Bonviva® (Bonviva®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIbandronic acidIbandronic acid
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  • Bonviva®
    pills inwards 
    Hoffmann-La Roche Ltd.     Switzerland
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  • Ibandronic acid Sandoz®
    concentrate d / infusion 
    Sandoz d.     Slovenia
    • Dosage form: & nbsppills, film-coated
    Composition:

    One tablet contains:

    active substance: Ibandronic acid - 150 mg (in the form of ibandronate sodium monohydrate - 168.75 mg);

    Excipients: povidone K25 - 22.5 mg, lactose monohydrate - 162.75 mg, microcrystalline cellulose - 60 mg, crospovidone - 22.5 mg, stearic acid 95-9 mg, silicon dioxide colloid (anhydrous) - 4.5 mg;

    shell material: mixture for coating (hypromellose, titanium dioxide E171, talc) - 12.75 mg, macrogol 6000 - 2.25 mg; Allowed the use of a ready mix Opadry (Opadry®) 00A28646 (hypromellose, titanium dioxide, talc).

    Description:

    Oblong tablets covered with a film coat of white or almost white color; on one side of the tablet engraving "BNVA", on the other - "150".

    Length 13,9-14,4 mm, width 6,9-7,4 mm, height 4,8-5,8 mm.

    Pharmacotherapeutic group:Bone resorption inhibitor-bisphosphonate
    ATX: & nbsp

    M.05.B.A.06   Ibandronic acid

    Pharmacodynamics:

    Ibandronic acid is a highly active nitrogen-containing bisphosphonate, inhibitor of bone resorption and osteoclast activity. Ibandronic acid prevents bone destruction caused by the termination of the function of the sexual glands, retinoids, tumors and extracts of tumors in vivo. In studies on young (fast-growing) rats ibandronic acid also inhibited endogenous bone resorption, which led to an increase in bone mass compared to the animals in the control group.

    In experimental animal models, it was confirmed that ibandronic acid is a potent inhibitor of osteoclast activity and does not impair the mineralization of bones even when administered at doses more than 5000 times that for osteoporosis.

    With prolonged use of ibandronic acid in two different dosing regimens (daily or intermittent administration of the drug with a long period without treatment), studies in rats, dogs and monkeys have resulted in the formation of a new normal bone tissue and / or an increase in mechanical strength even with doses exceeding therapeutic, including doses of the toxic range. The effectiveness of the use of Bonviva ® in both regimens was confirmed in the clinical study MF4411 - daily intake of 2.5 mg or intermittent administration of 20 mg of the drug with a period of 9-10 weeks without treatment resulted in a decrease in the incidence of fractures.

    In postmenopausal women, oral administration of Bonviva® (both daily and intermittent administration of the drug with a period of 9-10 weeks without treatment) led to biochemical changes characteristic of dose-dependent inhibition of bone resorption, including a decrease in the concentration of biochemical bone collagen splitting markers (deoxypyridinoline and cross-linked C- and N -lopeptides of type I collagen) in the urine.

    After cessation of treatment, a return to the increased level of bone resorption typical for postmenopausal osteoporosis occurs before the treatment.

    Histological analysis of bone biopsy specimens taken from postmenopausal women in the second and third year of treatment showed the presence of normal bone tissue, as well as the absence of mineralization defects.

    In the Phase I bioequivalence study, conducted with the participation of 72 postmenopausal women, subjects received oral Bonviva® preparation 150 mg every 28 days (total 4 doses).In this study, it was found that a decrease in the concentration of the cross-linked C-telopeptide of type I collagen (CTX) in the blood serum was observed already in the first 24 hours after the first dose (28% on average), and the average maximum decrease in concentration (by 69% ) was observed after 6 days. After taking the 3rd and 4th doses, the average maximum decrease in the concentration 6 days after each dose was 74%, and after 28 days after taking the 4th dose, the average decrease in concentration was 56%. With the discontinuation of the drug after the 4th dose, the concentration of biochemical markers showed an end to the inhibitory effect of the drug with respect to bone resorption.

    Ibandronic acid does not affect the process of replenishing the pool of osteoclasts. The selective effect of ibandronic acid on bone tissue is due to its high affinity for hydroxyapatite, which is the mineral matrix of bone.

    Ibandronic acid inhibits bone resorption and does not directly affect the formation of bone tissue. Postmenopausal women reduce the increased rate of bone tissue renewal to the reproductive age, which leads to a progressive increase in bone mass.Daily or intermittent reception of ibandronic acid leads to a decrease in bone resorption, which is demonstrated by a decrease in the concentration of biochemical markers of bone remodeling in urine and serum, an increase in bone mineral density (BMD), and a decrease in fracture frequency.

    High activity and breadth of the therapeutic range provide the possibility of a flexible dosing regimen in relatively low doses and intermittent application of the drug with a long period without treatment.

    Efficiency

    Mineral bone density (BMD)

    In a 2-year, double-blind, multicentre study (BM16549) with the participation of postmenopausal women suffering from osteoporosis (MIC of the lumbar vertebrae: initially T-test below -2.5 SD), based on an increase in the BMD, it was shown that the appointment of Bonviva® 150 mg once monthly is at least as effective as taking the drug at a dose of 2.5 mg daily.

    The data obtained during the initial analysis after the first year of the study were confirmed in the subsequent analysis after the second year of the study.

    Table 1.The mean increase in the BMD of the lumbar vertebrae, hip, cervix and trochanter compared to the baseline values ​​obtained after the first (primary analysis) and the second year ("pcr-protocol population"- persons who fulfilled the protocol conditions and completed the study) of the study VM16549

    Mean increase in BMD compared with baseline% (confidence interval (CI) 95%)

    The first year of study BM16549 Bonviva® 150 mg

    1 time per month (N = 320)

    The first year of study BM16549 Bonviva® 2.5 mg

    daily

    (N = 318)

    The second year of study BM16549 Bonviva® 150 mg

    1 time per month (N = 291)

    The second year of study BM16549 Bonviva® 2.5 mg

    daily

    (N = 294)

    MIC of the lumbar vertebrae L2-L4

    by 4.9%

    (CI 4.4, 5.3)

    by 3.9%

    (CI 3.4, 4.3)

    on 6,6%

    (CI 6.0, 7.1)

    by 5.0%

    (CI 4.4, 5.5)

    IPC thigh

    by 3.1%

    (CI 2.8, 3.4)

    on 2,0%

    (CI 1.7, 2.3)

    by 4.2%

    (CI 3.8, 4.5)

    by 2.5%

    (CI 2.1, 2.9)

    MIC of cervical hip

    on 2,2%

    (CI 1.9, 2.6)

    by 1.7%

    (CI 1.3, 2.1)

    by 3.1%

    (CI 2.7, 3.6)

    by 1.9%

    (CI 1.4, 2.4)

    IPC skewers

    by 4.6%

    (CI 4.2, 5.1)

    by 3.2%

    (CI 2.8, 3.7)

    on 6,2%

    (CI 5.7, 6.7)

    by 4.0%

    (CI 3.5, 4.5)

    In addition, in a prospective assay, it was demonstrated that Bonviva®, with a 150 mg dosing regimen, once every month exceeds Bonviva® 2.5 mg daily in terms of the increase in the MIC of the lumbar vertebrae (in the first year of study, p =0,002 and in the second year of study p less than 0,001).

    After the first year of the study (primary analysis), 91.3% (p = 0.005) of patients receiving Bonviva® 150 mg once a month, compared with 84.0% of patients receiving the Bonviva® preparation 2.5 mg daily, there was an increase in the MIC of the lumbar vertebrae or the preservation of its basal level. By the end of the second year, 93.5% (p = 0.004) of patients receiving Bonviva® 150 mg once a month, and 86.4% of patients receiving Bonviva® 2.5 mg daily, had a positive response to therapy .

    Regarding the MIC values ​​of the femur after the first year of the study, 90.0% (p <0.001) of patients receiving Bonviva® 150 mg once a month, and 76.7% of patients receiving Bonviva® 2.5 mg daily received an increase in the MIC or the retention of its baseline level. By the end of the second year, 93.4% (p less than 0.001) of patients receiving Bonviva® 150 mg once a month, and 78.4% of patients receiving Bonviva® 2.5 mg daily, had an increase in the hip BMD or preservation of its initial level.

    Using a more rigorous criterion that includes an overall assessment of the lumbar spine and hip BMD, by the end of the first year of the study, a positive response was observed in 83.9% (p <0.001)receiving Bonviva® 150 mg once a month, and 65.7% of patients receiving the Bonviva® preparation 2.5 mg daily. By the end of the second year, 87.1% (p <0.001) of patients receiving Bonviva® 150 mg once a month and 70.5% of patients receiving Bonviva® 2.5 mg daily.

    Biochemical markers of bone resorption

    A clinically significant decrease in serum CTX concentration was obtained after 3, 6, 12 and 24 months of therapy. After a year of therapy with Bonviva® 150 mg once a month (primary analysis), the average decrease was 76%, and when taken at a dose of 2.5 mg daily, 67%. By the end of the second year of the study, when taking Bonviva® 150 mg once a month, the average decrease was 68%, and when taken at a dose of 2.5 mg daily, 62%.

    Reduction of the CTX concentration by more than 50% in comparison with baseline was noted in 83.5% (p = 0.006) of patients receiving Bonviva® 150 mg once a month and in 73.9% of patients receiving Bonviva® 2.5 mg daily, during the first year of the study. By the end of the second year, a positive response to therapy was observed in 78.7% (p = 0.002) of patients receiving Bonviva® 150 mg once a month, and in 65.6% of patients receiving Bonviva® 2.5 mg daily.

    The BM16549 study showed that the administration of Bonviva® 150 mg once a month and 2.5 mg daily with respect to reducing the risk of fractures is characterized by at least similar efficacy.

    Preclinical safety data

    In animal studies, a toxic effect was observed only when the drug was significantly exposed to the maximum exposure of the drug in humans, and therefore appears to be of little significance for the clinical use of the drug. Data indicating possible carcinogenic and genotoxic activity have not been identified.

    Pharmacokinetics:

    There was no direct relationship between the efficacy of ibandronic acid and the concentration of the substance in the blood plasma. The similar efficacy of ibandronic acid when administered in different dosing regimens (daily or with interruptions of several weeks) has been demonstrated in various studies conducted with the participation of volunteers and animal studies. The total dose received throughout the study period was identical. In rats, the interval between doses of the drug with the intermittent dosing regimen was at least 6weeks, dogs - 11 weeks, monkeys - 30 days and people - 9.5 weeks.

    Suction

    After oral administration ibandronic acid quickly absorbed in the upper parts of the gastrointestinal tract. The concentration in the blood plasma increases dose-dependently with increasing dose to 50 mg and significantly more - with a further increase in the dose. Time to reach the maximum concentration (TCmOh) 0.5-2 h (median -1 h) after administration on an empty stomach, absolute bioavailability of 0.6%. Simultaneous intake of food or drinks (except pure water) reduces the bioavailability of ibandronic acid by 90%. When taking ibandronic acid 60 minutes before eating, a significant reduction in bioavailability is not observed. Eating food or liquid less than 60 min after ibandronic acid reduces its bioavailability and the resulting increase in BMD.

    Distribution

    After entering the systemic circulation ibandronic acid quickly binds to bone tissue or is excreted in the urine, 40-50% of the amount of the drug circulating in the blood, penetrates into bone tissue and accumulates in it. The apparent final volume of the distribution is 90 liters. The association with blood plasma proteins at therapeutic concentrations is quite low (about 85%), thus,The probability of inter-drug interaction due to the displacement of plasma from the bond with proteins is small.

    Metabolism

    Data that ibandronic acid metabolized in animals or in humans, no.

    Excretion

    40-50% of the orally absorbed dose absorbed into the bloodstream binds in the bones, and the remainder is excreted unchanged by the kidneys. Not absorbed drug is excreted unchanged with feces.

    The magnitude of the observed apparent final half-life period varies within a wide range (10-72 hours) and depends on the dose of the drug and the sensitivity of the assay. The concentration of the drug in the blood plasma decreases rapidly and is 10% of the maximum at 3 and 8 hours after intravenous administration and oral intake, respectively. The total clearance of ibandronic acid is low, its average values ​​are in the range of 84-160 ml / min. Kidney clearance (60 ml / min in healthy postmenopausal women) is 50-60% of the total clearance and depends on the creatinine clearance. The difference between general and renal clearance reflects the capture of matter in bone tissue.

    Pharmacokinetics in specific patient groups

    The pharmacokinetics of ibandronic acid are independent of sex.

    No clinically relevant interracial differences distribution of ibandronic acid in Caucasoid and Mongoloid races. Relatively Negroid race data is not enough.

    Patients with impaired renal function

    In patients with impaired renal function, renal clearance of ibandronic acid depends linearly on creatinine clearance (CC). For patients with impaired renal function of mild or moderate severity (CK> 30 ml / min), dose adjustment is not required, according to the results of the BM16549 study, where the majority of patients had renal dysfunction. In patients with severe renal dysfunction (CC <30 mL / min) who received the drug at a dose of 10 mg orally for 21 days, the concentration of ibandronic acid in the blood plasma was 2-3 times higher than in people with normal renal function total clearance 129 ml / min).

    With severe renal dysfunction, the overall clearance of ibandronic acid is reduced to 44 ml / min. However, an increase in systemic concentration does not impair the tolerability of the drug.

    Patients with impaired hepatic function

    Data on the pharmacokinetics of ibandronic acid in patients with impaired liver function are absent.The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized, but is excreted through the kidneys and by binding to the bone tissue. Therefore, for patients with impaired liver function, dose adjustment is not required. Since in therapeutic concentrations ibandronic acid weakly binds to blood plasma proteins (85%), it is likely that hypoproteinemia in severe liver disease does not lead to a clinically significant increase in the concentration of free substance in the blood.

    Elderly age

    The studied pharmacokinetic parameters do not depend on age (multifactorial analysis). It should be taken into account the possible reduction in kidney function in elderly patients (see subsection "Patients with impaired renal function").

    Children

    Data on the use of Bonviva® in persons under the age of 18 are not available.

    Indications:Postmenopausal osteoporosis in order to prevent fractures.
    Contraindications:

    Hypersensitivity to ibandronic acid or other components of the drug.

    Hypocalcemia. Before starting the use of Bonviva ®, as with the appointment of all bisphosphonates used to treat osteoporosis, hypocalcemia should be eliminated.

    As with other bisphosphonates, contraindications are esophageal lesions, leading to a delay in its emptying, such as stricture or achalasia (see section "Special instructions").

    Failure to be in a sitting or standing position for 60 minutes (see sections "Method of administration and dose" and "Special instructions").

    Hereditary intolerance to galactose, deficiency of lactase Lapp or glucose-galactose malabsorption.

    Severe renal impairment (creatinine clearance <30 mL / min).

    Carefully:

    Active pathological processes localized in the upper gastrointestinal tract (eg, established Barrett's esophagus, dysphagia, other diseases of the esophagus, gastritis, duodenitis, or ulcers).

    Pregnancy and lactation:

    Pregnancy

    Do not use Bonviva ® during pregnancy.

    In rats and rabbits who received ibandronic acid orally, no signs of direct embryotoxic or teratogenic effects were found; There was no adverse effect on the development of offspring in rats F1. The adverse effects of ibandronic acid in studies of reproductive toxicity in rats were similar,as in all bisphosphonates - a decrease in the number of embryos, a violation of the process of childbirth (dystocia), an increase in the frequency of visceral anomalies (constriction syndrome of the ureterocarillary segment). Special studies of the regimen of taking the drug once a month was not conducted.

    The experience of clinical use of the drug Bonviva® in pregnant women is not.

    Breastfeeding period

    It is excreted in milk in rats. In lactating rats with intravenous ibandronate doses of 0.08 mg / kg per day, the highest concentration of ibandronic acid in breast milk was observed in the first 2 hours after intravenous administration and was 8.1 ng / ml. After 24 hours, the concentration of ibandronic acid in blood plasma and milk was the same and corresponded to 5% of the maximum.

    It is not known whether ibandronic acid with breast milk in women. Do not use Bonviva® during lactation.

    Dosing and Administration:

    Inside, 150 mg (1 tablet) once a month (preferably on the same day of each month), 60 minutes before the first meal on that day, liquid (except water) (see section "Interaction with other medicines ") or other medicines and food additives (including calcium).Tablets should be swallowed whole by washing a glass (180-240 ml) of clean water in a sitting or standing position and not lie down for 60 minutes after taking Bonviva ®. Tablets can not be chewed or rassasyvat because of possible ulceration of the upper divisions of the gastrointestinal tract. Do not use mineral water that contains a lot of calcium.

    If you miss a scheduled appointment, take one Bonviva® tablet 150 mg, if before the scheduled intake more than 7 days, and continue taking Bonviva ® once a month according to the established schedule. If the next scheduled reception is less than 7 days, you must wait until the next scheduled reception, and then continue to receive in accordance with the established schedule, tk. Do not take more than 1 Bonviva® pill per week.

    Dosing in special patient groups

    Impaired liver function

    Correction of the dose is not required (see subsection "Pharmacokinetics in special patient groups").

    Impaired renal function

    With a weak and moderately severe renal impairment (creatinine clearance> 30 ml / min), dose adjustment is not required.

    With creatinine clearance <30 ml / min, the use of Bonviva ® is not recommended, as the experience of clinical use is limited (see subsection "Pharmacokinetics in special patient groups").

    Elderly age

    Correction of the dose is not required.

    Children

    Safety and efficacy in persons younger than 18 years of age have not been established.

    Side effects:

    The most frequent adverse reactions were arthralgia and the flu-like syndrome, which were usually observed after the first dose of Bonviva®, were characterized by mild or moderate intensity, a short duration, and resolved without treatment (see "Green-like syndrome" below). An evaluation of the safety of Ibandronic acid (2.5 mg daily) was conducted in four placebo-controlled clinical trials (N = 1251). Most of the patients participating in these studies, previously participated in the main 3-year study of MF4411. The overall safety profile of ibandronic acid (2.5 mg daily) in all of the above studies was similar to that of placebo.

    In the 2-year study BM16549 with the participation of postmenopausal women suffering from osteoporosis, the overall safety profile of the use of Bonviva® 150 mg once a month was similar to that of Bonviva® 2.5 mg daily. The total proportion of patients who showed adverse reactions was 22.7% and 25.0% after a year and 2 years of receiving Bonviva® 150 mg once a month, respectively. In most cases, adverse reactions were weak or moderate in intensity and did not lead to drug withdrawal.

    Undesirable reactions that have a causal relationship with the use of Bonviva® (according to the researchers) are divided into classes of organ systems and are listed below.

    The following categories are used to describe the frequency of unwanted reactions: often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100) and rarely (≥1 / 10000 and <1/1000). In each subgroup, unwanted reactions are arranged in order of decreasing severity.

    Table 2. Undesirable reactions identified with the use of Bonviva ® in clinical trials and in the postmarketing period

    Class of organ system

    Frequency

    Unwanted reaction

    From the side immune system

    Rarely

    Hypersensitivity reactions.

    Rarely

    Anaphylactic reactions / shock*†, allergic reactions, in particular, exacerbation of bronchial asthma†.

    From the nervous system

    Often

    Head

    pain.

    Infrequently

    Dizziness.

    From the side of the organ of vision

    Rarely

    Inflammation of the eye*†.

    From the gastrointestinal tract

    Often

    Esophagitis, gastritis, gastroesophageal reflux disease, dyspepsia, diarrhea, abdominal pain, nausea.

    Infrequently

    Esophagitis, including ulceration of the esophagus or stricture, dysphagia, vomiting, flatulence.

    Rarely

    Duodenitis.

    From the side skin and subcutaneous fat

    Often

    Rash.

    Rarely

    Angioedema, edema of the face, urticaria.

    From the side of the musculoskeletal system

    Often

    Arthralgia, myalgia, musculoskeletal pain, muscle spasms, musculoskeletal stiffness.

    Infrequently

    Back pain.

    Rarely

    Atypical susceptible and diaphyseal fractures of the femur†.

    Rarely

    Osteonecrosis jaws* and other maxillofacial regions, including the external auditory canal†.

    From the body as a whole

    Often

    The flu-like syndrome*.

    Infrequently

    Fatigue.

    *See below

    †Revealed during post-marketing application

    Description of individual adverse reactions

    Undesirable reactions from the gastrointestinal tract

    In clinical trials involving patients with a history of gastrointestinal disease, including peptic ulcer without recent bleeding or hospitalization, and patients with dyspepsia or reflux who receive the necessary therapy, there was no difference in the incidence of adverse events from the upper divisions gastrointestinal tract when taking Bonviva® in various dosing regimens (2.5 mg daily and 150 mg once a month).

    In the study BM16549 after the first and second year of taking Bonviva® there were no differences in laboratory parameters in both groups with different dosing regimens (2.5 mg daily and 150 mg once a month).

    The flu-like syndrome

    The flu-like syndrome can include acute reactions or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

    Osteonecrosis of the jaw

    Most cases of osteonecrosis of the jaw, developed with the use of bisphosphonates, are registered in cancer patients, several cases - in patients with osteoporosis.Osteonecrosis of the jaw was mainly associated with tooth extraction and / or local infection (in particular, osteomyelitis). Other risk factors for osteonecrosis of the jaw include the established diagnosis of cancer, chemotherapy (including angiogenesis inhibitors), radiation therapy, the use of glucocorticosteroids and poor oral hygiene (see section "Special instructions").

    Inflammation of the eye

    In the treatment of bisphosphonates, including ibandronic acid, inflammatory diseases of the eye, such as episcleritis, scleritis and uveitis have been reported. In some cases, despite ongoing treatment, the recovery came only after the removal of bisphosphonates.

    Anaphylactic reactions / shock

    In the treatment of ibandronic acid for intravenous administration, cases of anaphylactic reactions / shock, including fatal, have been reported.

    Disturbances from the skin and subcutaneous tissues

    Severe skin adverse reactions, including Stevens-Johnson syndrome, erythema multiforme and bullous dermatitis, have been reported.

    Overdose:

    Possible Symptoms for Oral Reception

    Undesirable effects from the upper parts of the gastrointestinal tract, such as stomach upsets, heartburn, esophagitis, gastritis, ulcers of the upper gastrointestinal tract.

    Treatment

    Information about treatment in case of drug overdose is absent. To bind Bonviva®, milk or antacids are used. Because of the risk of irritation of the esophagus, one should not induce vomiting and should remain in the erect standing position.

    Interaction:

    Products containing calcium and other polyvalent cations (for example, aluminum, magnesium, iron), including milk and solid foods, can interfere with the absorption of the drug (which is consistent with animal studies), they should be consumed no earlier than 60 minutes after oral administration of Bonviva®.

    Food supplements with calcium, antacids and oral medications containing polyvalent cations (for example, aluminum, magnesium, iron) can disrupt the absorption of ibandronic acid, so they should be taken no sooner than 60 minutes after taking Bonviva®.

    In pharmacokinetic studies with the participation of women in postmenopausal women,absence of any inter-drug interaction of ibandronic acid with tamoxifen or hormone replacement therapy (estrogen). Also, there were no signs of inter-drug interaction with the simultaneous use of ibandronic acid and melphalan / prednisolone in patients with multiple myeloma.

    Bisphosphonates and non-steroidal anti-inflammatory drugs (NSAIDs) can cause irritation of the gastrointestinal mucosa. Care should be taken with the use of NSAIDs concomitantly with Bonviva®. In a clinical study with the participation of postmenopausal women with osteoporosis (BM16549) with simultaneous use of acetylsalicylic acid or other NSAIDs and Bonviva® (2.5 mg daily or 150 mg once a month) for 1 year, the incidence of side effects from the upper divisions The gastrointestinal tract was the same.

    In studies involving healthy volunteers (men) and postmenopausal women, ranitidine intravenously increased the bioavailability of ibandronic acid by 20%, probably due to a decrease in the acidity of gastric juice. However, this increase is within the limits of the bioavailability of ibandronic acid. Correction of a dose of ibandronic acid with simultaneous use with blockers H2-gistaminovyh receptors or other drugs that increase pH in the stomach, is not required.

    As ibandronic acid does not inhibit the main isoenzymes of the cytochrome P450 system, and in studies on rats it has been shown that its inducing effect is absent, the presence of clinically significant inter-drug interactions is unlikely. In therapeutic concentrations ibandronic acid weakly binds to blood plasma proteins, and therefore it is unlikely that it will displace other drugs from the binding sites with proteins. Ibandronic acid is excreted only through the kidneys and is not subjected to any biotransformation. Apparently, the route of excretion of ibandronic acid does not include any transport systems involved in the excretion of other drugs.

    In the BM16549 study, with the participation of 1500 patients, the dosing regimens of ibandronic acid were compared (daily and once a month); Of these, 14% of the subjects also received blockers H2histamine receptors or proton pump inhibitors. The incidence of adverse events from the upper gastrointestinal tract at different dosage regimens (Bonviva® 150 mg once a month and 2.5 mg daily) was the same.

    Special instructions:

    Osteoporosis can be confirmed by detecting a low BMD (T index <-2.0 SD [Standard deviation - standard deviation]) and fracture (including history) or low bone mineral density (T index <-2.5 SD) in the absence of a confirmed fracture.

    Hypocalcemia

    Prior to the use of Bonviva ®, hypocalcemia and other metabolic disorders of bone tissue and electrolyte balance should be corrected. Patients should consume sufficient amounts of calcium and vitamin D. If the patient does not receive calcium and vitamin D with food, then they should additionally be taken as food supplements.

    Irritation of the gastrointestinal tract

    The use of oral bisphosphonates can lead to local irritation of the mucosa of the upper gastrointestinal tract. In connection with the possible irritant effect of the drug and worsening of the current underlying gastrointestinal disease, caution should be exercised when prescribing Bonviva® to patients with active pathological processes localized in the upper gastrointestinal tract (for example, established Barrett's esophagus, dysphagia, other diseases of the esophagus, gastritis, duodenitis, or ulcers).

    In patients receiving oral bisphosphonates, cases of adverse events such as esophagitis, ulcers or erosion of the esophagus, occasionally accompanied by bleeding or the development of strictures or perforations of the esophagus, are described. In some cases, adverse events were severe and required hospitalization. Probably, the risk of developing severe adverse events on the side of the esophagus is higher in patients who do not follow the dosing regimen and / or continue to take oral bisphosphonates after the appearance of symptoms indicative of esophageal irritation. Patients should carefully read the recommendations for taking the drug and carefully follow them (see section "Method of administration and dose").

    Doctors should be especially attentive to any signs or symptoms that indicate possible reactions from the esophagus, and patients should be warned about the need to stop taking Bonviva ® and consult a doctor if they have dysphagia, pain when swallowing or behind the sternum, the appearance or increased heartburn.

    When using oral bisphosphonates (post-registration observation), individual cases of stomach and duodenal ulcer development, sometimes severe and complicated, are described,although there was no increase in the risk of these diseases in clinical studies.

    Since the use of NSAIDs and bisphosphonates may be accompanied by irritation of the gastrointestinal mucosa, caution should be exercised while using NSAIDs with Bonviva®.

    Osteonecrosis of the jaw

    When bisphosphonates are used, cases of osteonecrosis of the jaw are noted. Most cases have been reported in cancer patients during dental procedures, several cases in patients with postmenopausal osteoporosis or other diseases. Risk factors for osteonecrosis of the jaw include the established diagnosis of cancer, concomitant therapy (chemotherapy, including angiogenesis inhibitors, radiation therapy, corticosteroids) and other disorders (anemia, coagulopathy, infection, existing dental diseases). The majority of reported cases were noted with the iv appointment of bisphosphonates, but individual cases were observed in patients receiving drugs inward.

    Surgical dental intervention against the background of bisphosphonate therapy can enhance the manifestations of the osteonecrosis of the jaw.It is not known whether the elimination of bisphosphonates reduces the risk of osteonecrosis. The decision to conduct treatment should be taken for each patient individually after assessing the risk / benefit ratio.

    In patients receiving bisphosphonate therapy, including ibandronic acid, osteonecrosis of other maxillofacial regions, including the external auditory canal, was observed. Additional risk factors may include recurring minor injuries (eg, regular use of cotton buds). The risk factors for osteonecrosis coincided with those in osteonecrosis of the jaw. Patients receiving bisphosphonates and having hearing impairments, including chronic ear infections, should be monitored for osteonecrosis.

    Atypical Hip Fractures

    Atypical susceptible and diaphyseal fractures of the femur are marked against the background of bisphosphonate administration, primarily in patients receiving long-term treatment for osteoporosis. Transverse and short oblique fractures can be localized along the entire length of the femur from a small spit to an epicondylitis elevation.The occurrence of atypical fractures occurs spontaneously or as a result of minor injuries. In the weeks or months before the onset of a hip fracture, some patients experience pain in the thigh or in the groin, which is often accompanied by radiographic signs of a stress fracture. Due to the fact that atypical fractures are often bilateral, it is necessary to monitor the condition of another femur in patients with diaphyseal fracture of the femur. Poor healing of atypical fractures was noted.

    If a suspected atypical fracture is suspected and the results of the survey are obtained, consideration should be given to discontinuing bisphosphonate therapy, based on an assessment of the benefit / risk ratio in each case. Patients should be informed of the need to report any pain in the thigh or in the groin during therapy with bisphosphonates. If these symptoms are present, a check should be performed to identify incomplete hip fracture.

    Effect on the ability to drive transp. cf. and fur:

    Studies on the effect of taking Bonviva® on the ability to drive and other mechanisms have not been carried out.The drug causes undesirable phenomena that can affect the ability to drive vehicles, etc.

    Form release / dosage:

    Tablets, film-coated, 150 mg

    Packaging:

    1 or 3 tablets in a blister of PVC / PVDC film and aluminum foil.

    Blister, along with instructions for use, as well as information for the patient (with a reminder of the frequency and date of taking the drug, a self-adhesive sticker for the calendar, etc.) is placed in a cardboard box.

    Storage conditions:

    Store at a temperature of no higher than 30 ° C in a dry place.

    Keep out of the reach of children.

    Shelf life:

    5 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-001348
    Date of registration:20.07.2010 / 22.09.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp09.04.2017
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