Belklasta

General characteristics. Structure:

Active ingredient: 5 mg of zoledronovy acid (in the form of zoledronovy acid of monohydrate).

Excipients: mannitol, sodium citrate 5,5-water.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Zoledronovy acid belongs to a class of nitrogen-containing bisfosfonat and affects first of all a bone. It is inhibitor of the resorption of a bone tissue mediated by osteoclasts.

The selection action of bisfosfonat is based on high affinity to the mineralized bone tissue. Zoledronovy acid which is applied intravenously is quickly distributed in a bone tissue and, like other bisfosfonata, is localized preferential in places of intensive exchange in bones. The main molecular target of zoledronovy acid in an osteoclast is enzyme of a farnezilpirofosfatsintaz; at the same time the possibility of other mechanisms of effect of medicine is not excluded. The long period of effect of zoledronovy acid is predetermined by its high affinity to linkng with an active center of a farnezilpirofosfatsintaza and with the mineralized bone tissue.

Pharmakodinamichesky effects. Osteoporosis. Against the background of use of zoledronovy acid bystry decrease in indicators of bone exchange from the increased post-menopausal values to minimum tolerance level is observed (by 7th day for indicators of a bone resorption and by 12th week for indicators of bone formation). After that indicators of bone exchange were established in limits пременопаузальньгх values. The progressing decrease in level of markers of metabolism in a bone tissue at introduction of repeated annual doses was not observed.

Clinical performance of treatment of post-menopausal osteoporosis. Efficiency and safety of use of zoledronovy acid was studied in the research HORIZON-PFT; the drug was administered within three years in a dose of 5 mg in 100 ml of solution within not less than 15 minutes once a year, thus, each patient received three doses of drug. Two main indicators of efficiency were: frequency of cases of fractures of the vertebras for 3 years confirmed with data of a morphometry and frequency of cases of fractures of femur for 3 years. Frequency of cases of fractures of vertebras authentically decreased at use of zoledronovy acid within three years, since first year of treatment.

Reduction of frequency of fractures of vertebras within three years was stable and did not depend on age, the geographical region, race, a reference value of an index of body weight, quantity of initial fractures of vertebras, T-point of mineral density of a bone tissue (MPK) of a neck of a hip or the previous use of bisfosfonat.

Influence on the frequency of developing of a fracture of hip: at reception of zoledronovy acid decrease in risk of developing of a fracture of bones of a hip joint by 40% within 3 years is observed.

Influence on the frequency of developing of all clinical fractures: at reception of zoledronovy acid absolute decrease in frequency of developing of all clinical fractures by 4,5%, clinical fractures of vertebras for 2% and not vertebral changes for 2,8% was observed.

Influence on the mineral density of a bone tissue: zoledronovy acid raises MPK of lumbar department of a backbone for 6,9%, a femur - for 6,0%, hip necks - for 5,0% and distal department of a beam bone - for 3,2% within 3 years.

Histology of a bone tissue: when carrying out a dynamic gistomorfometriya at patients with post-menopausal osteoporosis a normality of a bone tissue without signs of disturbance of remodeling and disturbance of a mineralization was observed. The research conducted with use of a microcomputer tomography showed preservation of architecture of a trabecular bone at patients of group of treatment by zoledronovy acid in comparison with group of placebo.

Markers of metabolism of a bone tissue: during the research in blood serum the alkaline phosphatase (AP), specific to a bone tissue, and N-terminal pro-peptide of collagen like I (TPK) beta-S-telopeptida were periodically estimated. Treatment by zoledronovy acid in annual doses of 5 mg reduced the level of markers of metabolism of a bone to the range of values which were observed to a menopause. Repeated administration of drug did not lead to the subsequent decrease in level of markers of metabolism of a bone tissue.

Influence on growth. During the three-year research of osteoporosis annually measured growth (in a standing position). At patients who received zoledronovy acid decrease in rates of loss of growth in comparison with group of placebo (4,2 mm in comparison with 6,7 mm, respectively was observed (р <0,0001).

Number of days of disability. Zoledronovy acid authentically reduced both the number of days with limited activity, and the number of days of the bed mode because of a dorsodynia and changes in comparison with placebo (in all cases р <0,01).

Clinical performance of prevention of clinical changes after a hip fracture. Efficiency and safety of use of zoledronovy acid for the prevention of developing of clinical fractures at patients with a low-traumatic fracture of a neck of a hip is confirmed in the research HORIZON-RFT. Frequency of developing of clinical fractures, including vertebral, not vertebral fractures and fractures of a hip, was estimated at 2127 patients with recent (within 90 days) a low-traumatic fracture of a femur within 2 years. All participants of a research received from 1000 to 1500 mg of elementary calcium and from 800 to 1200 ME of vitamin D a day. The quantity of clinical changes during time of carrying out a research was the main indicator of efficiency.

Influence on all clinical changes: reduction of frequency of developing of any clinical fractures by 35% was observed. Reduction of frequency of developing of clinical spinal fractures - for 46%, not vertebral changes - for 27%, fractures of bones of a hip joint - for 30%.

Influence on the mineral density of bones: in the research HORIZON-RFT at treatment zoledronovy acid observed increase in MPK in all bones of a hip joint for 5,4% and for 4,3% - in a hip neck within 24 months.

Treatment of osteoporosis at men. Efficiency and safety of use of zoledronovy acid for men with osteoporosis was estimated in a biennial research on changes (in percentage expression) by MPK of lumbar department of a backbone.

Influence on the mineral density of bones: the effect according to percentage change of MPK in lumbar vertebrae on the 24th month (compared with reference values) at administration of zoledronovy acid was not less once a year, than in case of weekly reception of an alendronat (zoledronovy acid of 6,1% in comparison with alendronaty 6,2%). Percentage increase in MPK in vertebrae of lumbar department of a backbone on the 12th month was also analogous in groups of the patients receiving these drugs.

Treatment and prevention a glucocorticoid - the induced osteoporosis. Efficiency and safety of zoledronovy acid in treatment and prevention a glucocorticoid - the induced osteoporosis was estimated in the annual research with participation of the patients receiving Prednisolonum in a dose of ≥7,5 mg/days orally (or equivalent drug).

Influence on the mineral density of bones: increase in MPK of lumbar department of a backbone, neck of a hip, femur in general, acetabular hollows and distal department of a beam bone was observed (in all cases р <0,03).

Histology of a bone tissue: qualitative and quantification showed normal architecture and quality of a bone tissue, without disturbances of a mineralization.

Pedzhet's disease. Clinical performance of treatment of a disease of Pedzhet. Efficiency of zoledronovy acid was estimated in two six-months comparative researches. In both researches zoledronovy acid showed advantage and more bystry therapeutic effect in comparison with rizedronaty what biochemical markers of formation of a bone tissue testified to: FKT, N-terminal pro-peptide of collagen like I (TPK) in blood serum and resorption markers (STh 1 in blood and alpha STH in urine). Practically at all patients of group zoledronovy acid the therapeutic effect remained within 18 months. Histologic researches of a bone tissue showed that the bone tissue has normal quality without signs of disturbance of bone remodeling and without signs of disturbance of a mineralization.

Research of safety of influence on a bone tissue: the dose reaction and duration of action of single intravenous administration of zoledronovy acid (from 0,8 to 500 mg/kg) were investigated at animals. The received results showed efficiency and safety of zoledronovy acid for a bone tissue at its introduction in clinically acceptable doses. Signs of any aberrations in tissue of bones or marrow, signs of disturbance of a mineralization, accumulation of osteoids and a webby retikulofibrozny bone tissue were not observed.

Pharmacokinetics. As a result of performing single and repeated 5-and 15-minute infusions to 64 patients in doses of 2, 4, 8 and 16 mg of zoledronovy acid the following pharmacokinetic data which are not depending on a dose were obtained below.

After the beginning of infusions of zoledronovy acid plasma concentration of active agent quickly increased, reaching peak at the end of infusions, then quickly decreased to <10% of peak in 4 hours and to <1% of peak - in 24 hours, with the further long period of very low concentration which do not exceed 0,1% of peak levels.

The Zoledronovy acid entered intravenously is emitted with kidneys in three stages: bystry two-phase removal of drug from system circulation with elimination half-lives of t1/2α 0,24 and t1/2β 1,87 hours, then a long phase of elimination with a final elimination half-life of t1/2γ 146 hours. Accumulation of active agent in plasma after repeated doses which are entered each 28 days was not observed. On early phases of dispositions (an alpha and a beta, with t1/2γ value above) perhaps bystry distribution in bones and removal through kidneys. Zoledronovy acid is not metabolized and emitted in not changed look with kidneys. Within the first 24 hours 39 ± 16% of the entered dose are removed with urine whereas the drug rest generally contacts a bone tissue. Afterwards there is a slow return release of zoledronovy acid from a bone tissue in system circulation and its allocation by kidneys. The general clearance of drug makes 5,04 ± 2,5 l/hour. It does not depend on a dose, a sex, age, race and body weight of the patient. Increase in duration of infusion from 5 to 15 minutes leads to decrease in concentration of zoledronovy acid at the end of infusion, but does not influence the square under a pharmacokinetic curve.

As zoledronovy acid is not metabolized in a human body and the found substance has only insignificant activity as directly operating and/or irreversible inhibitor of enzymes of P450 cytochrome, or has no at all, zoledronovy acid will hardly reduce metabolic clearance of substance which is metabolized by system of enzymes of P450 cytochrome. Zoledronovy acid has no high extent of linkng with proteins of plasma (binding makes about 43 - 55%), and this binding does not depend on concentration.

Separate populations. The renal clearance of zoledronovy acid correlated with clearance of creatinine, and made 75 ± 33% of clearance of creatinine which average value 84 ± 29 ml/min. (range from 22 to 143 ml/min.) at 64 studied patients. Insignificant increase in AUC0-24 approximately by 30 - 40% at easy and moderate renal failures, in comparison with norm, and lack of cumulation of drug at repeated introduction irrespective of function of kidneys, demonstrate that in regulation of a dose of zoledronovy acid at a renal failure easy (ClCr = 50 - 80 ml/min.) and moderated (ClCr = 30-50 ml/min.) does not have degree need. Use of zoledronovy acid is contraindicated to patients with heavy renal failures (clearance of creatinine <35 ml/min.) in connection with the increased risk of development of a renal failure in this population. There is no need for dose adjustment for patients with clearance of creatinine> 35 ml/min.

Indications to use:

Treatment of osteoporosis:

· in the post-menopausal period at women

· at men with the increased risk of changes, including with a recent fracture of a hip.

Treatment of the osteoporosis connected with long-term therapy by system glucocorticoids:

· in the post-menopausal period at women

· at men with the increased risk of changes.

Treatment of a disease of Pedzhet at adults.

Route of administration and doses:

Posology. For treatment of postclimacteric osteoporosis, osteoporosis at men and treatment of the osteoporosis connected with long-term system glucocorticoid therapy the recommended drug dose ~ single intravenous infusion of 5 mg of Belklast which is entered once a year.

The optimum duration of treatment of osteoporosis bisfosfonaty is not established.

Need of continuation of treatment should be reconsidered periodically on the basis of benefits and potential risks of use of Belklast based on individual approach to the patient, especially after 5 or more years of use.

Patients with a recent change have hips, it is recommended to appoint Belklast's infusions during the period of two and more weeks after healing of a fracture of hip.

For treatment of a disease of Pedzhet Belklast it has to be appointed only the doctor having experience in treatment of a disease of Pedzhet. The recommended dose - single intravenous infusion of 5 mg of Belklast.

Repeated treatment of a disease of Pedzhet: after primary treatment from Belklast at Pedzhet's disease, the long period of remission is observed at most of patients. Repeated treatment consists of additional intravenous administration of 5 mg of Belklast at an interval of one year and more from initial treatment of patients which had a recurrence.

There are limited data on repeated treatment of a disease of Pedzhet. Patients have to be appropriately hydrated before Belklast's introduction. It is especially important for elderly people and for the patients receiving therapy by diuretics. Enough calcium and vitamin D are recommended in connection with the subsequent introduction of Belklast. Besides, at patients with Pedzhet's disease, obtaining adequate additional amount of the calcium corresponding to at least 500 mg of elementary calcium twice a day and lasting at least 10 days after Belklast's introduction is strongly recommended.

Patients with a recent change have hips, the load dose from 50000 to 125000 ME of vitamin D is orally or intramusculary recommended before the first infusion of Belklast.

The symptoms connected with Belklast's introduction occur during the first three days after introduction which extent of manifestation can be reduced by reception of paracetamol or an ibuprofen soon after administration of zoledronovy acid.

Patients with a renal failure. Belklasta is contraindicated to patients with clearance of creatinine <35 ml/min. Dose adjustment is not required from patients with clearance of creatinine ≥ 35 ml/min.

Patients with an abnormal liver function. Dose adjustment is not required.

Patients of advanced age (≥ 65 years). Dose adjustment is not required as bioavailability, distribution and elimination are similar at patients of advanced age and at young people.

Children. Safety and Belklast's efficiency at children and teenagers up to 18 years is not established.

Route of administration. For intravenous use. Time of infusion should not be less than 15 minutes.

Rules of preparation and use of solution. Solution should be prepared in aseptic conditions. To dissolve contents of a bottle in 5 ml of water for injections then to dissolve in 100 ml 0,9% of solution of sodium of chloride or 5% of solution of glucose. It is impossible to apply the solutions containing calcium ions. It is desirable to use the prepared solution of zoledronovy acid directly after preparation.

Solution unused at once can be stored in the refrigerator at a temperature from 2 to 8 °C no more than 24 watch. Before introduction solution from the refrigerator should be sustained indoors before achievement of room temperature by it. Solution of zoledronovy acid should not be mixed with any other medicines.

Features of use:

Use during pregnancy or feeding by a breast. The uses of zoledronovy acid given relatively for treatment of pregnant women are absent. Researches on animals showed toxic influence of drug on reproductive function. The potential risk for the person is not known. Zoledronovy acid is contraindicated during the periods of pregnancy and feeding by a breast.

Children. It is not recommended to children to appoint Zoledronovy acid aged up to 18 years as there are not enough data on safety and efficiency of use of drug in this age group.

Use of zoledronovy acid is contraindicated to patients with heavy renal failures (clearance of creatinine <35 ml/min.), in connection with the increased risk of development of a renal failure in this population. At use of zoledronovy acid cases of a renal failure were observed or there were other risk factors, including advanced age, the accompanying reception of nephrotoxic drugs, the accompanying therapy by diuretics or dehydration. At patients the renal failure was observed after single use of drug. In rare instances at patients with other diseases of kidneys or with any of the listed above risk factors, the renal failure which is demanding carrying out dialysis, or entailed a lethal outcome was observed.

For minimization of risk of development of undesirable reactions from kidneys it is necessary to observe the following precautionary measures:

· control of clearance of creatinine has to be carried out before each administration of zoledronovy acid; intermediate monitoring of clearance of creatinine is recommended for patients with risk of development of renal failures. The clearance of creatinine has to be calculated taking into account the patient's weight by Kokrofta-Gault's formula.

· at the accompanying use of other medicines capable to influence function of kidneys, to apply zoledronovy acid with care.

· before use of zoledronovy acid for patients, especially elderly and receiving therapy by diuretic drugs, it is necessary to provide sufficient extent of hydration.

· the single dose of zoledronovy acid should not exceed 5 mg, and duration of infusion has to make not less than 15 minutes.

Infusion of zoledronovy acid is carried out on condition of adequate hydration of the patient. It is especially important for patients of advanced age and receiving therapy by diuretics. In the presence of a hypocalcemia before use of zoledronovy acid it is necessary to carry out treatment by adequate doses of calcium and vitamin D. It is also necessary to carry out therapy of other available disturbances of mineral exchange (for example, epithelial body reduction, disturbance of absorption of calcium in intestines). The doctor has to control a condition of these patients carefully.

It was reported about the single heavy and resulting in temporary disability ostealgias, joints and muscles at patients who applied bisfosfonata, including zoledronovy acid.

Belklast's drug, productions of RUP of Belmedpreparata, contains the same active agent (zoledronovy acid), as drug of Zoledronovaya acid of 4 mg, productions of RUP of Belmedpreparata which is applied to treatment of oncological diseases therefore the patients using drug of Zoledronovaya acid of 4 mg should not accept Belklast's drug.

Jaw osteonecrosis. About an osteonecrosis of a jaw it was reported, mainly, at patients with oncological diseases which received medical treatment for bisfosfonata, including zoledronovy acid. Many of these patients applied chemotherapy and corticosteroids. The majority of the known cases were associated with dental procedures, for example, an odontectomy. At many of these patients symptoms of a local infection, including osteomyelitis were noted. Therefore, before therapy of a bisfosfonatama at patients with concurrent factors of risk (cancer, chemotherapy, corticosteroids, non-compliance with hygiene of an oral cavity) it is necessary to consider expediency of dental inspection and appropriate dental prevention. During treatment to these patients if it is possible, it is necessary to avoid invasive dental procedures. At patients with developed a jaw osteonecrosis during therapy of a bisfosfonatama dental surgery can worsen a current of an osteonecrosis. Data on decrease in risk of an osteonecrosis of a jaw at cancellation of therapy of a bisfosfonatama at patients who need dental procedures, no. Clinical assessment of the attending physician has to be taken as a basis of treatment planning of the patient, taking into account individual assessment of advantage/risk.

Treatment of post-menopausal osteoporosis, osteoporosis at men and treatment and prevention a glucocorticoid - the induced osteoporosis

Additional purpose of drugs of calcium and vitamin D at insufficient receiving these substances with food is recommended to patients with osteoporosis.

Prevention of repeated changes after hip fractures. Additional purpose of calcium and vitamin D is recommended.

Atypical fracture of a hip. At therapy of a bisfosfonatama it was reported about cases of developing of atypical subtrochanterian fractures and changes of a diaphysis of a femur which were observed, mainly, among the patients receiving long therapy at osteoporosis. These cross or short slanting changes can arise in any site of a femur, since a point directly below a trochantin and finishing with a point directly above nadmyshechny expansion. These changes can result from the minimum traumatic influence or even without it, and some patients for several weeks or months before development of a complete fracture of a femur can have a feeling of pain in the field of a hip joint or in inguinal area. Changes usually are bilateral therefore at the patients receiving therapy of a bisfosfonatama and which had a femur fracture it is also necessary to conduct examination and an opposite femur. Also it was reported that such changes badly grow together. At patients with suspicion of an atypical fracture of a femur, being guided by individual assessment of risk and advantage, it is necessary to consider the possibility of the termination of therapy of a bisfosfonatama, the sufficient specifying inspection of this patient will not be executed yet. The causal relationship was not proved as such changes also arise at the patients having osteoporosis and not receiving therapy of a bisfosfonatama.

During treatment of a bisfosfonatama, including zoledronovy acid, patients should be informed on need to tell the doctor in case of pain in the field of a hip joint, a hip and a groin. At the same time each patient who has such symptoms needs to be inspected regarding possible developing of a fracture of femur.

Treatment of a disease of Pedzhet. The raised resorption of bones - a characteristic symptom of a disease of Pedzhet. As a result of bystry manifestation of influence of zoledronovy acid on a resorption of bones the tranzitorny hypocalcemia, sometimes - symptomatic which is usually maximum in the first 10 days after infusion of zoledronovy acid can develop. Therefore at use of zoledronovy acid adequate reception of vitamin D is recommended. Besides, for patients with Pedzhet's disease, within at least 10 days later began uses of zoledronovy acid, adequate use of drugs of calcium - not less than 500 mg of elementary calcium twice a day is strongly recommended.

Patients should be informed on hypocalcemia symptoms. For patients of risk group clinical monitoring has to be provided.

Ability to influence speed of response at control of motor transport or work with other mechanisms

This, testimonial that zoledronovy acid influences ability to manage motor transport or to use mechanisms, no.

Side effects:

About side effects it was reported from different researches of the clinical program.

Side effects which were observed in a research of treatment of post-menopausal osteoporosis: fervescence (18,1%), a mialgiya (9,4%), grippopodobny symptoms (7,8%), an arthralgia (6,8%) and a headache (6,5%), the majority of which arose within the first 3 days after administration of zoledronovy acid. Expressiveness of the majority of these symptoms was from soft to moderate degree, they disappeared within 3 days. Frequency of emergence of these symptoms significantly decreased at the following administration of zoledronovy acid.

Weight of the symptoms stated above can be reduced approximately by 50% by purpose of such means as paracetamol or an ibuprofen directly after administration of drug.

Side reactions which are connected with administration of drug are listed below and were observed at use of drug for: treatments of osteoporosis at men and women of the postclimacteric period, prevention of clinical changes after a low-traumatic fracture of a femur, treatment and the prevention a glucocorticoid - the induced osteoporosis and Pedzhet's disease; side reactions are systematized according to classes of systems of bodies and frequencies of manifestation, with use of the following symbols: very often (> 1/10), it is frequent (> 1/100, <1/10), infrequently (> 1/1 000, <1/100), is rare (> 1/10 000, <1/1 000).

Infections and invasions: infrequently - grippopodobny symptoms, a nasopharyngitis.

From system of blood and lymphatic system: infrequently - anemia.

Disturbance of metabolism and food: often - anorexia, a loss of appetite.

From TsNS: often - a headache, dizziness; infrequently - a lethargy, paresthesia, drowsiness, a tremor, a syncope (syncope).

From organs of sight: infrequently - conjunctivitis, eye pain; seldom - a uveitis, an episcleritis, an inflammation of an iris of the eye.

From acoustic organs and a labyrinth: infrequently - вертиго.

From vascular system: infrequently - hypertensia, rushes of blood to the person.

From a respiratory path, bodies of a thorax and a mediastinum: infrequently - cough, short wind.

From a GIT: often - nausea, vomiting, diarrhea; infrequently - dyspepsia, an abdominal pain, a gastroesophagal reflux, pain in upper parts of a stomach, a lock, dryness in a mouth, an esophagitis.

From skin and hypodermic fabric: infrequently - rash, a hyperhidrosis, an itch, an erythema.

From skeletal and muscular system and connecting fabric: often - a mialgiya, an arthralgia, an ostealgia, a dorsodynia, extremity pain; infrequently - neck pain, bone muscular constraint, puffiness of joints, spasms of muscles, shoulder pain, a musculoskeletal stethalgia, musculoskeletal pain, constraint of joints, arthritis, muscular weakness.

From urinogenital system: infrequently - a pollakiuria, a proteinuria.

Laboratory indicators: infrequently - increase in level of creatinine in blood.

The general disturbances and disturbances connected with way of introduction: very often - fever; often - grippopodobny symptoms, a fever, fatigue, an adynamy, pain, an indisposition; infrequently - peripheral hypostasis, thirst, ostrofazovy reaction, a stethalgia of not cordial origin.

During the separate researches the following side reactions which development frequency in group of zoledronovy acid was lower, than at the patients who are not receiving drug were registered: a hyperemia of eyes, increase in level of S-reactive protein, a hypocalcemia, a dysgeusia, a dentagra, gastritis, a heart consciousness, reaction in an injection site.

During the 3-year research of osteoporosis at women in the postclimacteric period the general frequency of side reaction of fibrillation of auricles made 2,5% (96 of 3862 patients) in group zoledronovy acid in comparison with 1,9% (75 of 3 852 patients) in group of placebo; frequency of serious side reaction of fibrillation of auricles made 1,3% (51 of 3 862) at patients who received zoledronovy acid in comparison with 0,6% (22 of 3 852) at patients who received placebo. The mechanism which caused increase in frequency of fibrillation of auricles is not known.

Renal failure. At intravenous administration of bisfosfonat, including zoledronovy acid, cases of a renal failure were observed (for example, increase in level of creatinine of blood serum) and it is rare - an acute renal failure. The renal failure was observed against the background of use of zoledronovy acid, especially at patients with pathology of kidneys in the anamnesis or accessory factors of risk (for example, oncological patients with chemotherapy, a concomitant use of nephrotoxic drugs, heavy dehydration); most of such patients received drug in a dose of 4 mg each 3-4 weeks, but in certain cases the renal failure was observed after single use of drug.

In the research HORIZON-PFT of change of clearance of creatinine (define annually before administration of drug) and the frequency of development of a renal failure or disturbance of renal function are comparable in groups zoledronovy acid and placebo within 3 years. Temporary increase in level of creatinine of blood serum within 10 days at 1,8% of patients which appointed zoledronovy acid, in comparison with 0,8% of patients of group of placebo was observed.

In researches which were conducted for the purpose of justification of purpose of drug for the prevention of clinical changes after a hip neck fracture (bones of a hip joint) at men and women of treatment of osteoporosis at men, treatment and the prevention a glucocorticoid - the induced osteoporosis, changes of clearance of creatinine were comparable in groups zoledronovy acid and placebo or drug of comparison.

Datas of laboratory. In the research HORIZON-PFT approximately at 0,2% of patients noticeable decrease in level of calcium in blood serum (less than 1,87 mmol/l) after use of zoledronovy acid was observed. Symptomatic cases of a hypocalcemia were not observed.

In the research HORIZON-RPT at treatment of osteoporosis men and prevention a glucocorticoid - the induced osteoporosis at one of patients calcium level in blood serum had no lower than 1,87 mmol/l.

During the research at patients with a disease Pedzheta approximately in 1% of cases was observed a symptomatic hypocalcemia (all cases ended with normalization of level of calcium in blood).

Local reactions. During the research HORIZON-PFT it was reported about local reactions in the place of infusion (0,7%): reddening, puffiness and/or morbidity in an injection site. In the same research the frequency of development of local reactions was similar for groups of zoledronovy acid and placebo.

At treatment of osteoporosis at men the frequency of development of local reactions made 2,6% in group of zoledronovy acid and 1,4% in group of an alendronat. At treatment and prevention a glucocorticoid - the induced osteoporosis was not reported about development of local reactions.

Jaw osteonecrosis. Cases of development of an osteonecrosis (most often jaws) were preferential observed at oncological patients who accepted bisfosfonata, including zoledronovy acid. Many of these patients had symptoms of local infections, including osteomyelitis, and the majority of messages concerned patients with oncological diseases at which the osteonecrosis developed after an odontectomy or other dental operations.

The osteonecrosis of a jaw has a lot of the confirmed risk factors, including the diagnosis of cancer, the accompanying treatment (for example, chemotherapy, radiation therapy, use of corticosteroids). Though the causal relationship is not established, it is recommended to avoid carrying out dental interventions as process of recovery can be long.

In the research HORIZON-PFT among 7 736 patients only 1 case of development of an osteonecrosis of a jaw in the patient to which entered zoledronovy acid was observed, and the patient who accepted placebo has 1 case. All cases ended with normalization of a state, In the same research at treatment of men with osteoporosis and at treatment and prevention a glucocorticoid - the induced osteoporosis was not reported about cases of development of an osteonecrosis of a jaw.

Post-marketing experience. In the post-marketing period there were messages on hypersensitivity reactions: seldom - a bronchospasm, a small tortoiseshell and a Quincke's disease; very seldom - anaphylactic reaction / shock.

In rare instances at use of zoledronovy acid in clinical practice at patients renal failures, including the renal failure demanding carrying out dialysis or cases of a lethal outcome, especially among patients with existence of renal pathology in the anamnesis, or accessory factors of risk (advanced age, the accompanying therapy by nephrotoxic drugs or diuretics were noted, at heavy dehydration).

Seldom or never it was also reported about the following phenomena: dehydration against the background of such symptoms arising owing to administration of drug as fever, vomiting and diarrhea; hypertensia at patients with conditioning factors of risk; mandible osteonecrosis; sclerite and inflammation of an eye-socket.

Interaction with other medicines:

Special researches of interaction of medicines with zoledronovy acid were not conducted. Zoledronovy acid is not exposed to system metabolism and does not influence enzymes of P450 cytochrome of the person of in vitro.

Zoledronovy acid contacts proteins of plasma in insignificant quantity (binding makes about 43-55%) therefore the interactions resulting from substitution of drugs with high extent of binding are improbable.

Zoledronovy acid is removed from an organism by renal excretion.

It is necessary to be careful at use of zoledronovy acid in combination with drugs which can influence substantially function of kidneys (for example, with aminoglycosides or diuretics which can cause dehydration). At patients with a renal failure system exposure of the accompanying medicines which are removed from an organism mainly by kidneys can increase.

Incompatibility. Solution of zoledronovy acid for infusion cannot be mixed with solutions which contain calcium ions and other bivalent cations.

Contraindications:

· hypersensitivity to active agent or to any component of drug;

· hypocalcemia; pregnancy and period of feeding by a breast;

· heavy renal failures (clearance of creatinine less than 35 ml/min.).

Overdose:

About cases of overdose it was not reported. In case of overdose which leads to clinically significant hypocalcemia compensation of a state can be reached at additional use of calcium orally and/or gluconate calcium infusion.

Storage conditions:

In the place protected from moisture and light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 5 mg of active agent in bottles with a capacity of 10 ml. The bottle together with the application instruction is placed in a pack from a cardboard. Packaging for hospitals: 40 bottles with the corresponding number of application instructions in group boxes.