Bondronat, inn-ibandronic acid

2009 רבוטקואב רשואו קדבנ ונכותו תואירבה דרשמ י ע __________________________________________________________________________________ __________________________________________________________________________________
Ibandronic Acid

1.
NAME OF THE MEDICINAL PRODUCT

Bonat® 50 mg Film Coated Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronic sodium
monohydrate).
Bonat® is also available as 6 mg/6 ml concentrate solution for injection. Before prescribing,
please refer to Bonat® Vials 6 mg/6 ml MoH approved prescribing information.
Excipients:
For a full list of excipients, see section 6.1.
Bonat® tablets contain lactose and should not be administered to patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption.
3. PHARMACEUTICAL

Film-coated tablets.
White to off-white film-coated tablets,of oblong shape engraved “L2” on one side and “IT” on
the other side.
4. CLINICAL
PARTICULARS

4.1 Therapeutic
indications

Bonat® is indicated for the prevention of skeletal events (pathological fractures, bone
complications requiring radiotherapy or surgery) in patients with breast cancer and bone
metastases.
4.2 Posology and method of administration

Bonat® therapy should only be initiated by physicians experienced in the treatment of cancer.
For oral use.

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

Bonat® tablets should be taken after an overnight fast (at least 6 hours) and before the first
food or drink of the day. Medicinal products and supplements (including calcium) should
similarly be avoided prior to taking Bonat® tablets. Fasting should be continued for at least 30
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________ minutes after taking the tablet. Plain water may be taken at any time during the course of Bonat® treatment. - The tablets should be swallowed whole with a full glass of plain water (180 to 240 ml) while the patient is standing or sitting in an upright position. Patients should not lie down for 60 minutes after taking Bonat®. Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration. Plain water is the only drink that should be taken with Bonat®. Please note that some mineral waters may have a higher concentration of calcium and therefore should not be used.
Patients with hepatic impairment
No dosage adjustment is required (see section 5.2 ).
Patients with renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal impairment
where creatinine clearance is equal to or greater than 30 ml/min.
Below 30 ml/min creatinine clearance, the recommended dose is 50 mg once weekly. See
dosing instructions, above.
Elderly
No dose adjustment is necessary.
Children and adolescents
Bonat® is not recommended for patients below age 18 years due to insufficient data on safety
and efficacy.
4.3 Contraindications

Hypersensitivity to ibandronic acid or to any of the excipients.
Bonat® should not be used in children.
4.4 Special warnings and precautions for use
Caution is indicated in patients with known hypersensitivity to other bisphosphonates.
Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively
treated before starting Bonat® therapy. Adequate intake of calcium and vitamin D is important
in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake
is inadequate.
Oral bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal
or gastric ulcers. Therefore, patients should pay particular attention to the dosing instructions
(see section 4.2).
Physicians should be alert to signs or symptoms signalling a possible oesophageal reaction
during therapy, and patients should be instructed to discontinue Bonat® and seek medical
attention if they develop symptoms of oesophageal irritation such as new or worsening
dysphagia, pain on swallowing, retrosternal pain, or heartburn.
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
Since NSAIDS are associated with gastrointestinal irritation, caution should be taken during
concomitant oral medication with Bonat®.
Clinical studies have not shown any evidence of deterioration in renal function with long term
Bonat® therapy. Nevertheless, according to clinical assessment of the individual patient, it is
recommended that renal function, serum calcium, phosphate and magnesium should be
monitored in patients treated with Bonat®.
Bonat® tablets contain lactose and should not be administered to patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Drug-Food Interactions
Products containing calcium and other multivalent cations (such as aluminium, magnesium,
iron), including milk and food, are likely to interfere with absorption of Bonat® tablets.
Therefore, with such products, including food, intake must be delayed at least 30 minutes
following oral administration.
Bioavailability was reduced by approximately 75% when Bonat® tablets were administered 2
hours after a standard meal. Therefore, it is recommended that the tablets should be taken
after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes
after the dose has been taken (see section 4.2).
Drug-Drug Interactions
When co-administered with melphalan/prednisolone in patients with multiple myeloma, no
interaction was observed.
Other interaction studies in postmenopausal women have demonstrated the absence of any
interaction potential with tamoxifen or hormone replacement therapy (oestrogen).
In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an
increase in ibandronic acid bioavailability of about 20% (which is within the normal variability
of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity.
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________ However, no dosage adjustment is required when Bonat® is administered with H2-antagonists or other drugs that increase gastric pH.
In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic
acid is eliminated by renal secretion only and does not undergo any biotransformation. The
secretory pathway does not appear to include known acidic or basic transport systems
involved in the excretion of other active substances. In addition, ibandronic acid does not
inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic
cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations
and ibandronic acid is therefore unlikely to displace other active substances.
Caution is advised when bisphosphonates are administered with aminoglycosides, since
both agents can lower serum calcium levels for prolonged periods. Attention should also be
paid to the possible existence of simultaneous hypomagnesaemia.
In clinical studies, Bonat® has been administered concomitantly with commonly used
anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions
occurring.

4.6 Pregnancy
lactation

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in
rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown. Therefore, Bonat® should not be used during pregnancy.
It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats
have demonstrated the presence of low levels of ibandronic acid in the milk following
intravenous administration. Bonat® should not be used during lactation.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable
The safety profile of Bonat® is derived from controlled clinical trials in the approved indication and after the oral administration of Bonat® at the recommended dose. In the pooled database from the 2 pivotal phase III trials (286 patients treated with Bonat® 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Bonat® was 27%. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ≥10%), common ( ≥1% and <10%), uncommon ( ≥0.1% and <1%), rare ( ≥0.01% and <0.1%), very rare ( ≤0.01%). Table 1 lists common adverse reactions from the pooled phase III trials. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo-treated patients are excluded. Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
Table 1
Adverse ReactionsReported Commonly and Greater than Placebo

Adverse Reaction
Bonat® 50 mg
p. o. daily
p.o. daily
(n=277 patients)
(n=286 patients)
Metabolism and Nutrition
Disorders
Gastrointestinal Disorders
General Disorders

Adverse drug reactions occurring at a frequency <1%:
The following list provides information on adverse drug reactions reported in study MF 4414
and MF 4434 occurring more frequently with Bonat® 50 mg than with placebo:
Uncommon:
Blood and Lymphatic System Disorders anaemia
Nervous System Disorders
paraesthesia, dysgeusia (taste perversion) Gastrointestinal Disorders
haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth Skin and Subcutaneous Tissue Disorders pruritus
Renal and Urinary Disorders azotaemia
General Disorders:
chest pain, influenza-like illness, malaise, pain Investigations

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The
majority of the reports refer to cancer patients, but such cases have also been reported in
patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth
extraction and / or local infection (including osteomyelitis). Diagnosis of cancer,
chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk
factors (see section 4.4).
4.9 Overdose
No case of overdose has been reported.
No specific information is available on the treatment of overdosage with Bonat®. However,
oral overdosage may result in upper gastrointestinal events, such as upset stomach,
heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind Bonat®.
Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient
should remain fully upright.
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
5. PHARMACOLOGICAL
PROPERTIES

5.1 Pharmacodynamic
properties
Pharmaco-therapeutic group: Bisphosphonate, ATC Code: M05B A 06 Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear. In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton. At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation. Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease. Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events. Prevention of skeletal events in patients with breast cancer and bone metastases with Bonat® 50 mg tablets was assessed in two randomized placebo controlled phase III trials with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg Bonat® (287 patients). The results from these trials are summarised below. Primary Efficacy Endpoints The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components: - radiotherapy to bone for treatment of fractures/impending fractures surgery to bone for treatment of fractures The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore, counted only once in any given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrated a significant advantage for Bonat® 50 mg p.o. over placebo in the reduction in SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE for Bonat® treated patients when compared with placebo (relative risk 0.62, p=0.003). Efficacy results are summarised in Table 2. Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
Table 2
Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

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

* Mean change from baseline to last assessment.
** Median change from baseline to last assessment
5.2 Pharmacokinetic
properties
Absorption The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration. Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other than 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. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal. Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
Bioavailability was reduced by approximately 75% when Bonat® tablets were administered 2
hours after a standard meal. Therefore, it is recommended that the tablets should be taken
after an overnight fast (minimum 6 hours) and fasting should continue for at least 30 minutes
after the dose has been taken (see Section 4.2).
Distribution
After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine.
In humans, the apparent terminal volume of distribution is at least 90 l and the amount of
dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in
human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug
interaction due to displacement is unlikely.
Metabolism
There is no evidence that ibandronic acid is metabolized in animals or humans.
Elimination
The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption
(estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The
unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.
The range of observed apparent half-lives is broad and dependent on dose and assay
sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours.
However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours
after intravenous or oral administration respectively.
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min.
Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60%
of total clearance and is related to creatinine clearance. The difference between the apparent
total and renal clearances is considered to reflect the uptake by bone.
Pharmacokinetics in Special Populations

Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race
There is no evidence for clinically relevant interethnic differences between Asians and
Caucasians in ibandronic acid disposition. There are only very few data available on patients
with African origin.
Patients with renal impairment
Renal clearance of ibandronic acid in patients with various degrees of renal impairment is
linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for
patients with mild or moderate renal impairment (CLcr >30 ml/min). Subjects with severe
renal impairment (CLcr ≤ 30 ml/min) receiving oral administration of 10 mg ibandronic acid
daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal
function. Total clearance of ibandronic acid was reduced to 44 ml/min in the subjects with
severe renal impairment. 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 impairment. However, there was no reduction in tolerability associated with the
increase in exposure. Reduction of the oral dose to one 50 mg tablet once weekly is
recommended in patients with severe renal impairment (CLcr <30 ml/min) (see Section 4.2).
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
Patients with hepatic impairment
There are no pharmacokinetic data for ibandronic acid in patients who have hepatic
impairment. The liver has no significant role in the clearance of ibandronic acid since it is not
metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage
adjustment is not necessary in patients with hepatic impairment. Further, as protein binding
of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in
severe liver disease is unlikely to lead to clinically significant increases in free plasma
concentration.
Elderly
In a multivariate analysis, age was not found to be an independent factor of any of the
pharmacokinetic parameters studied. As renal function decreases with age, this is the only
factor to take into consideration (see renal impairment section).
Children and adolescents
There are no data on the use of Bonat® in patients less than 18 years old.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures sufficiently in excess of the
maximum human exposure indicating little relevance to clinical use. As with other
bisphosphonates, the kidney was identified to be the primary target organ of systemic
toxicity.
Mutagenicity/Carcinogenicity:
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no
evidence of genetic activity for ibandronic acid.
Reproductive toxicity:
No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid in
intravenously or orally treated rats and rabbits. Adverse effects of ibandronic acid in
reproductive toxicity studies in the rat were those expected for this class of drugs
(bisphosphonates). They include a decreased number of implantation sites, interference with
natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and
teeth abnormalities in F1 offspring in rats.
6. PHARMACEUTICAL
PARTICULARS

6.1 List of excipients
Tablet core:
Lactose monohydrate
Povidone
Cellulose, microcrystalline
Crospovidone
Stearic acid
Silica, anhydrous colloidal
Tablet coat:
Hypromellose
Titanium dioxide E171
Talc
Macrogol 6000
Bonat® Tablets 50mg MoH approved Prescribing Information
__________________________________________________________________________________________
6.2 Incompatibilities
Not applicable.
6.3 Shelf

5 years.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Bonat® 50 mg film coated tablets are supplied in blisters (aluminium) containing 7 tablets,
which are presented as packs containing 28 or 84 tablets. Not all pack sizes may be
marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
MARKETING AUTHORISATION HOLDER

Roche Pharmaceuticals (Israel) Ltd., P.O. Box 7543, Petach-Tikva 49170.
8.
MARKETING AUTHORISATION NUMBER(S)
BONAT® Tablets 50 MG 132.63.31042

Manufacturer: F. Hoffmann-La Roche Ltd., Basel, Switzerland
1123BONA1009

Source: http://www.roche.co.il/fmfiles/re7128001/Product_Leaflets/Bonat_Tabs_50mg_MoH_approved_PI_1009.pdf