Bondronat

General characteristics. Structure:

Active agent: ibandronovy acid of 50 mg (in the form of an ibandronat of sodium of monohydrate of 56.25 mg);

Excipients: lactoses monohydrate – 92.75 mg, K25 povidone – 5.0 mg, cellulose microcrystallic – 30.0 mg, кросповидон – 10.0 mg, stearic acid of 95 - 4.0 mg, silicon dioxide colloid (anhydrous) – 2.0 mg;

Cover: a gipromelloza, titanium dioxide (Е 171), talc – 8.5 mg; macrogoal of 6000 - 1.5 mg; use of the ready mix Opadry 00A28646 is allowed.

Pharmacological properties:

Pharmacodynamics. Inhibitor of a bone resorption, nitrogen-containing бисфосфонат. Has specific selection effect on a bone tissue thanks to high affinity to mineral components of a bone. Suppresses activity of osteoclasts, reduces the frequency of skeletal complications at malignant diseases.
Ibandronovy acid reduces an osteoclast - the associated release of growth factors of a tumor, slows down distribution and an invasion of cells of a tumor, shows synergy effect with in vitro taxons. Ibandronovy acid prevents the bone destruction caused by blockade of function of gonads, retinoids, tumoral processes or administration of extracts of tumoral in vivo fabric.
In the doses considerably exceeding pharmacological effective ibandronovy acid does not influence a mineralization of a bone tissue.
At a hypercalcemia the inhibiting effect of ibandronovy acid on the ossifluence induced by a tumor and, in particular, on the hypercalcemia accompanying tumoral process is followed by decrease in level of calcium in blood serum and excretion of calcium with urine. In most cases the content of calcium in blood is normalized within 4-7 days after administration of drug. Time median before repeated increase serumal calcium albumine-korregirovannogo to 3 mmol/l – 18-26 days.
Ibandronovy acid prevents development of new and reduces growth of already available bone metastasises that leads to decrease in frequency of skeletal complications, intensity of a pain syndrome, the need for performing radiation therapy and surgical interventions concerning metastatic process in bones, thereby leading to considerable improvement of quality of life of patients.
Ibandronovy acid дозозависимо inhibits tumoral ossifluence that is defined by means of markers of a bone resorption (a pyrrolidinolean and дезоксипиридинолин).

Pharmacokinetics. Absorption. After oral administration ibandronovy acid is quickly soaked up in upper parts of digestive tract. Time of achievement of the maximum concentration of TCmax of 0,5-2 h (a median - 1 h) after reception on an empty stomach, absolute bioavailability - 0.6%. The concomitant use of food or drinks (except clear water) reduces bioavailability of ibandronovy acid by 90%. The use of food or drinks in 30 min. after reception of ibandronovy acid reduces its bioavailability by 30%. At reception of ibandronovy acid in 60 min. prior to food of significant decrease in bioavailability it is not observed.
Concentration of ibandronovy acid in plasma increases in proportion to a dose entered intravenously (in a dose to 6 mg) or the drug accepted inside (in a dose to 100 mg).
Bioavailability of ibandronovy acid decreases to 75% at its reception in 2 hours after food in this connection the drug Bondronat® in the form of tablets is recommended to be accepted on an empty stomach with the subsequent meal not earlier than in 30 min.

Distribution. After hit in a system blood stream ibandronovy acid quickly communicates in a bone tissue or is removed with urine. The seeming final volume of distribution - 90 l; the amount of drug in a bone tissue, usually, reaches 40-50% of the dose circulating in blood. Communication with proteins of plasma at therapeutic concentration of drug - 87%. Thus, probability of emergence of intermedicinal interaction owing to replacement from communication with proteins rather low.

Metabolism. Animals have no data that ibandronovy acid is metabolized (both at people, and).

Removal. 40-50% of amount of the drug circulating in blood get into a bone tissue and collects in it, the remained drug is removed in not changed look by kidneys. Not soaked up drug after peroral introduction is removed in not changed view with a stake.
The size of the observed seeming final elimination half-life varies in wide limits (10-60 h) and depends on a dose of drug and sensitivity of the analysis. Concentration of drug in blood decreases quickly and reaches 10% from maximum in 3 h later in/in introductions and 8 h after intake.
After 12 months of oral administration by patients with osteoporosis no more than double cumulation of drug in plasma was observed. At in purpose of ibandronovy acid with an interval of 4 weeks within 48 weeks at patients with metastatic damage of bones of system cumulation it is noted.
The general clearance of ibandronovy acid low with average values of 84-160 ml/min. The renal clearance (healthy women have 60 ml/min. in a menopause) causes 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 and bioavailability of ibandronovy acid does not depend on a floor. Also clinically significant interracial distinctions of distribution of ibandronovy acid at persons of Caucasian and Mongoloid race are not revealed. Rather negroid race of data is not enough.
Patients with a renal failure
Exposure of ibandronovy acid at patients with various renal failures depends on the clearance of creatinine (CC).
At patients with a heavy renal failure (KK <30 ml/min.) at administration of drug inside in a dose of 10 mg daily within 21 days, concentration of ibandronovy acid in a blood plasma was noted 2-3 times above, than at patients with normal function of kidneys (KK> of 80 ml/min.). Also at patients with a heavy renal failure decrease in the general clearance to 44 ml/min. in comparison with patients with normal function of kidneys and the general clearance of 129 ml/min. was observed. For patients with a renal failure of easy severity (KK> 50 and <80 ml/min.) dose adjustment at oral administration is not required. For patients with a renal failure of moderate severity (KK> 30 and <50 ml/min.) or with a heavy renal failure (KK <30 ml/min.) is necessary drug dose adjustment.
37% of ibandronovy acid are removed from an organism during the standard 4-hour procedure of a hemodialysis.
Patients with an abnormal liver function
Patients with an abnormal liver function have no data on pharmacokinetics of ibandronovy acid. The liver does not play an essential role in clearance of ibandronovy acid which is not metabolized, and is removed through kidneys or communicates in a bone tissue. With an abnormal liver function of dose adjustment it is not required from patients. Besides, in therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma (85%) therefore probably that the hypoproteinemia at a serious illness of a liver does not lead to clinically significant increase in concentration of ibandronovy acid 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.
Children
Data on use of the drug Bondronat® for persons under 18 are absent.

Indications to use:

Metastatic damage of bones for the purpose of decrease in risk of emergence of a hypercalcemia, pathological changes, reduction of pain, decrease in need for performing radiation therapy at a pain syndrome and threat of changes.
Hypercalcemia at malignant new growths.

Route of administration and doses:

Бондронат® in the form of a concentrate to preparation of solution for infusions it is usually applied in the conditions of a hospital.
Standard mode of dosing
Inside on 50 mg once in days, daily.
It is necessary to take a pill inside not less than in 30 min. prior to meal, the first this day, or liquids (except clear water) 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. It is impossible to lay down within 60 min. after administration of drug of Bondronat®. To swallow tablets entirely, it is impossible to chew or rassasyvat because of possible formation of oropharyngeal ulcerations. Tablets should be washed down only with ordinary clear water. It is impossible to use mineral water with high content of calcium.
Dosing at special groups of patients
Bed rest
Drug researches for oral administration with the assistance of the patients incapable is in a standing position or sitting within 60 minutes, were not carried out.
Abnormal liver function
Dose adjustment is not required.
Renal failure
At a weak renal failure (clearance of creatinine> 50 and <80 ml/min.) dose adjustment is not required.
At moderately expressed renal failure (clearance of creatinine> 30 and <50 ml/min.) 1 time in two days is recommended to reduce a drug dose to 1 tablet.
At a heavy renal failure (clearance of creatinine <30 ml/min.) it is necessary to reduce a drug dose to 1 tablet, once a week.
Advanced age
Dose adjustment is not required.
Children
Safety and efficiency at persons under 18 is not established.

Features of use:

Бондронат® it is not necessary to apply at children due to the lack of clinical experience.
Prior to therapy by the drug Bondronat® it is necessary to correct 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.
Development of a hypocalcemia is possible. In that case patients should carry out the corresponding correction of level of calcium in serum.
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 Bondronat® 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 are described: an esophagitis, ulcers or erosion of a gullet which are occasionally followed by bleeding or development further of strictures or perforation of a gullet. 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.
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 Bondronat® 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 NPVS (non-steroidal anti-inflammatory drugs) is associated with irritation of digestive tract, it is necessary to be careful at simultaneous use of NPVS with oral administration of the drug Bondronat®.
In clinical placebos controlled randomized researches with the assistance of patients with metastatic damage of bones at a breast cancer data on a renal failure at long administration of drug of Bondronat® are absent. Despite it, in compliance with clinical assessment of each patient, it is necessary to control function of kidneys, content of serumal calcium, phosphorus and magnesium during treatment.
It is necessary to avoid an overhydratation at patients with risk of development of heart failure.
At purpose of bisfosfonat cases of development of an osteonecrosis of a jaw were seldom 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 of cancer, the accompanying therapy (chemotherapy, radiation therapy, corticosteroids) and other disturbances (anemia, a coagulopathy, an infection, diseases of teeth). The majority of 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 reduces risk of emergence of an osteonecrosis cancellation of bisfosfonat at patients in need of holding dental procedures. The decision on performing treatment needs to be made for each patient individually after ratio assessment risk/advantage.

Influence on ability to driving of vehicles and work with cars and mechanisms
Researches on studying of influence of the drug Bondronat® on ability to driving of vehicles or work with cars and mechanisms were not conducted.

Side effects:

For assessment of frequency of undesirable effects the following categories of frequency are used: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); seldom (> 0.01%, <0.1%); very seldom (<0.01% including separate cases).
At oral administration of the drug Bondronat® in a dose of 50 mg daily for the purpose of treatment of metastatic damage of bones, the following undesirable reactions were observed:
from the alimentary system: often – dyspepsia;
from a metabolism: often – a hypocalcemia.
Post-marketing observation
Disturbances from a musculoskeletal system and connecting fabric: very seldom at purpose of ibandronovy acid the jaw osteonecrosis was noted.
Disturbances from organs of sight: 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.

Interaction with other medicines:

Existence of clinically significant medicinal interactions is improbable. Ibandronovy acid is removed only through kidneys and is not exposed to biotransformation. The way of removal of ibandronovy acid does not include any transport systems participating in removal of other drugs. Ibandronovy acid does not inhibit and does not induce (it is shown in researches on rats) activity of the main isoenzymes of system of P450 cytochrome. In therapeutic concentration ibandronovy acid poorly contacts proteins of a blood plasma therefore the possibility of the medicinal interaction caused by replacement of drugs from binding sites with proteins is small.
Products, calciferous and other polyvalent cations (for example, aluminum, magnesium, iron), including milk and firm food, can break drug absorption, they should be used not earlier than in 30 min. after oral administration of the drug Bondronat®.
Signs of intermedicinal interaction at co-administration with Melphalanum/Prednisolonum at patients with a multiple myeloma were not revealed.
In clinical trials purpose of the drug Bondronat® was followed by a concomitant use of various antineoplastic drugs, diuretics, antibiotics and analgetic means without signs of clinically significant interaction.
At in introduction at healthy volunteers and patients in a postmenopause ranitidine increased bioavailability of ibandronovy acid by 20% (however, this value is in limits of normal values of bioavailability of ibandronovy acid) that is possibly caused by decrease in acidity of a gastric juice. Dose adjustment of drug at simultaneous use with the blockers of H2-histamine receptors or other drugs increasing рН a stomach is not required. Interaction between the drug Bondronat® and Tamoxifenum, replaceable hormonal therapy (therapy by estrogen drugs) at patients in a postmenopause, no.

Contraindications:

Hypersensitivity to ibandronovy acid or other components of drug.
Hypocalcemia.
Children's age (lack of clinical experience).
Pregnancy and period of feeding by a breast.

With care
Hypersensitivity to other bisfosfonata.
Clearance of creatinine less than 50 ml/min.
At intake - in a combination with non-steroidal anti-inflammatory drugs (NPVP).

Pregnancy and period of feeding by a breast
Pregnancy
It is not necessary to apply Bondronat® during pregnancy. During preclinical trials fertility disturbance, and also reduction of quantity of embryos (places of implantation), disturbance of normal process of childbirth was revealed (dystocia). Fetotoksichesky or teratogenic action is not revealed. Increase in frequency of visceral anomalies (a syndrome of narrowing of a lokhanochno-ureteric segment) is revealed.
There is no experience of use of the drug Bondronat® for pregnant women.
Feeding period breast
It is unknown whether Bondronat® with breast milk at women is removed.
In researches on rats existence of a small amount of ibandronovy acid in milk after intravenous administration of drug is revealed.
It is not necessary to apply Bondronat® during feeding by a breast.

Overdose:

Now, there are no messages on acute overdose of the drug Bondronat® at oral administration or intravenous administration.
Specific information on treatment in case of overdose of drug is absent. However, at overdose of the drug accepted inside development of the undesirable phenomena, such as is possible: gastric disturbance, heartburn, esophagitis, gastritis or ulcer.
For binding of the drug accepted inside it is necessary to use milk or antacids. Because of risk of irritation of a gullet it is impossible to cause vomiting and it is necessary to remain in the straightened standing position.
Holding standard procedures of a hemodialysis leads to considerable decrease in concentration of ibandronovy acid in a blood plasma.

Storage conditions:

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, 50 mg
On 7 tablets in the blister from a film of three-layered (OPA/Al/PVC) and aluminum foil.
4 blisters together with the application instruction place in a cardboard pack.