Bonviva

General characteristics. Structure:

Active agent: ibandronovy acid — 150 mg (in the form of an ibandronat of sodium of monohydrate — 168.75 mg);

Excipients: K25 povidone — 22.5 mg, lactoses monohydrate — 162.75 mg, cellulose microcrystallic — 60 mg, кросповидон — 22.5 mg, stearic acid of 95 — 9 mg, silicon dioxide colloid (anhydrous) — 4.5 mg;

Cover substances: mix for drawing a cover (a gipromelloz, titanium E171 dioxide, talc) — 12.75 mg, a macrogoal of 6000 — 2.25 mg; use of ready mix of Opadray (Opadry®) 00A28646 is allowed (a gipromelloza, titanium dioxide, talc).

Pharmacological properties:

Ibandronovy acid — highly active nitrogen-containing бисфосфонат, inhibitor of a bone resorption and activity of osteoclasts. Ibandronovy acid prevents the bone destruction caused by the termination of function of gonads, retinoids, tumors and extracts of tumors in vivo. In researches on young (fast-growing) rats ibandronovy acid also inhibited an endogenous bone resorption that led to increase in bone weight in comparison with animals of control group.
In experimental models on animals it was confirmed that ibandronovy acid is powerful inhibitor of activity of osteoclasts and does not break a mineralization of bones even at appointment in doses, more than by 5000 times exceeding doses for treatment of osteoporosis.
At prolonged use of ibandronovy acid in two various modes of dosing (daily or intermittent administration of drug with the long period without treatment) in researches at rats, dogs and monkeys formation of a new normal bone tissue and/or increase in mechanical durability even was observed at use of the doses exceeding therapeutic including doses of toxic range. Efficiency of use of the drug Bonviva® in both modes was confirmed in clinical trial of MF4411 — daily reception of 2.5 mg or intermittent reception of 20 mg of drug with the period of 9-10 weeks without treatment led to reduction of frequency of developing of fractures.
At women in a postmenopause oral administration of the drug Bonviva® (both daily, and intermittent administration of drug with the period of 9-10 weeks without treatment) led to the biochemical changes characteristic of dozozavisimy inhibition of a bone resorption, including to decrease in concentration of biochemical markers of splitting of bone collagen (a deoksipiridinolin and cross sewed With — and type collagen I N-telopeptidov) in urine.
After the termination of treatment there is a return to the former, noted before treatment, increased level of a bone resorption characteristic of post-menopausal osteoporosis.
The histologic analysis of the bone bioptat taken from women in a postmenopause on the second and third year of treatment showed existence of a normal bone tissue, and also lack of defects of a mineralization.
In a research of bioequivalence of the 1st phase, carried out with the assistance of 72 women in a postmenopause, examinees received orally the mg drug Бонвива® 150 each 28 days (only 4 doses). In this research it was revealed that reduction of concentration of the collagen I which is cross sewed S-telopeptida like (CTX) in blood serum is observed in the first 24 hours after reception of the first dose (on average for 28%), and average maximum decrease in concentration (for 69%) was observed in 6 days. After reception of the 3rd and 4th doses average maximum decrease in concentration in 6 days after reception of each dose made 74%, and in 28 days after reception of the 4th dose average decrease in concentration made 56%. At the termination of administration of drug after the 4th dose concentration of biochemical markers showed the termination of an inhibiting effect of drug concerning a bone resorption.
Ibandronovy acid does not influence process of replenishment of a pool of osteoclasts. The selection effect of ibandronovy acid on a bone tissue is caused by its high affinity to the hydroxyapatite making a mineral matrix of a bone.
Ibandronovy acid brakes a bone resorption and does not exert a direct impact on formation of a bone tissue. At women in a postmenopause reduces the increased speed of updating of a bone tissue to the level of reproductive age that leads to the progressing increase in bone weight. Daily or intermittent reception of ibandronovy acid leads to decrease in a bone resorption that is shown by decrease in concentration of biochemical markers of bone remodeling in urine and blood serum, increase in the mineral density of a bone (MDB) and decrease in frequency of changes.
High activity and width of therapeutic range provide a possibility of the flexible mode of dosing in rather low doses and intermittent use of drug with the long period without treatment.
Efficiency
Mineral Density of a Bone (MDB).
In a 2-year double blind multicenter research (BM16549) with the assistance of the women in a postmenopause having osteoporosis (MPK of lumbar vertebrae: initially the T-criterion is lower — 2.5 SD), on the basis of increase in indicators of MPK was shown that purpose of the drug Bonviva® in a dose of 150 mg is characterized, at least, by the same efficiency once a month, as well as administration of drug in a dose of 2.5 mg daily. The data obtained when carrying out primary analysis after the first year of a research were confirmed when carrying out the subsequent analysis after the second year of a research.
Table 1. Average increase in MPK of lumbar vertebrae, hips, necks of a hip and a spit in comparison with the reference values received after the first (primary analysis) and the second year ("perprotocol population" is the persons who satisfied conditions of the protocol and completed a research) the researches BM16549. 

Average increase in MPK in comparison with reference values of % (the confidence interval (CI) of 95%)	First year of the research BM16549 Бонвива® 150 of mg once a month (N=320)	First year of the research BM16549 Бонвива® 2.5 of mg daily (N=318)	Second year of the research BM16549 Бонвива® 150 of mg once a month (N=291)	Second year of the research BM16549 Бонвива® 2.5 of mg daily (N=294)
MPK of lumbar vertebrae L2-L4	for 4.9% (DEE 4.4, 5.3)	for 3.9% (DEE 3.4, 4.3)	for 6.6% (DEE 6.0, 7.1)	for 5.0% (DEE 4.4, 5.5)
Hip MPK	for 3.1% (DEE 2.8, 3.4)	for 2.0% (DEE 1.7, 2.3)	for 4.2% (DEE 3.8, 4.5)	for 2.5% (DEE 2.1, 2.9)
Hip neck MPK	for 2.2% (DEE 1.9, 2.6)	for 1.7% (DEE 1.3, 2.1)	for 3.1% (DEE 2.7, 3.6)	for 1.9% (DEE 1.4, 2.4)
MPK twirled	for 4.6% (DEE 4.2, 5.1)	for 3.2% (DEE 2.8, 3.7)	for 6.2% (DEE 5.7, 6.7)	for 4.0% (DEE 3.5, 4.5)

Besides, when carrying out the prospective analysis it was proved that Bonviva® at the mode of dosing of 150 mg surpasses the mg drug Бонвива® 2.5 daily in extent of increase in MPK of lumbar vertebrae once a month (on the first year of a research р =0.002 and on the second year of a research р less than 0.001).
After the first year of a research (primary analysis) at 91.3% (р =0.005) the patients receiving the mg drug Бонвива® 150 once a month, in comparison with 84.0% of the patients receiving the mg drug Бонвива® 2.5 daily increase in MPK of lumbar vertebrae or preservation of its initial level was noted. By the end of the second year at 93.5% (р =0.004) the patients receiving the mg drug Бонвива® 150 once a month, and at 86.4% of the patients receiving the mg drug Бонвива® 2.5 daily affirmative answer on therapy was observed.
Concerning MPK values of a hip after the first year of a research at 90.0% (р less than 0.001) the patients receiving the mg drug Бонвива® 150 once a month, and at 76.7% of the patients receiving the mg drug Бонвива® 2.5 daily increase in MPK or preservation of its initial level was observed. By the end of the second year at 93.4% (р less than 0.001) the patients receiving the mg drug Бонвива® 150 once a month, and at 78.4% of the patients receiving the mg drug Бонвива® 2.5 daily increase in MPK of a hip or preservation of its initial level was noted.
When using more strict criterion which includes the general assessment of MPK of lumbar vertebrae and a hip by the end of the first year of a research affirmative answer was observed at 83.9% (р less than 0.001) the patients receiving the mg drug Бонвива® 150 once a month, and at 65.7% of the patients receiving the mg drug Бонвива® 2.5 daily. By the end of the second year — at 87.1% (р less than 0.001) the patients receiving the mg drug Бонвива® 150 once a month, and at 70.5% of the patients receiving the mg drug Бонвива® 2.5 daily.
Biochemical markers of a bone resorption
Clinically significant decrease in concentration of serumal CTX is received in 3, 6, 12 and 24 months of therapy. In a year of therapy by the mg drug Бонвива® 150 once a month (primary analysis) average decrease made 76%, and at administration of drug in a dose of 2.5 mg daily — 67%. By the end of the second year of a research at administration of drug of Бонвива® 150 mg once a month average decrease made 68%, and at reception in a dose of 2.5 mg daily — 62%.
Decrease in concentration of CTX more than 50% in comparison with a reference value is noted at 83.5% (р =0.006) the patients receiving the mg drug Бонвива® 150 once a month, and at 73.9% of the patients receiving the mg drug Бонвива® 2.5 daily within the first year of a research. By the end of the second year affirmative answer on therapy was observed at 78.7% (р =0.002) the patients receiving the mg drug Бонвива® 150 once a month, and at 65.6% of the patients receiving the mg drug Бонвива® 2.5 daily.
In the research BM16549 it was shown that purposes of the drug Бонвива® 150 of mg and 2.5 mg daily concerning reduction of risk of changes are characterized once a month, at least, by similar efficiency.
Preclinical data on safety
In researches on animals the toxic effect was observed only on the drug exposure significantly exceeding the maximum exposure of drug at the person and therefore it is represented a little significant for clinical use of drug.
The data indicating possible cancerogenic and genotoksichny activity are not revealed.

Pharmacokinetics. Direct dependence of efficiency of ibandronovy acid on concentration of substance in a blood plasma is not revealed. Similar efficiency of ibandronovy acid at reception in the different modes of dosing (daily or with the breaks making several weeks) was shown in various researches conducted both with the assistance of volunteers and in researches on animals. The general dose received throughout the entire period of a research was identical. At rats the break between administrations of drug at the intermittent mode of dosing made the most smaller 6 weeks, at dogs — 11 weeks, at monkeys — 30 days and at people — 9.5 weeks.

Absorption. After oral administration ibandronovy acid is quickly soaked up in upper parts of digestive tract. Concentration in a blood plasma дозозависимо increases at increase in a dose up to 50 mg and much more — at further increase in a dose. Time of achievement of the maximum concentration (TCmax) of 0.5-2 h (a median — 1 h) after reception on an empty stomach, absolute bioavailability of 0.6%. The concomitant use of food or drinks (except clear water) reduces bioavailability of ibandronovy acid by 90%. At reception of ibandronovy acid in 60 min. prior to food of significant decrease in bioavailability it is not observed. Meal or liquids less than in 60 min. after ibandronovy acid reduces its bioavailability and the caused increase in MPK.

Distribution. After hit in a system blood stream ibandronovy acid quickly communicates in a bone tissue or is removed with urine. 40-50% of amount of the drug circulating in blood get into a bone tissue and collects in it. The seeming final volume of distribution of 90 l. Communication with proteins of a blood plasma at therapeutic concentration rather low (about 85%), thus, probability of intermedicinal interaction, owing to replacement from communication with proteins of plasma, small.

Metabolism. Data that ibandronovy acid is metabolized at animals or at people no.

Removal. 40-50% of orally accepted dose which is soaked up in a blood stream communicate in bones, and other part is removed in not changed look by kidneys. Not soaked up drug is removed in not changed view with a stake.
The size of the observed seeming final elimination half-life varies in wide limits (10-72 h) and depends on a dose of drug and sensitivity of the analysis. Concentration of drug in a blood plasma decreases quickly and makes 10% from maximum in 3 and 8 h after intravenous administration and oral administration, respectively.
The general clearance of ibandronovy acid low, its average values are in limits of 84-160 ml/min. The renal clearance (healthy women have 60 ml/min. in a postmenopause) makes 50-60% of the general clearance and depends on clearance of creatinine. The difference between the general and renal clearance reflects capture of substance in a bone tissue.

Pharmacokinetics at special groups of patients. The pharmacokinetics of ibandronovy acid does not depend on a floor.
Clinically significant interracial distinctions of distribution of ibandronovy acid at persons of Caucasian and Mongoloid races are not revealed. Rather negroid race of data is not enough.
Patients with a renal failure
At patients with a renal failure the renal clearance of ibandronovy acid linearly depends on the clearance of creatinine (CC). For patients with a renal failure easy or moderate severity (KK> of 30 ml/min.) dose adjustment is not required, by results of the research BM16549 where most of patients had renal failures. At patients with a heavy renal failure (concentration of ibandronovy acid in a blood plasma was 2-3 times higher than KK <30 ml/min.) receiving drug in a dose of 10 mg orally within 21 days, than at people with normal function of kidneys (the general clearance of 129 ml/min.). At a heavy renal failure the general clearance of ibandronovy acid decreases to 44 ml/min. However increase in system concentration does not worsen portability of drug.
Patients with an abnormal liver function
Data on pharmacokinetics of ibandronovy acid at patients with an abnormal liver function are absent. The liver does not play an essential role in clearance of ibandronovy acid which is not metabolized, and is removed through kidneys and by linkng with a bone tissue. Therefore for patients with an abnormal liver function of dose adjustment it is not required. As in therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma (85%) probably that the hypoproteinemia at a serious illness of a liver does not lead to clinically significant increase in concentration of free substance in blood.
Advanced age
The studied pharmacokinetic parameters do not depend on age (the multifactorial analysis). It is necessary to consider possible depression of function of kidneys at elderly patients (see the subsection "Patients with a Renal Failure").
Children
Data on use of the drug Bonviva® for persons under 18 are absent.

Indications to use:

Post-menopausal osteoporosis for the purpose of the prevention of changes.

Route of administration and doses:

Inside, 150 mg (1 tablet) once a month (it is desirable in the same day of every month), in 60 min. prior to the first in this day meal, liquid (except water) (see the section "Interaction with Other Medicines") or other medicines and nutritional supplements (including calcium). Tablets should be swallowed entirely, washing down with a glass (180-240 ml) of clear water in a sitting position or standing and not to lay down within 60 min. after administration of drug of Bonviva®. Tablets cannot be chewed or rassasyvat because of a possible ulceration of upper parts of digestive tract. It is impossible to use mineral waters which contain a lot of calcium.
In case of the admission of planned reception it is necessary to take one pill of the drug Бонвива® 150 of mg if before the planned reception it is more than 7 days, and further to accept the drug Bonviva® according to the established schedule once a month. If before the following planned reception less than 7 days, it is necessary to wait to the following according to the plan of reception, and further to continue reception according to the established schedule since it is impossible to take more than 1 pill of the drug Bonviva® a week.
Dosing at special groups of patients
Abnormal liver function
Dose adjustment is not required (see the subsection "Pharmacokinetics at Special Groups of Patients").
Renal failure
At the weak and moderately expressed renal failure (clearance of creatinine of ≥30 ml/min.) of dose adjustment it is not required.
At clearance of creatinine <30 ml/min. use of the drug Bonviva® is not recommended as experience of a clinical use is limited (see the subsection "Pharmacokinetics at Special Groups of Patients").
Advanced age
Dose adjustment is not required.
Children
Safety and efficiency at persons under 18 is not established.

Features of use:

Osteoporosis can be confirmed at identification of low MPK (T an index <-2.0 SD [to Standard deviation — a standard deviation]) and a change (including in the anamnesis) or the low mineral density of a bone tissue (T an index <-2.5 SD) in the absence of the confirmed change.
Hypocalcemia
Prior to use of the drug Bonviva® it is necessary to skorrigirovat a hypocalcemia and other disturbances of metabolism of a bone tissue and electrolytic balance. Patients should use enough calcium and vitamin D.
If the patient receives with food not enough calcium and vitamin D, then it is necessary to accept in addition them in the form of nutritional supplements.
Irritation of digestive tract
Use of peroral bisfosfonat can lead to local irritation of a mucous membrane of upper parts of digestive tract. Due to the possible irritant action of drug and deterioration in a current of the available basic disease of a GIT, patients should be careful at purpose of the drug Bonviva® with the active pathological processes localized in upper parts of digestive tract (for example, the established Barret's gullet, a dysphagy, other diseases of a gullet, gastritis, a duodenitis or ulcers).
At the patients receiving treatment by peroral bisfosfonata cases of emergence of the undesirable phenomena, such as an esophagitis, the ulcers or erosion of a gullet which are occasionally followed by bleeding or development further of strictures or perforation of a gullet are described. In certain cases the undesirable phenomena were heavy and demanded hospitalization. Possibly, the risk of development of the heavy undesirable phenomena from a gullet is higher at the patients who are not observing the mode of dosing and/or continuing to accept peroral bisfosfonaty after emergence of the symptoms indicating irritation of a gullet. Patients have to study attentively recommendations about administration of drug and carefully observe them (see the section "Route of Administration and Doses").
Doctors have to be especially attentive to any signs or symptoms indicating possible reactions from a gullet, and patients have to be warned about need to stop administration of drug of Bonviva® and to see a doctor in case of emergence at them of a dysphagy, pain when swallowing or behind a breast, emergence or strengthening of heartburn.
At use of peroral bisfosfonat (post-registration observation) separate cases of development of stomach ulcer and a duodenum, sometimes heavy and complicated though in clinical trials of increase in risk of these diseases it was not observed are described.
As use of NPVP and bisfosfonat can be followed by irritation of a mucous membrane of digestive tract, it is necessary to be careful at simultaneous use of NPVP with the drug Bonviva®.
Jaw osteonecrosis
At use of bisfosfonat jaw osteonecrosis cases are noted. The majority of cases is registered at oncological patients during the dental procedures, several cases — at patients with post-menopausal osteoporosis or other diseases. Risk factors of development of an osteonecrosis of a jaw include the established diagnosis "cancer", the accompanying therapy (chemotherapy, radiation therapy, corticosteroids) and other disturbances (anemia, a coagulopathy, an infection, the available diseases of teeth). The majority of the registered cases is noted at in purpose of bisfosfonat, but separate cases were observed at the patients receiving drugs inside.
Surgical dental intervention against the background of therapy of a bisfosfonatama can strengthen manifestations of an osteonecrosis of a jaw. It is unknown whether cancellation of bisfosfonat reduces risk of emergence of an osteonecrosis. The decision on performing treatment needs to be made for each patient individually after ratio assessment risk/advantage.
Atypical fractures of a hip
Atypical subtrochanterian and diaphyseal fractures of a hip are noted against the background of reception of bisfosfonat, first of all at the patients receiving prolonged treatment concerning osteoporosis. Cross and short slanting changes can be localized on all length of a femur from a trochantin to an epicondylic eminence. Developing of atypical fractures happens spontaneously or as a result of small injuries. One weeks or months prior to developing of a fracture of hip some patients feel hip pain or in inguinal area which often is followed by radiological symptoms of a stressful fracture. For the reason that atypical changes often are bilateral, it is necessary to control a condition of other hip at patients with a diaphyseal fracture of a femur. Bad healing of atypical changes is noted.
At suspicion on existence of an atypical change and before obtaining results of inspection it is necessary to consider a question of the termination of therapy of a bisfosfonatama, proceeding from ratio assessment advantage/risk in each case.
It is necessary to inform patients on need to report about any hip pain or in inguinal area during therapy of a bisfosfonatama. In the presence of these symptoms it is necessary to conduct examination for detection of an incomplete fracture of hip.

Influence on ability to manage vehicles and mechanisms
Researches about influence of administration of drug of Bonviva® on ability to drive the car and other mechanisms were not conducted. Drug causes the undesirable phenomena which can affect ability to manage vehicles, etc.

Side effects:

The most frequent undesirable reactions were the arthralgia and a grippopodobny syndrome which were observed usually after reception of the first dose of the drug Bonviva®, were characterized by weak or moderate degree of intensity, small duration and resolved without treatment (see the subsection "Grippopodobny Syndrome" below).
Assessment of safety of use of ibandronovy acid (2.5 mg daily) was carried out in four placebos controlled clinical trials (N=1251). Most of the patients participating in these researches participated in the main 3-year research MF4411 earlier. The general profile of safety of use of ibandronovy acid (2.5 mg daily) in all above-mentioned researches was similar to placebo, that at use.
In the 2-year research BM16549 with the assistance of the women in a postmenopause having osteoporosis, the general profile of safety of use of the drug Бонвива® 150 of mg was similar to that at use of the drug Бонвива® 2.5 of mg daily once a month. The general share of patients at whom undesirable reactions were revealed made 22.7% and 25.0% after a year and 2 years of administration of drug of Бонвива® 150 mg once a month, respectively. In most cases undesirable reactions were on intensity poorly or are moderately expressed and did not lead to drug withdrawal.
The undesirable reactions having relationship of cause and effect with administration of drug of Bonviva® (according to researchers), are distributed on classes of systems of bodies and listed below.
For the description of frequency of undesirable reactions the following categories are used: often (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100) and it is rare (≥1/10000 and <1/1000). In each subgroup undesirable reactions are located as reduction of degree of their gravity.
Table 2. The undesirable reactions revealed at use of the drug Bonviva® in clinical trials and in the post-marketing period.

Class of system of bodies	Frequency	Undesirable reaction
From immune system	Seldom Very seldom	Hypersensitivity reactions. Anaphylactic reactions / shock *†, allergic reactions, in particular, exacerbation of bronchial asthma †.
From a nervous system	Often Infrequently	Headache. Dizziness.
From an organ of sight	Seldom	Inflammatory diseases of eyes *†.
From digestive tract	Often Infrequently Seldom	Esophagitis, gastritis, gastroesophageal reflux disease, dyspepsia, diarrhea, abdominal pain, nausea. Esophagitis, including an ulceration of a gullet or a stricture, a dysphagy, vomiting, a meteorism. Duodenitis.
From skin and a hypodermic fatty tissue	Often	Rash. Quincke's disease, face edema, small tortoiseshell.
From a musculoskeletal system	Often Infrequently Seldom Very seldom	Arthralgia, mialgiya, musculoskeletal pains, muscular spasms, skeletal and muscular constraint. Dorsodynias. Atypical subtrochanterian and diaphyseal fractures of a femur †. Jaw osteonecrosis *†.
From an organism in general	Often Infrequently	Grippopodobny синдром*. Fatigue.

* See below
† It is revealed during post-marketing use
Description of separate undesirable reactions
Undesirable reactions from digestive tract
In clinical trials with the assistance of patients with existence in the anamnesis of diseases of digestive tract, including a round ulcer without cases of recent bleeding or hospitalization, and also the patients with dyspepsia or a reflux receiving necessary therapy distinctions in occurrence of the undesirable phenomena from upper parts of digestive tract at administration of drug of Bonviva® in various modes of dosing were not revealed (2.5 mg daily and 150 mg once a month).
In the research BM16549 after the first and second year of administration of drug of Bonviva® distinctions in laboratory indicators in both groups with various modes of dosing were not noted (2.5 mg daily and 150 mg once a month).
Grippopodobny syndrome
The Grippopodobny syndrome can include ostrofazny reactions or symptoms, such as a mialgiya, an arthralgia, fever, a fever, fatigue, nausea, loss of appetite or an ostealgia.
Jaw osteonecrosis
The majority of cases of the osteonecrosis of a jaw which developed at use of bisfosfonat is registered at oncological patients, several cases — at patients with osteoporosis. The jaw osteonecrosis, mainly, was associated with an odontectomy and/or a local infection (in particular, osteomyelitis). Carry the established diagnosis of an oncological disease, chemotherapy, radiation therapy, use of glucocorticosteroids and insufficient hygiene of an oral cavity to other risk factors of development of an osteonecrosis of a jaw (see the section "Special Instructions").
Inflammatory diseases of eyes
At therapy of a bisfosfonatama, including ibandronovy acid, it was reported about inflammatory diseases of eyes, such as an episcleritis, a sclerite and a uveitis. In certain cases, despite the carried-out treatment, recovery occurred only after cancellation of bisfosfonat.
Anaphylactic reactions / shock
At treatment ibandronovy acid for intravenous administration registered cases of anaphylactic reactions / shock, including with a lethal outcome.

Interaction with other medicines:

Products, calciferous and other polyvalent cations (for example, aluminum, magnesium, iron), including milk and firm food, can break drug absorption (that will be coordinated with data of researches on animals), they should be used not earlier than in 60 min. after oral administration of the drug Bonviva®.
Nutritional supplements with calcium, the antacids and peroral medicines containing polyvalent cations (for example, aluminum, magnesium, iron), can break absorption of ibandronovy acid therefore it is necessary to accept them not earlier than in 60 min. after administration of drug of Bonviva®.
In pharmacokinetic researches with the assistance of women in a postmenopause lack of any intermedicinal interaction of ibandronovy acid with Tamoxifenum or gormonozamestitelny therapy was shown it (is oestrogenic). Also signs of intermedicinal interaction at simultaneous use of ibandronovy acid and Melphalanum/Prednisolonum for patients with a multiple myeloma were not revealed.
Bisfosfonaty and non-steroidal anti-inflammatory drugs (NPVP) can cause irritation of a mucous membrane of a GIT. It is necessary to show extra care at use of NPVP along with the drug Bonviva®. In clinical trial with the assistance of women in a postmenopause with BM16549 osteoporosis at simultaneous use of acetylsalicylic acid or other NPVP and the drug Bonviva® (2.5 mg daily or 150 mg once a month) during 1 year the frequency of side effects from upper parts of a GIT was identical.
In researches with the assistance of healthy volunteers (men) and women in a postmenopause, ranitidine in/in increased bioavailability of ibandronovy acid by 20% probably due to reduction of acidity of a gastric juice. However this increase is in limits of limits of standard of bioavailability of ibandronovy acid. Dose adjustment of ibandronovy acid at simultaneous use with the blockers of H2-histamine receptors or other drugs increasing рН in a stomach is not required.
As ibandronovy acid does not inhibit the main isoenzymes of system of P450 cytochrome, and in researches on rats lack of its inducing influence was shown, existence of clinically significant intermedicinal interactions is improbable. In therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma and therefore it is improbable that it will force out from binding sites with proteins other medicines. Ibandronovy acid is removed only through kidneys and is not exposed to any biotransformation. Apparently, the way of removal of ibandronovy acid does not include any transport systems participating in removal of other drugs.
In the research BM16549 with the assistance of 1500 patients comparison of the modes of dosing of ibandronovy acid was carried out (daily and once a month); from them 14% of examinees also accepted blockers of H2-histamine receptors or inhibitors of the proton pump. Frequency of the undesirable phenomena from upper parts of a GIT at the different modes of dosing (Бонвива® 150 mg once a month and 2.5 mg daily) was identical.

Contraindications:

Hypersensitivity to ibandronovy acid or other components of drug.
Hypocalcemia. Prior to use of the drug Bonviva® the same as at purpose of all bisfosfonat used for treatment of osteoporosis it is necessary to eliminate a hypocalcemia.
As well as for other bisfosfonat, a contraindication are the damages of a gullet leading to a delay of its emptying such as stricture or achalasia (see the section "Special Instructions").
Or costing inability to be in a sitting position within 60 min. (see the sections "Route of Administration and Doses" and "Special Instructions").
Hereditary intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption.
Heavy renal failure (clearance of creatinine <30 ml/min.).
Children's age (safety and efficiency at persons under 18 is not established).

With care
The active pathological processes localized in upper parts of digestive tract (for example, the established Barret's gullet, a dysphagy, other diseases of a gullet, gastritis, a duodenitis or ulcers).

Pregnancy and period of feeding by a breast
Pregnancy
It is not necessary to use the drug Bonviva® during pregnancy.
At the rats and rabbits receiving ibandronovy acid orally signs of direct embriotoksichesky or teratogenic action are not revealed; adverse influence on development of posterity in rats of F1 is not revealed. In researches of reproductive toxicity rats had same adverse effects of ibandronovy acid, as at all bisfosfonat — reduction of quantity of embryos, disturbance of process of childbirth (dystocia), increase in frequency of visceral anomalies (a syndrome of narrowing of a lokhanochno-ureteric segment). Special researches of the mode of administration of drug were not conducted once a month.
Pregnant women have no experience of a clinical use of the drug Bonviva®.
Feeding period breast
It is removed with milk at rats. At the lactating rats at intravenous administration of an ibandronat in doses of 0.08 mg/kg a day the greatest concentration of ibandronovy acid in breast milk was observed in the first 2 hours after intravenous administration and made 8.1 ng/ml. In 24 h concentration of ibandronovy acid in a blood plasma and milk was identical and corresponded to 5% of maximum.
It is unknown whether ibandronovy acid with breast milk at women is removed. It is not necessary to use the drug Bonviva® during feeding by a breast.

Overdose:

Possible symptoms at oral administration
The undesirable phenomena from upper parts of digestive tract, such as gastric disturbances, heartburn, esophagitis, gastritis, ulcer of upper parts of digestive tract.

Treatment. Information on treatment in case of overdose of drug is absent. Apply milk or antacids to binding of the drug Bonviva®. Because of risk of irritation of a gullet it is not necessary to cause vomiting and it is necessary to remain in the straightened standing position.

Storage conditions:

To store at a temperature not above 30 °C in the dry place.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 150 mg
On 1 or 3 tablets in the blister from a film of PVH/PVDH and aluminum foil.
The blister together with the application instruction, and also information for the patient (with a reminder on frequency and date of administration of drug, a self-adhesive sticker for a calendar and so forth) is placed in a cardboard pack.