 3 ml solution contains 3 mg of ibandronic acid (as 3.375 mg of ibandronic
acid, monosodium salt, monohydrate).
3.
LIST OF EXCIPIENTS
Also contains sodium chloride, glacial acetic acid, sodium acetate trihydrate, water for injections. See
the package leaflet for further information.
4.
Solution for injection
1 pre-filled syringe + 1 injection needle
4 pre-filled syringes + 4 injection needles
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
For intravenous use only
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
33
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/03/266/005 1 pre-filled syringe
EU/1/03/266/006 4 pre-filled syringes
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
[Justification for not including Braille accepted]
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
PRE-FILLED SYRINGE
1.
Bondenza 3 mg solution for injection
Ibandronic acid
For IV use only
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3 mg/3 ml
6.
OTHER
35
B. PACKAGE LEAFLET
36
PACKAGE LEAFLET: INFORMATION FOR THE USER
Bondenza
150 mg film-coated tablets
Ibandronic acid
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
Page
Planning when to take Bondenza
with peel-off stickers for your personal calendar
1.
What Bondenza is and what it is used for
2.
Before you take Bondenza
4.
Possible side effects
5.
How to store Bondenza
6.
Further information
1.
WHAT BONDENZA IS AND WHAT IT IS USED FOR
Bondenza belongs to a group of medicines called
bisphosphonates
. It contains ibandronic acid. It
does not contain hormones.
Bondenza may reverse bone loss by stopping more loss of bone and increasing bone mass in most
women who take it, even though they won’t be able to see or feel a difference. Bondenza may help
lower the chances of breaking bones (fractures). This reduction in fractures was shown for the spine
but not for the hip.
Bondenza is prescribed to you to treat postmenopausal osteoporosis because you have an
increased risk of fractures
. Osteoporosis is a thinning and weakening of the bones, which is common
in women after the menopause. At the menopause, a woman’s ovaries stop producing the female
hormone, oestrogen, which helps to keep her skeleton healthy.
The earlier a woman reaches the menopause, the greater her risk of fractures in osteoporosis. Other
things that can increase the risk of fractures include:
-
not enough calcium and vitamin D in the diet
-
not enough walking or other weight-bearing exercise
-
a family history of osteoporosis
Many people with osteoporosis have no symptoms. If you have no symptoms you may not know if
you have the condition. However, osteoporosis makes you more likely to break bones if you fall or
hurt yourself. A broken bone after the age of 50 may be a sign of osteoporosis. Osteoporosis can also
cause back pain, height loss and a curved back.
Bondenza prevents loss of bone from osteoporosis, and helps to rebuild bone. Therefore Bondenza
makes bone less likely to break.
37
3.
How to take Bondenza
-
smoking, or drinking too much alcohol
A healthy lifestyle
will also help you to get the most benefit from your treatment. This includes eating
a balanced diet rich in calcium and vitamin D; walking or any other weight-bearing exercise; not
smoking; and not drinking too much alcohol.
2.
BEFORE YOU TAKE BONDENZA
Do not take Bondenza
-
If you are allergic (hypersensitive) to ibandronic acid, or to any of the other ingredients of
Bondenza.
-
If you have certain problems with your oesophagus (the tube connecting your mouth with your
stomach) such as narrowing or difficulty swallowing.
-
If you can’t stand or sit upright for at least one hour (60 minutes) at a time.
-
If you have, or had in the past low blood calcium
. Please consult your doctor.
Children and teenagers
Do not give Bondenza to children or teenagers.
Take special care with Bondenza
Some people need to be especially careful while they’re taking Bondenza. Check with your doctor:
-
If you have any disturbances of mineral metabolism (such as vitamin D deficiency).
-
If your kidneys are not functioning normally.
-
If you have any swallowing or digestive problems.
- If you are under dental treatment or will undergo dental surgery, tell your dentist that you are
being treated with Bondenza.
Irritation, inflammation or ulceration of the oesophagus (the tube connecting your mouth with your
stomach) often with symptoms of severe pain in the chest, severe pain after swallowing food and/or
drink, severe nausea, or vomiting may occur, especially if you do not drink a full glass of plain water
and/or if you lie down within an hour of taking Bondenza. If you develop these symptoms, stop taking
Bondenza and tell your doctor straight away.
Taking other medicines
Please tell your doctor or pharmacist if you are taking, or have recently taken any other medicines,
including medicines obtained without prescription. Especially:
-
Supplements containing calcium, magnesium, iron or aluminium,
as they could possibly
influence the effects of Bondenza.
-
Aspirin and other non-steroidal anti-inflammatory medicines (NSAIDs)
( including
ibuprofen, diclofenac sodium and naproxen) may irritate the stomach and intestine.
Bisphosphonates (like Bondenza) may also do so. So be especially careful if you take
painkillers or anti-inflammatories
while you’re taking Bondenza.
After swallowing your monthly Bondenza tablet,
wait for 1 hour before taking any other
medication
, including indigestion tablets, calcium supplements, or vitamins.
Taking Bondenza with food and drink:
Do not take Bondenza with food.
Bondenza is less effective if it’s taken with food.
You can drink plain water but no other drinks
(see 3. HOW TO TAKE BONDENZA).
Pregnancy and breast feeding
Do not take Bondenza if you’re pregnant or breast feeding. If you’re breast feeding, you may need to
stop in order to take Bondenza.
Ask your doctor or pharmacist for advice before taking any medicines.
38
Driving and using machines
You can drive and use machines as it’s very unlikely that Bondenza will affect your ability to drive
and use machines.
Important information about some of the ingredients of Bondenza
Bondenza contains an ingredient called lactose. If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE BONDENZA
Always take Bondenza exactly as your doctor has told you. If you’re not sure about anything, ask your
doctor or pharmacist.
The usual dose of Bondenza is one tablet once a month
.
Taking your monthly tablet
It’s important to follow these instructions carefully. They are designed to help your Bondenza tablet
reach your stomach quickly, so it’s less likely to cause irritation.
-
Take one Bondenza 150 mg tablet once a month.
-
Choose one day of the month
that will be easy to remember. You can choose either the same
date (such as the 1
st
of each month) or the same day (such as the first Sunday of each month) to
take your Bondenza tablet. Choose the date that best fits your routine.
-
Take your Bondenza tablet
at least 6 hours after you last had anything
to eat or drink except
plain water.
-
Take your Bondenza tablet
-
after you first get up for the day
, and
-
before you have anything to eat or drink
(on an empty stomach)
-
Swallow your tablet with a full glass of plain water
(at least 180 ml).
Do not
take your tablet with mineral water, fruit juice or any other drinks.
-
Swallow your tablet whole
— do not chew it, crush it or let it dissolve in your mouth.
-
For the next hour (60 minutes)
after you’ve taken your tablet
-
do not lie down
; if you do not stay upright (standing or sitting), some of the medicine
could leak back into your oesophagus
-
do not eat anything
-
do not drink anything
(except plain water if you need it)
-
do not take any other medicines
-
After you’ve waited for an hour, you can have your first food and drink of the day. Once you’ve
eaten, it’s OK to lie down if you wish, and to take any other medication you need.
39
Do not
take your tablet at bedtime or before you get up for the day.
Continuing to take Bondenza
It’s important to keep taking Bondenza every month, as long as your doctor prescribes it for you.
Bondenza can treat osteoporosis only as long as you keep taking it.
If you take too much Bondenza
If you’ve taken more than one tablet by mistake,
drink a full glass of milk and talk to your doctor
straight away.
Do not make yourself vomit, and do not lie down
— this could cause Bondenza to irritate your
oesophagus.
If you forget a dose
If you forget to take your tablet on the morning of your chosen day,
do not take a tablet later in the
day
. Instead, consult your calendar and find out when your next scheduled dose is:
If your next scheduled dose is only 1 to 7 days away…
You should wait until the next scheduled dose is due and take it as normal; then, continue taking one
tablet once a month on the scheduled days you’ve marked on your calendar.
If your next scheduled dose is more than 7 days away…
You should take one tablet the next morning after the day you remember;
then, continue taking one
tablet once a month on the scheduled days you’ve marked on your calendar.
Never take two Bondenza tablets within the same week.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Bondenza can cause side effects, although not everybody gets them.
Talk to a nurse or a doctor straight away if you notice any of the following serious side effects -
you may need urgent medical treatment:
• rash, itching, swelling of your face, lips, tongue and throat, with difficulty breathing. You may
be having an allergic reaction to the medicine.
•
severe pain in the chest, severe pain after swallowing food or drink, severe nausea, or vomiting.
•
flu-like symptoms (if any effects become troublesome or last more than a couple of days).
•
pain or sore in your mouth or jaw
•
eye pain and inflammation (if prolonged)
Other possible side effects
Common
(affects less than 1 in 10 people)
•
headache
•
heartburn, stomach pain (such as “gastroenteritis” or “gastritis”), indigestion, nausea, having
diarrhoea or constipation
•
rash
•
pain or stiffness in your muscles, joints, or back
•
flu-like symptoms (including fever, shaking and shivering, feeling of discomfort, fatigue, bone
pain and aching muscles and joints)
•
fatigue
40
Uncommon
(affects less than 1 in 100 people)
•
bone pain
•
feeling weak
•
dizziness
•
flatulence
Rare
(affects less than 1 in 1000 people):
•
hypersensitivity reaction; swelling of the face, lips and mouth (see allergy)
•
itching
•
eye pain or inflammation
Very rare
(affects less than 1 in 10000 people)
•
a condition involving exposed bone in the mouth called “osteonecrosis of the jaw”.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE BONDENZA
Keep out of the reach and sight of children.
There are no special storage instructions.
Do not use after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the
last day of that month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Bondenza contains
-
The active substance is ibandronic acid. One tablet contains 150 mg of ibandronic acid (as
ibandronic sodium monohydrate).
-
The other ingredients are:
tablet core
: lactose monohydrate, povidone, cellulose microcrystalline, crospovidone, stearic acid
purified, silica colloidal anhydrous
tablet coat
: hypromellose, titanium dioxide (E 171), talc, macrogol 6000
What Bondenza looks like and contents of the pack
Bondenza tablets are white to off white, of oblong shape and marked “BNVA” on one side, and “150”
on the other side. The tablets are supplied in blisters containing 1 or 3 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder:
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
41
United Kingdom
Manufacturer:
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 112 401
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Faes Farma, S.A.
Tel: +34 – 94 481 83 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Tel: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
42
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
G.A Stamatis & Co.(Cyprus) Ltd
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 -6 7 039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in {date}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
43
REMINDER STICKERS TEXT
PLANNING WHEN TO TAKE BONDENZA
The dose of Bondenza is one tablet once a month. Choose one day of the month that will be easy to
remember:
-
either the same date (such as the 1
st
of each month)
-
or the same day (such as the first Sunday of each month).
Use the peel-off stickers below to mark the dates on your calendar.
Once you’ve taken your tablet, put a tick in the box on the sticker.
PEEL-OFF STICKERS
FOR YOUR PERSONAL CALENDAR
Monthly tablet
Monthly tablet
Monthly tablet
Bondenza Bondenza Bondenza
It’s important to keep taking Bondenza every month.
44
PACKAGE LEAFLET: INFORMATION FOR THE USER
Bondenza 3 mg solution for injection
ibandronic acid
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Bondenza is and what it is used for
3.
How to receive Bondenza
4.
Possible side effects
5.
How to store Bondenza
6.
Further information
1.
WHAT BONDENZA IS AND WHAT IT IS USED FOR
Bondenza belongs to a group of medicines called bisphosphonates. It contains ibandronic acid. It does
not contain hormones.
Bondenza may reverse bone loss by stopping more loss of bone and increasing bone mass in most
women who take it, even though they won’t be able to see or feel a difference. Bondenza may help
lower the chances of breaking bones (fractures). This reduction in fractures was shown for the spine
but not for the hip.
Bondenza 3 mg solution for injection in pre-filled syringes is a solution for intravenous injection by a
health care professional.
Do not inject Bondenza yourself.
Bondenza is prescribed to you to treat postmenopausal osteoporosis because you have an
increased risk of fractures
. Osteoporosis is a thinning and weakening of the bones, which is common
in women after the menopause. At the menopause, a woman’s ovaries stop producing the female
hormone, oestrogen, which helps to keep her skeleton healthy.
The earlier a woman reaches the menopause, the greater her risk of fractures in osteoporosis. Other
things that can increase the risk of fractures include:
-
not enough calcium and vitamin D in the diet
-
not enough walking or other weight-bearing exercise
-
a family history of osteoporosis
Many people with osteoporosis have no symptoms. If you have no symptoms you may not know if
you have the condition. However, osteoporosis makes you more likely to break bones if you fall or
hurt yourself. A broken bone after the age of 50 may be a sign of osteoporosis. Osteoporosis can also
cause back pain, height loss and a curved back.
Bondenza prevents loss of bone from osteoporosis, thus helping to rebuild lost bone. Therefore,
Bondenza makes bones less likely to break.
45
-
Keep this leaflet. You may need to read it again.
2.
Before you receive Bondenza
-
smoking cigarettes, or drinking too much alcohol
A healthy lifestyle
will also help you to get the most benefit from your treatment. This includes eating
a balanced diet rich in calcium and vitamin D, walking or other weight-bearing exercise, not smoking
and not drinking too much alcohol.
2.
BEFORE YOU RECEIVE BONDENZA
Do not receive Bondenza
-
if you have, or had in the past , low blood calcium
. Please consult your doctor
-
if you are allergic (hypersensitive) to ibandronic acid or any of the other ingredients in
Bondenza injection
Take special care with Bondenza
Some patients need to be especially careful when using Bondenza. Tell your doctor:
-
if you have or have ever had kidney problems, kidney failure or have needed dialysis, or if you
have any other disease that may affect your kidneys
-
if you have any disturbance of mineral metabolism (such as vitamin D deficiency)
-
You should take calcium and vitamin-D supplements while receiving Bondenza. If you are
-
If you are under dental treatment or will undergo dental surgery, tell your dentist that you are
being treated with Bondenza.
Taking other medicines
Tell your doctor, nurse or pharmacist if you are taking, or have recently taken, any other medicines.
Mention to your doctor, nurse or pharmacist anything you are taking which you bought over the
counter, without a prescription.
Pregnancy and breast-feeding
You should not be given Bondenza if you are pregnant, or if there is a possibility you may become
pregnant. If you are breast-feeding, you will need to stop breast-feeding in order to receive Bondenza.
Ask your doctor or pharmacist for advice before taking any medicines.
Driving and using machines
You can drive and use machines as it’s very unlikely that Bondenza will affect your ability to drive
and use machines.
Important information about some of the ingredients of Bondenza
This medicinal product contains less than 1 mmol sodium (23 mg) per dose (3 ml), i.e. essentially
“sodium-free”.
3.
HOW TO RECEIVE BONDENZA
The recommended dose of Bondenza for the intravenous injection is 3 mg (1 pre-filled syringe) once
every 3 months.
The injection should be given into the vein by a physician or qualified/trained health care worker. Do
not administer the injection to yourself.
The solution for injection must be administered into a vein only, and not anywhere else in the body.
Continuing to receive Bondenza
To get the most benefit from the treatment it is important to continue receiving the injections every 3
months for as long as your doctor prescribes it for you. Bondenza can treat osteoporosis only for as
long as you keep receiving the treatment, even though you will not be able to see or feel a difference.
46
unable to do so, you should inform your doctor.
You should also take calcium and vitamin-D supplements, as recommended by your doctor.
If too much Bondenza is given
You may develop low levels of calcium, phosphorus or magnesium in the blood. Your doctor may
take steps to correct such changes and may give you an injection containing these minerals.
If a dose of Bondenza is missed
You should arrange an appointment to get the next injection as soon as possible. After that, go back to
getting the injections every 3 months from the date of the most recent injection.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Bondenza can cause side effects, although not everybody gets them.
Talk to a nurse or a doctor straight away if you notice any of the following serious side effects -
you may need urgent medical treatment:
• rash, itching, swelling of your face, lips, tongue and throat, with difficulty breathing. You may
be having an allergic reaction to the medicine.
•
severe pain in the chest, severe pain after swallowing food or drink, severe nausea, or vomiting.
•
flu-like symptoms (if any effects become troublesome or last more than a couple of days).
•
pain or sore in your mouth or jaw
•
eye pain and inflammation (if prolonged)
Other possible side effects
Common
(affects less than 1 in 10 people)
•
headache
•
heartburn, stomach pain (such as “gastroenteritis” or “gastritis”), indigestion, nausea, having
diarrhoea or constipation
•
rash
•
pain or stiffness in your muscles, joints, or back
•
flu-like symptoms (including fever, shaking and shivering, feeling of discomfort, fatigue, bone
pain and aching muscles and joints)
•
fatigue
Uncommon
(affects less than 1 in 100 people)
•
bone pain
•
feeling weak
•
dizziness
•
flatulence
•
inflammation of a vein and pain or injury at the injection site
Rare
(affects less than 1 in 1000 people):
•
hypersensitivity reaction; swelling of the face, lips and mouth (see allergy)
•
itching
•
eye pain or inflammation
Very rare
(affects less than 1 in 10000 people)
•
a condition involving exposed bone in the mouth called “osteonecrosis of the jaw”.
47
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE BONDENZA
Keep out of the reach and sight of children.
This medicinal product does not require any special storage conditions.
Do not use Bondenza 3 mg solution for injection in pre-filled syringes after the expiry date which is
stated on the carton and on the syringe after “EXP”. The expiry date refers to the last day of that
month.
The person giving the injection should throw away any unused solution and put the used syringe and
injection needle into an appropriate disposal container.
6.
FURTHER INFORMATION
What Bondenza 3 mg solution for injection in pre-filled syringes contains
-
The active substance is ibandronic acid. One pre-filled syringe contains 3 mg of ibandronic acid
in 3 ml of solution (as 3.375 mg of ibandronic acid, monosodium salt, monohydrate).
-
The other ingredients are sodium chloride, acetic acid, sodium acetate trihydrate and water for
injections.
What Bondenza 3 mg solution for injection in pre-filled syringes looks like and contents of the
pack
Bondenza 3 mg solution for injection in pre-filled syringes is a clear colourless solution. Each pre-
filled syringe contains 3 ml of solution. Bondenza is available in packs of 1 pre-filled syringe and 1
injection needle or 4 pre-filled syringes and 4 injection needles.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
48
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 112 401
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Faes Farma, S.A.
Tel: +34 – 94 481 83 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Tel: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
G.A Stamatis & Co.(Cyprus) Ltd
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 -6 7 039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
49
This leaflet was last approved in {date}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
50
-----------------------------------------------------------------------------------------------------------------------------
This information is intended for medical or healthcare professionals only.
INFORMATION FOR THE HEALTHCARE PROFESSIONALS
Please see the Summary of Product Characteristics for more information.
Administration of Bondenza 3 mg solution for injection in pre-filled syringe:
Bondenza 3 mg solution for injection in pre-filled syringe should be injected intravenously over a
period of 15 - 30 seconds.
The solution is irritant, therefore strict adherence to the intravenous route of administration is
important. If you inadvertently inject into the tissues around the vein, patients may experience local
irritation, pain and inflammation at the injection site.
Bondenza 3 mg solution for injection in pre-filled syringe
must not
be mixed with calcium-containing
solutions (such as Ringer-Lactate solution, calcium heparin) or other intravenously administered
medicinal products. Where Bondenza is administered via an existing intravenous infusion line, the
intravenous infusate should be restricted to either isotonic saline or 50 mg/ml (5 %) glucose solution.
Missed dose:
If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injections
should be scheduled every 3 months from the date of the last injection.
No specific information is available on the treatment of overdosage with Bondenza.
Based on knowledge of this class of compounds, intravenous overdosage may result in hypocalcaemia,
hypophosphataemia, and hypomagnesaemia, which can cause paraesthesia. In severe cases
intravenous infusion of appropriate doses of calcium gluconate, potassium or sodium phosphate, and
magnesium sulfate, may be needed.
General advice:
Bondenza 3 mg solution for injection in pre-filled syringe like other bisphosphonates administered
intravenously, may cause a transient decrease in serum calcium values.
Hypocalcaemia and other disturbances of bone and mineral metabolism should be assessed and
effectively treated before starting Bondenza injection therapy. Adequate intake of calcium and
vitamin D is important in all patients. All patients must receive supplemental calcium and vitamin D.
Patients with concomitant diseases, or who use medicinal products which have a potential for
undesirable effects on the kidney, should be reviewed regularly in line with good medical practice
during treatment.
Any unused solution for injection, syringe and injection needle should be disposed of in accordance
with local requirements.
51
Source: European Medicines Agency
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