Золерикс

General characteristics. Structure:

Active ingredient: 0,8 mg of zoledronovy acid monohydrate.

Excipients: Mannitolum, citrate sodium a dihydrate (in terms of sodium citrate), water for injections.

Pharmacological properties:

Pharmacodynamics. Zoledronovy acid belongs to the highly effective bisfosfonata possessing selective effect on a bone tissue. Drug suppresses a resorption of a bone tissue, influencing osteoclasts.
 
Selective impact of bisfosfonat on a bone is caused by their high affinity to the mineralized bone, however their exact molecular mechanism of action still remains obscure. After intravenous administration zoledronovy acid is quickly redistributed in a bone and, like other bisfosfonata, is localized preferential in places of remodeling of a bone tissue. The main molecular target of zoledronovy acid in an osteoclast is enzyme of a farnezilpirofosfatsintetaz (FPS); at the same time the possibility of other mechanisms of effect of drug is not excluded. The long period of effect of drug is defined by high affinity to an active center of FPS and the expressed affinity to the mineralized bone tissue. On experimental models of the accelerated resorption at prolonged use of zoledronovy acid, it is shown that zoledronovy acid considerably inhibits a bone resorption, without making undesirable impact on formation, a mineralization and mechanical properties of a bone tissue, дозозависимо reduces activity of osteoclasts and frequency of activation of the new centers of remodeling both in trabecular (spongy), and in a cortical (compact) bone tissue, without causing formation of a fibrous bone tissue and aberrant accumulation of osteoid, and also defects of a mineralization of a bone tissue. Except for high anti-resorptive action, influence of zoledronovy acid on a bone is similar to that for other bisfosfonat.
 
In addition to an inhibiting effect on a bone resorption zoledronovy acid has various antineoplastic properties which can promote achievement of cumulative effect at therapy of metastatic process in bones. Zoledronovy acid, thanks to synergy effect, in a combination with hormonal therapy or chemotherapy suppresses proliferation and induces apoptosis, has direct antineoplastic effect concerning cells of a myeloma of the person and a breast cancer, and also reduces penetration of cells of a breast cancer through an extracellular matrix that demonstrates existence at it anti-metastatic properties. Besides, zoledronovy acid inhibits proliferation of cells of an endothelium of the person and animals and has antiangiogenic effect.
 
At patients with cancer of a mammary gland, prostate and other solid tumors with metastatic damage of bones zoledronovy acid prevents development of pathological changes, compressions of a spinal cord, reduces the need for performing radiation therapy and operative measures, reduces a tumoral hypercalcemia. Drug is capable to constrain progressing of a pain syndrome. The medical effect is less expressed at patients with the osteoblastic centers, than with osteolytic.

At patients with a tumoral hypercalcemia effect of zoledronovy acid is characterized by decrease in concentration of calcium in blood serum and calcium removal by kidneys. Average time before normalization of concentration of calcium makes about 4 days. By 10th day concentration of calcium is normalized at 87-88% of patients. Average time prior to a recurrence (corrected on albumine concentration of calcium of serum not less than 2,9 mmol/l) makes 30-40 days. Significant distinctions between efficiency of zoledronovy acid in doses of 4 and 8 mg at treatment of a hypercalcemia are not observed.
 
At use of zoledronovy acid at post-menopausal osteoporosis 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 11th week for indicators of bone formation). Afterwards indicators of bone exchange are stabilized within premenopauzalny values. Use of zoledronovy acid at post-menopausal osteoporosis authentically reduces relative risk of development of any changes and leads to increase in mineral density of a bone tissue (MPK).
 
At introduction by the patient with recent (within 90 days) changes of proximal department of a femur drug reduces the frequency of the subsequent osteoporotichesky changes of any localization and reduces risk of a lethal outcome.
 
At use for patients with other types of osteoporosis (senile osteoporosis, osteoporosis at a hypogonadism, the osteoporosis caused by use of glucocorticosteroids) and for prevention of post-menopausal osteoporosis at women with various duration of a menopause clinically significant increase in MKP and decrease in indicators of bone exchange in a blood plasma is also noted.
 
At treatment zoledronovy acid at patients with a bone disease of Pedzhet notes bystry and it is long the remaining normalization of level of bone exchange and activity of an alkaline phosphatase in a blood plasma.
 
Drug is highly effective at the patients receiving earlier treatment by peroral bisfosfonata. On analgeziruyushchy effect effect of zoledronovy acid is comparable with effect of rizedronovy acid.
 
At patients with post-menopausal osteoporosis and a bone disease of Pedzhet zoledronovy acid does not influence a qualitative condition of a normal bone tissue, does not break processes of bone remodeling and a mineralization and promotes preservation of normal very tectonics of a trabecular bone.

Pharmacokinetics. Data on pharmacokinetics are obtained after single and repeated 5-and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronovy acid at 64 patients. Pharmacokinetic parameters do not depend on a drug dose.
 
Distribution: the drug is administered intravenously, after the beginning of infusion concentration in blood serum quickly increases, reaching the maximum concentration (Smakh) at the end of infusion, bystry reduction of concentration by 10% after 4 h and for less than 1% from Smakh in 24 h with the further long period of the low concentration which are not exceeding 0,1% from Smakh before repeated infusion for the 28th day further follows.
 
Low affinity of zoledronovy acid to blood components is shown, linkng with proteins of plasma low (60-77%) and poorly depends on concentration of drug.

Metabolism: is not exposed to metabolism. Zoledronovy acid does not inhibit P450 cytochrome isoenzymes.
 
Removal: it is removed by kidneys in not changed look in 3 stages: 1 and 2 phases - bystry removal of drug from a system blood-groove, with an elimination half-life (Т½) of 0,24 h and 1,87 h, respectively, and the 3rd phase - long, from final T1/2 146 h. Cumulation of drug at repeated introductions is noted each 28 days. During the first 24 h in urine 23-55% of the entered dose are found. Other amount of drug contacts a bone tissue then there is its slow return release in a system blood stream and removal by kidneys; through intestines less than 3% are removed. The general plasma clearance makes 2,54-7,54 l/h and does not depend on a dose of drug, a sex, age, race and body weight of the patient. It is established that variability of plasma clearance at the same patient and at different patients makes 36% and 34%, respectively. Increase in duration of infusion from 5 to 15 min. leads to reduction of concentration of zoledronovy acid by 30% at the end of infusion, but "concentration time" (AUC) does not influence the square under a curve.

Pharmacokinetics in special groups of patients. Patients with an abnormal liver function: pharmacokinetic researches at patients with a hypercalcemia and an abnormal liver function were not conducted. According to the data obtained by in vitro, zoledronovy acid does not inhibit isoenzymes of system of P450 cytochrome of the person and is not exposed to biotransformation that allows to assume that the condition of function of a liver significantly does not influence pharmacokinetics of zoledronovy acid. Dose adjustment of drug is not required.

Patients with a renal failure: the renal clearance positively correlates with the clearance of creatinine (CC) and makes 75±33% of KK averaging 84±29 ml/min. (range of 22-143 ml/min.) at 64 patients included in a research. Small increase in AUC0-24, for 30-40%, at a renal failure of easy and moderate degree, in comparison with norm, and lack of cumulation of drug at repeated introduction irrespective of function of kidneys, allow to consider that there is no need for dose adjustment of zoledronovy acid at a renal failure easy (clearance of creatinine = 50-80 ml/min.) and moderated (clearance of creatinine = 30-50 ml/min.) degrees. At patients with a renal failure of heavy and moderate degree the clearance of zoledronovy acid makes 37% and 72%, respectively, of value of clearance of a zoledronat at patients with clearance of creatinine> 84 ml/min. Use of drug for patients with a renal failure of heavy degree (clearance of creatinine <35 ml/min.) it is contraindicated because of increase in risk of a renal failure.

Indications to use:

• A hypercalcemia (concentration of the serumal calcium corrected on albumine> of 12 mg/dl or 3 mmol/l), induced by malignant tumors.
• Metastatic damage of bones at malignant solid tumors and a multiple myeloma (for decrease in risk of pathological changes, a compression of a spinal cord, the hypercalcemia caused by a tumor and decrease in need for performing radiation therapy).
• A post-menopausal form of primary osteoporosis (for decrease in risk of fractures of femur, vertebrae and vnevertebralny changes, for increase in mineral density of a bone);
• Senile form of primary osteoporosis;
• Secondary osteoporosis;
• Bone disease of Pedzhet.

Route of administration and doses:

Золерикс® apply intravenously kapelno, within not less than 15 min.
 
It is necessary to correct dehydration at patients (at its existence) before administration of zoledronovy acid, (it is especially important for patients aged> 65 years, and also at the patients receiving therapy by diuretics).
 
At the hypercalcemia caused by malignant tumors. At concentration of the serumal calcium corrected on albumine> 12 mg/dl or 3 mmol/l the maximum recommended single dose makes 4 mg. Before infusion of the drug Zoleriks® it is necessary to check concentration of creatinine in blood serum. For ensuring adequate hydration of the patient introduction of normal saline solution before, at the same time or after drug infusion is recommended. Repeated administration of drug in a dose of 4 mg is shown in case of an aggravation of symptoms after clear effect (i.e. achievements of concentration of Sa2 + in blood serum of 2,7 mmol/l and below) or in case of a refrakternost to the first introduction. Repeatedly Zoleriks® can be entered in the maximum dose of 8 mg within 15 min. In need of repeated introduction it is necessary to define concentration of creatinine of blood serum before each infusion. The interval before repeated introduction has to make not less than 7 days, it is necessary for implementation of full clinical effect of an initial dose.
 
At metastatic damage of bones at malignant solid tumors and a multiple myeloma the recommended dose of drug makes 4 mg, each 3-4 weeks. It is in addition recommended to appoint inside calcium in a dose of 500 mg a day and vitamin D in a dose 400 ME in days.
 
At a post-menopausal and senile form of primary osteoporosis for the purpose of increase in mineral density of a bone tissue, prevention of fractures of bodies of vertebrae and other bones of a skeleton, the recommended dose of Zoleriksa® makes 5 mg, once a year.
 
At secondary osteoporosis the recommended dose of Zoleriksa® makes 5 mg, once a year. If receipt in an organism of calcium and vitamin D with food is not enough, patients with osteoporosis should appoint drugs of calcium and vitamin D in addition. Duration of use of drug is defined by the doctor individually depending on a condition of the patient.
 
For treatment of a bone disease of Pedzhet it is recommended single in/in administration of drug in a dose of 5 mg. As, the bone disease of Pedzhet is characterized by the high level of bone exchange, all patients with this disease are recommended to accept standard daily rate of calcium and vitamin D during the first 10 days after administration of zoledronovy acid.
 
Repeated treatment by zoledronovy acid of a bone disease of Pedzhet. After the first administration of drug the long period of remission is observed. Now special data on performing repeated treatment of a bone disease of Pedzhet are not available. However the possibility of repeated administration of drug can be considered in case of detection at patients of a recurrence of a disease on the basis of the following criteria: lack of normalization of activity of an alkaline phosphatase of blood serum, increase in its activity in dynamics, and also existence of the clinical signs of a bone disease of Pedzhet found at medical examination 12 months later after introduction of the first dose of zolendronovy acid.
 
Use for patients with a renal failure. The hypercalcemia caused by malignant tumors. The decision on treatment by zoledronovy acid of patients with the expressed renal failures should be made only after careful assessment of a ratio risk/advantage. At concentration of creatinine in blood serum <400 µmol/l or <4,5 mg/dl, corrections of the mode of dosing are not required.
 
Metastatic damage of bones at malignant solid tumors and a multiple myeloma. The drug Zoleriks® dose at patients with a renal failure depends on initial clearance of the creatinine calculated by Kokrofta-Gault's formula. The recommended doses at patients with renal failures of easy or moderate degree (value of clearance of creatinine of 30-60 ml/min.) are given below.

Initial clearance of creatinine (ml/min.)	The recommended drug Zoleriks® dose
> 60	4,0 mg (5,0 ml of a concentrate)
50-60	3,5 mg (4,4 ml of a concentrate)
40-49	3,3 mg (4,1 ml of a concentrate)
30-39	3,0 mg (3,8 ml of a concentrate)

 

After the beginning of therapy concentration of creatinine should be measured in blood serum before introduction of each dose the drug Zoleriks®. If function of kidneys worsens, the next administration of drug should be postponed. Deterioration in function of kidneys is defined as follows:
 
• for patients with normal initial concentration of creatinine in blood serum (<1,4 mg/dl): increase in concentration of creatinine on> 0,5 mg/dl;
• for patients with the changed initial concentration of creatinine in blood serum (> 1,4 mg/dl): increase in concentration of creatinine on> 1,0 mg/dl.

Therapy by the drug Zoleriks® is resumed in the same dose, as before treatment interruption when concentration of creatinine returns to a reference value or will deviate from it no more than for 10%.
 
Therapy of primary and secondary osteoporosis. With clearance of creatinine> 35 ml/min. are not required from patients to drug dose adjustment. Use for patients with clearance of creatinine <35 ml/min. is contraindicated.
 
Patients with an abnormal liver function. Dose adjustment of drug is not required.
 
Patients of advanced age (> 65 years). Dose adjustment of drug is not required as bioavailability, distribution and removal of drug at patients of different age have similar character.
 
The instruction for preparation of solution for infusions. By preparation and performing infusion it is necessary to follow rules of an asepsis. Before administration of zoledronovy acid it is necessary to estimate quality and color of solution visually. Drug cannot be used at discoloration or emergence of not dissolved visible particles.
 
From a concentrate 4mg/5ml, 5 mg / 6,25 ml (contents of 1 bottle) solution for infusions. Before administration of drug part a concentrate (contents of 1 bottle or smaller volume if it is required) 100 ml of 0,9% of solution of sodium of chloride or 5% of solution of a dextrose. It is desirable to use the prepared solution directly after preparation. It is possible to store unused solution in the refrigerator at a temperature from 2 to 8 °C no more, than 24 hours. Before introduction solution should be sustained indoors before achievement of room temperature by it.
 
The general time between cultivation of a concentrate, storage of the prepared solution in the refrigerator at a temperature from 2 to 8 °C and the end of administration of drug should not exceed 24 hours.
 
Solution of the drug Zoleriks® should not be mixed with any other medicines or with solutions, calciferous or any other bivalent cations, such as Ringer's solution a lactate. Always it is necessary to use separate system for infusions.

Features of use:

Pregnancy and lactation. Data on use of zoledronovy acid for pregnant women are absent. In pilot studies existence of toxic effects from reproductive system is shown. The potential risk at use for the person is unknown. It is not known whether zoledronovy acid with breast milk is emitted. The drug Zoleriks® is contraindicated at pregnancy and during breastfeeding.

Infusion of drug has to be carried out by the qualified medical personnel having experience of introduction of bisfosfonat.
 
The doctor should inform patients on the main manifestations of a hypocalcemia and to provide regular observation of the patients entering into risk group.
 
For decrease in frequency of some NYa noted within 3 days after administration of drug it is possible to appoint paracetamol or an ibuprofen right after infusion of zoledronovy acid.
 
Before infusion of zoledronovy acid it is necessary to be convinced of adequate hydration of the patient. If necessary introduction of 0,9% of solution of sodium of chloride to, parallel to or after infusion of zoledronovy acid is recommended. It is necessary to avoid an overhydratation of the patient because of risk of emergence of complications from cardiovascular system.
 
After administration of zoledronovy acid constant control of concentration of calcium, phosphorus, magnesium and creatinine in blood serum is necessary. At development of a hypocalcemia, hypophosphatemia or hypomagnesiemia there can be a need for short-term additional administration of the corresponding substances. Patients with an uncured hypercalcemia, as a rule, have a renal failure therefore careful monitoring of function of kidneys at this category of patients is necessary.
 
At the solution of a question of treatment by zoledronovy acid of patients with bone metastasises it is necessary to take into account that the therapeutic effect occurs in 2-3 months after an initiation of treatment zoledronovy acid.
 
Hypocalcemia. 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. Also, whenever possible, it is necessary to carry out therapy of other available disturbances of mineral exchange (for example, the operations arising later on thyroid and parathyroid glands, at a hypoparathyrosis or decrease in absorption of calcium in intestines) and to provide regular observation of patients with a hypocalcemia.
 
In clinical practice it was reported about development of a hypocalcemia in the patients receiving zoledronovy acid. In case of development of a heavy hypocalcemia emergence of the undesirable phenomena from a nervous system (spasms, a tetany and numbness) can be noted, cardiac arrhythmia. In certain cases the hypocalcemia can pose a threat for life.
 
Renal failure. There are separate messages on a renal failure against the background of use of bisfosfonat. Dehydration, the previous renal failure, repeated administration of zoledronovy acid or other bisfosfonat, and also use of nefrotoksichny medicines, and too bystry administration of drug belongs to risk factors of emergence of similar complications. In spite of the fact that the risk of the above described complications decreases on condition of administration of zoledronovy acid in a dose of 4 mg within not less than 15 min., the possibility of a renal failure remains. Cases of deterioration in function of kidneys, progressing of a renal failure and emergence of need for carrying out a hemodialysis at the first or single use of zoledronovy acid were noted. Increase in serumal concentration of creatinine is also observed at some patients at prolonged use of zoledronovy acid in the recommended doses though it is less frequent. At the solution of a question of use of zoledronovy acid for patients with the hypercalcemia caused by a malignant tumor against the background of a renal failure, it is necessary to estimate a condition of the patient and to draw a conclusion on whether the potential advantage of administration of drug over possible risk prevails.
 
Jaw osteonecrosis. Jaw osteonecrosis cases at oncological patients against the background of treatment of a bisfosfonatama, including zoledronovy acid are described. At many patients signs of local infectious and inflammatory process, including osteomyelitis took place.
 
In clinical practice most often development of an osteonecrosis of a jaw was noted at patients with a widespread breast cancer and a multiple myeloma, and also in the presence of dental diseases (after an odontectomy, at diseases of a parodont, unsatisfactory fixing of dentures). The known risk factors of development of an osteonecrosis of a jaw is the oncological disease, the accompanying treatment (chemotherapy, radiation therapy, treatment by glucocorticosteroids), associated diseases (anemia, a coagulopathy, an infection, the previous oral cavity disease).
 
Before purpose of bisfosfonat patients should conduct dental examination and to perform necessary preventive procedures, and also to recommend strict observance of hygiene of an oral cavity. During treatment of these patients it is necessary to avoid dental operations whenever possible. There are no data that interruption of treatment of a bisfosfonatama reduces risk of development of an osteonecrosis of a jaw to dental interventions. Treatment planning of the specific patient has to be based on individual assessment of a ratio risk/advantage.
 
Atypical fractures of a femur. Cases of developing of atypical subtrochanterian and diaphyseal fractures of femur at patients, receiving treatment of a bisfosfonatama concerning osteoporosis a long time are described. Cross or short slanting changes can be localized in any place throughout a femur from a trochantin to an epicondylic pole. The described changes arise after the minimum injury or is spontaneous. Some patients feel the hip pains or in a groin which are often followed by visual symptoms of stressful fractures which arise one weeks and months prior to development of a complete (complete) fracture of a femur. Quite often changes arise on both sides therefore at the patients receiving bisfosfonata which had a fracture of one femur the contralateral femur has to be investigated. It was reported also about slow healing of these changes. Causal investigative connection of similar changes with therapy by zoledronovy acid was not established. The decision on the therapy termination by zoledronovy acid at patients at whom existence of an atypical fracture of femur is supposed has to be based on individual assessment of a ratio risk/advantage.
 
The patients receiving therapy by zoledronovy acid should be warned about need to inform medical personnel on any hip pains or inguinal area. Each patient showing complaints to such symptoms has to be inspected for detection of a possible incomplete (incomplete) fracture of femur.
 
Ostealgias. In clinical practice it was reported about infrequent cases of development strong and in certain cases to a disabling ostealgia, joints and muscles against the background of use of bisfosfonat to which also zoledronovy acid belongs. The specified symptoms developed during the period from one day to several months after an initiation of treatment. After the termination of treatment at most of patients symptoms passed. At several patients symptoms repeated during the resuming of therapy or purpose of other bisfosfonat.
 
Other instructions. Separate cases of emergence of a bronkhokonstriktion at patients with aspirinovy bronchial asthma against the background of use of bisfosfonat were noted. Though in clinical trials using zoledronovy acid such cases were not, it is recommended to use drug with care at patients with "aspirinovy" bronchial asthma.
 
As clinical data on use of drug for patients with a heavy liver failure are limited, it is not possible to make specific recommendations for this category of patients.
 
The patients receiving Zoleriks® should not receive other drugs of bisfosfonat at the same time.
 
Efficiency and safety of use of zoledronovy acid in pediatric practice are not established so far.

Influence on ability to manage vehicles and mechanisms. Studying of influence of zoledronovy acid on ability to manage vehicles and to work with mechanisms it was not carried out. In case of side reactions from a nervous system patients are recommended to refrain from control of vehicles and other mechanisms, and also occupations the types of activity demanding concentration of attention, tension of psychomotor functions.

Side effects:

The undesirable phenomena (UP) on bodies and systems with the indication of frequency of emergence according to WHO recommendations are listed below: very often (≥ 10%), it is frequent (from ≥ 1% to <10%), infrequently (from ≥ 0,1% to <1), is rare (≥ 0,01% and <0,1%), is very rare (<0,01%) and frequency is unknown (according to messages in literature).
 
At use for patients with metastatic damage of bones at malignant solid tumors and a multiple myeloma, a hypercalcemia:
 
Disturbances from blood and lymphatic system: often - anemia, infrequently - thrombocytopenia, a leukopenia; seldom - a pancytopenia.
 
Disturbances from immune system: infrequently - hypersensitivity reactions; seldom - a Quincke's disease, frequency it is unknown - anaphylactic reaction / shock.
 
Disturbances of mentality: often - a sleep disorder; infrequently - alarm.
 
Disturbances from a nervous system: often - a headache; paresthesias; infrequently - dizziness, taste disturbances, a hypesthesia, a hyperesthesia, a tremor; seldom - confusion of consciousness, frequency is unknown - drowsiness.
 
Disturbances from an organ of sight: often - conjunctivitis; infrequently - the sight illegibility, frequency is unknown - a uveitis, an episcleritis, a sclerite and inflammatory diseases of an eye-socket.
 
Disturbances from heart: seldom - bradycardia, frequency is unknown - fibrillation of auricles.
 
Disturbances from vessels often - increase in arterial pressure; infrequently - a lowering of arterial pressure, frequency it is unknown - the lowering of arterial pressure leading to a faint or a circulator collapse, generally at patients with risk factors.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: infrequently - short wind, cough, frequency is unknown - a bronchospasm, an intersticial pulmonary disease.
 
Disturbances from digestive tract: often - nausea, vomiting, anorexia, a lock; infrequently - diarrhea, abdominal pain, dyspepsia, stomatitis, dryness in a mouth.
 
Disturbances from skin and hypodermic fabrics: often - the increased perspiration; infrequently - an itch, rash (including erythematic and makulezny), frequency is unknown - a small tortoiseshell.
 
Disturbances from skeletal and muscular and connecting fabric: often - an ostealgia, a mialgiya, an arthralgia, generalized pains, rigidity of joints; infrequently - a mandible necrosis, muscular spasms, frequency it is unknown - the sudden expressed restriction of mobility of bones, joints and/or pain, atypical subtrochanterian and diaphyseal fractures of a femur.
 
Disturbances from kidneys and urinary tract: often - renal failures; infrequently - an acute renal failure, a hamaturia, a proteinuria.
 
The general frustration and disturbances in an injection site: often - ostrofazovy reaction, fever, a grippopodobny state (including a febricula, a fever, disease state, heat), peripheral hypostases, an adynamy; infrequently - reaction in an injection site (pain, irritation, puffiness, consolidation, reddening), thorax pain, increase in body weight.
 
Laboratory and tool data: very often - a hypophosphatemia; often - increase in concentration of creatinine and urea in blood, a hypocalcemia; infrequently - a hypomagnesiemia, a hypopotassemia; seldom - a hyperpotassemia, a hypernatremia. The above-mentioned NYa connected using zoledronovy acid according to the specified indications usually have slight and tranzitorny character, they can be observed at a third of the patients receiving treatment by drug.
 
At treatment and prevention of different types of osteoporosis, treatment of a bone disease of Pedzhet and for prevention of new changes at men and women with changes of proximal department of a femur
 
Disturbances from a nervous system: often - a headache *, dizziness; infrequently - block *, paresthesia, a hyposensitivity (occurred only at the patients receiving drug for the purpose of prevention of post-menopausal osteoporosis), drowsiness, a tremor *, a faint, a dysgeusia.
 
Disturbances of the party of an organ of sight: often - a sclera hyperemia; infrequently - conjunctivitis, eye pain, вертиго, indistinct sight (occurred only at the patients receiving drug for the purpose of prevention of post-menopausal osteoporosis); seldom - a uveitis *, an episcleritis, an iritis *; frequency is unknown - an inflammation of a sclera and an eye-socket.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: infrequently - an asthma *, cough.
 
Disturbances from the alimentary system: often - nausea *, vomiting, diarrhea; infrequently - anorexia *, a loss of appetite, dyspepsia *, an abdominal pain *, dryness in a mouth, an esophagitis *, a gastroesophageal reflux, pain in upper parts of a stomach *, a lock *, gastritis (at the patients receiving glucocorticosteroids), a dentagra.
 
Disturbances from skin and hypodermic cellulose: infrequently - rash, a hyperhidrosis *, an itch, an erythema.
 
Disturbances from skeletal and muscular system and connecting fabric: often - arthralgias *, mialgiya *; an ostealgia, a dorsodynia and extremities, a gnathalgia and neck pain (occurred only at the patients receiving drug for the purpose of prevention of post-menopausal osteoporosis); infrequently - pain in a neck, swelling of joints *, muscular spasms *, pain in the field of a shoulder girdle, pain in a thorax * a musculoskeletal origin, weakness in muscles, constraint in muscles * and joints *, arthritises, musculoskeletal pains, a stitch (occurred only at the patients receiving drug for the purpose of prevention of post-menopausal osteoporosis); frequency is unknown - a jaw osteonecrosis.
 
Disturbances from kidneys and urinary tract: infrequently - increase in level of creatinine of blood, a pollakiuria, a proteinuria. Frequency is unknown - a renal failure.
 
Disturbances from blood and lymphatic system: infrequently - anemia.
 
Disturbances from heart: fibrillation of auricles; infrequently - a heart consciousness.
 
Disturbances from vessels: infrequently - increase in arterial pressure, sudden face reddening; frequency is unknown - the expressed lowering of arterial pressure (at patients with risk factors).
 
Disturbance of mentality: infrequently - sleeplessness, alarm (occurred only at the patients receiving drug for the purpose of prevention of post-menopausal osteoporosis). Infections and invasions: infrequently - flu, a nasopharyngitis.
 
The general frustration and disturbances in an injection site: very often - temperature increase; often - a grippopodobny syndrome, a fever *, increased fatigue *, an adynamy, pain *, a febricula, reactions in the place of infusion; infrequently - peripheral hypostases, feeling of thirst *, ostrofazny reactions *, a stethalgia * (not connected with heart diseases); frequency is unknown - dehydration (develops for the second time in relation to post-infusional symptoms, such as fever, vomiting, diarrhea).
 
* - In separate researches, including at use of drugs of zoledronovy acid for the purpose of prevention of post-menopausal osteoporosis, the frequency of these undesirable phenomena was 10 times more.
 
The above-mentioned NYa connected using zoledronovy acid according to the specified indications, as a rule, easily or moderately expressed also pass within three days after emergence. At repeated administration of drug expressiveness of data of NYa decreased.
 
During the separate researches of zoledronovy acid NYa which development frequency in group of drug was lower, than in group not receiving drug were registered: reddening of eyes, increase in S-reactive protein in blood, a hypocalcemia, a dysgeusia, a dentagra, gastritis, a heart consciousness, reactions in an injection site.
 
Against the background of therapy zoledronovy acid in clinical practice noted the following undesirable phenomena regardless of existence of relationship of cause and effect using drug (frequency is not established): hypersensitivity reactions, including in rare instances a bronkhoobstruktion, a small tortoiseshell, a Quincke's disease and separate messages on development of anaphylactic reactions, including an acute anaphylaxis. Renal failures, including the renal failure demanding carrying out a hemodialysis or cases of a lethal outcome, especially at patients with existence or renal pathology in the anamnesis, or accessory factors of risk were in rare instances noted (for example, advanced age, the accompanying therapy by nephrotoxic drugs, diuretics or heavy dehydration).

Interaction with other medicines:

According to the data obtained in the researches in vitro, zoledronovy acid poorly contacts proteins of plasma and does not inhibit isoenzymes of system of P450 cytochrome. It is recommended to be careful at simultaneous use of bisfosfonat, aminoglycosides and loopback diuretics as simultaneous effect of these drugs causes more long decrease in concentration of calcium in a blood plasma.
 
Zoledronovy acid is removed by kidneys therefore care is necessary at simultaneous use of zoledronovy acid with the drugs which are potentially possessing nephrotoxic action. At patients with a renal failure at use of zoledronovy acid together with drugs which are removed preferential by kidneys increase in systemic action of these medicines is possible.
 
It is necessary to be careful at combined use of zoledronovy acid with angiogenesis inhibitors because of the cases of development of an osteonecrosis of a mandible taking place.
 
At simultaneous use with zoledronovy acid of other often applied medicines (antineoplastic means, diuretics (except for loopback), antibacterial drugs, analgeziruyushchy means) any clinically significant interactions are noted.
 
Patients with a multiple myeloma have a combined use of a thalidomide (100 or 200 mg of 1 times a day) and zoledronovy acid significantly does not influence pharmacokinetics of drug and clearance of creatinine and does not demand dose adjustment of drugs, except for use for patients with renal failures easy and moderate severity at which dose adjustment of zoledronovy acid can be required.
 
Pharmaceutical interaction. Divorced solution of zoledronovy acid cannot be mixed with the infusion solutions containing calcium ions (for example, Ringer's solution).
 
When using for administration of zoledronovy acid of glass bottles, infusional systems and bags of the different types made of polyvinylchloride, polyethylene and polypropylene (previously filled 0,9% solution of sodium chloride or 5% glucose solution) any signs of incompatibility are not revealed.

Contraindications:

• Hypersensitivity to the zoledronovy acid, other bisfosfonata or any other components which are a part of drug;
• Heavy disturbances of mineral exchange, including a hypocalcemia;
• Renal failure of heavy degree (clearance of creatinine <35 ml/min.);
• Pregnancy and period of breastfeeding;
• Age up to 18 years (since safety and efficiency of use of zoledronovy acid at children's and teenage age were not studied).

With care. At the solution of a question of use of zoledronovy acid for patients with the hypercalcemia caused by a malignant tumor against the background of a renal failure, it is necessary to estimate a condition of the patient and to draw a conclusion on whether the potential advantage of administration of drug over possible risk prevails. It is necessary to be careful at purpose of zoledronovy acid:
 
• to patients with a renal failure of easy and moderate severity,
• to patients in a condition of heavy dehydration,
• to patients with the accompanying oncological diseases and chemotherapy in the anamnesis,
• to patients with a liver failure,
• to patients with the bronchial asthma caused by acetylsalicylic acid
• at simultaneous use of zoledronovy acid with the drugs capable to exert significant impact on function of kidneys (for example, with the antibiotics aminoglycosides or diuretic means causing dehydration).

Overdose:

Symptoms: At acute overdose of zoledronovy acid (limited data) renal failures, including a renal failure, changes of electrolytic structure, including decrease in concentration of calcium, phosphates and magnesium in a blood plasma were noted.
 
Treatment: The patient who received the drug dose exceeding recommended has to be under constant observation. In case of the hypocalcemia which is followed by clinical manifestations performing infusion of calcium of a gluconate is shown.

Storage conditions:

To store at a temperature not above 30 °C. Not to freeze. To store in the place, unavailable to children. A period of validity - 2 years. Drug should not be used after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions, 0,8 mg/ml. Packaging: on 5 ml (4 mg), 6,25 ml (5 mg) in bottles of colourless neutral glass I of a hydrolytic class or in the plastic bottles which are hermetically corked by rubber bungs with a running in caps aluminum. On 1 or 5 bottles together with the application instruction place in a pack from a cardboard.