Резокластин® FS

General characteristics. Structure:

Active ingredient: 4 mg of zoledronovy acid in 5 ml of ready solution.

Excipients: D-Mannitolum, citrate sodium a dihydrate (corresponds sodium to citrate anhydrous), water for injections.

Pharmacological properties:

Pharmacodynamics. Drug Rezoklastin of FS belongs to the new class highly effective bisfosfonatov, possessing selective effect on a bone tissue. Zoledronovy acid suppresses activity of osteoclasts, does not make undesirable impact on formation, a mineralization and mechanical properties of a bone tissue. Selective effect of bisfosfonat on a bone tissue is based on high affinity to the mineralized bone tissue, but the exact molecular mechanism providing inhibition of activity of osteoclasts still remains obscure. Zoledronovy acid except an inhibiting effect on a resorption of a bone has the direct antineoplastic properties providing efficiency at bone metastasises.

In vitro is established that zoledronovy acid, suppressing proliferation and inducing apoptosis of cells, has direct antineoplastic effect on cells of a myeloma and a breast cancer, reduces risk of their innidiation. The inhibition of an osteoklastny resorption of a bone tissue leads to decrease in growth of tumor cells; antiangiogenic and analgetic activity is noted. Zoledronovy acid suppresses also proliferation of cells of an endothelium of the person. At the hypercalcemia caused by a tumor reduces concentration of calcium in blood serum.

At use of zoledronovy acid for patients with postmenopauzny osteoporosis (values of T-criterion of mineral density of a bone tissue of a neck of a hip less than-2,5) statistically reliable decrease in risk of vertebralny changes, and also reduction of risk of development of one or newer (repeated) fractures of vertebras was noted.

At treatment zoledronovy acid at patients with a bone disease of Pedzhet noted statistically authentic, prompt and long therapeutic reply, and also normalization of level of bone exchange and concentration of ShchF in a blood plasma.

Drug is also highly effective at the patients receiving earlier treatment by peroral bisfosfonata. It is established that at most of patients at use of zoledronovy acid the therapeutic answer remains throughout the entire period of treatment (about 2 years).

At patients with postmenopauzny osteoporosis and a bone disease of Pedzhet zoledronovy acid does not influence a qualitative condition of a normal bone, does not break processes of bone remodeling and a mineralization and promotes preservation of normal trabecular very tectonics of a bone.

Pharmacokinetics: Pharmacokinetic parameters do not depend on a dose. After the beginning of infusion concentration in blood serum quickly increases, reaching Cmax at the end of infusion, bystry reduction of concentration by 10% after 4 h and for less than 1% of Cmax in 24 h with the further long period of the low concentration which are not exceeding 0,1% of Cmax before repeated infusion for the 28th day further follows.

Linkng with proteins of plasma — 56%. The plasma clearance does not depend on a dose of drug, a sex, age, race and body weight of the patient. Is not exposed to metabolism.

From 20 to 50% are removed by kidneys in not changed look in 3 stages: 1 and 2 phases — bystry removal of drug from a system blood-groove with T1/2 — 0,24 and 1,87 h respectively; and a long 3rd phase with 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 a slow return release in a system blood stream and removal by kidneys; intestines remove less than 3% of zoledronovy acid. 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 does not influence AUC. The renal clearance of zoledronovy acid positively correlates with Cl of creatinine and makes 42–108% of Cl of the creatinine averaging 55–113%. At patients with heavy (Cl of creatinine of ≤20 ml/min.) and moderated (Cl of creatinine of 20-50 ml/min.) a renal failure the clearance of zoledronovy acid makes 37 and 72% respectively of values of clearance of drug at patients with creatinine Cl> 84 ml/min.

Indications to use:

 

- The hypercalcemia (concentration of the serumal calcium corrected on albumine ≥ 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).

- Post-menopausal form of primary osteoporosis.

- Senile form of primary osteoporosis.

- Secondary osteoporosis.

- Bone disease of Pedzhet.

Route of administration and doses:

Rezoklastin is intravenously kapelno entered by FS, within not less than 15 min. At the hypercalcemia caused by malignant tumors (concentration of calcium with correction on albumine level> 12 mg/dl or 3 mmol/l), the recommended dose of drug makes 4 mg, once. Infusion is carried out on condition of adequate hydration of the patient.

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 Rezoklastin's dose of FS makes 5 mg, once a year.

At secondary osteoporosis the recommended Rezoklastin's dose of FS 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.

At 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 dose of zoledronovy acid at patients with a renal failure depends on the initial level of the clearance of creatinine (CC) calculated by a formula Cockcroft-Gault.

At heavy renal failures (KK <30 ml/min.) is not recommended to apply zoledronovy acid. The recommended doses at easy or moderate renal failures (KK values of 30-60 ml/min.) are given below.

Reference value of Cl of creatinine, ml/min.	The recommended dose of zoledronovy acid, mg
50–60	3,5
40–49	3,3
30–39	3

Definition of concentration of serumal creatinine should be defined before introduction of each dose of drug. At identification of renal failures the next administration of zoledronovy acid should be postponed. Renal failures are determined by the following parameters: for patients with normal reference values of creatinine (<1,4 mg/dl) – increase in content of creatinine in blood serum on 0,5 mg/dl; for patients with deviations of initial level of creatinine (> 1,4 mg/dl) – increase in concentration of creatinine in blood serum on 1 mg/dl.

Therapy by zoledronovy acid is resumed only after concentration of creatinine reaches the values exceeding initial size no more than for 10%, in the same dose which was applied before treatment interruption.

Instruction for solution preparation. Solution is prepared in aseptic conditions. Before introduction drug part (contents of 1 bottle – 4 mg / 5 ml or 5 mg / 6,25 with ml, depending on the recommended dose) in 100 ml of solution for infusions, not calciferous (0,9% solution of sodium of chloride or 5% dextrose solution). It is desirable to use the prepared Rezoklastin's solution of FS directly after preparation. Unused solution can be stored in the refrigerator at a temperature from 2 to 8 °C no more than 24 watch.

Before introduction solution should be sustained indoors before achievement of room temperature by it. The prepared solution of zoledronovy acid needs to be entered with use of separate system for in/in infusions.

Features of use:

Before infusion it is necessary to exclude existence of dehydration at the patient. If necessary introduction of normal saline solution before, 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.

At the solution of a question of Rezoklastin's use of FS 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 a ratio of potential advantage and possible risk of treatment. After administration of drug constant control behind concentration of calcium, magnesium, phosphorus and creatinine in blood serum is necessary.

Against the background of therapy by zoledronovy acid it is necessary to monitor function of kidneys carefully. 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 belong to risk factors of emergence of a renal failure.

It must be kept in mind that at purpose of other bisfosfonat to patients with bronchial asthma, sensitive to acetylsalicylic acid, bronchospasm cases were noted, however at use of zoledronovy acid such cases are not registered yet.

At oncological patients, against the background of treatment of a bisfosfonatama, including zoledronovy acid, cases of development of an osteonecrosis of a jaw in this connection prior to treatment it is necessary to provide dental inspection and in case of existence of risk factors (anemia, coagulopathies, infections, bad hygiene or diseases of the oral cavity accompanying himio-or radiation therapy, treatment by corticosteroids) are described to carry out the corresponding preventive procedures. Against the background of treatment by zoledronovy acid patients with risk factors, whenever possible, should avoid dental operative measures. For decrease in frequency of undesirable reactions after performing infusion of Rezoklastin of FS, patients need to appoint paracetamol or an ibuprofen right after administration of drug.

Influence on ability to manage vehicles and other mechanisms. It is necessary to be careful at control of vehicles and other mechanisms.

Side effects:

Undesirable reactions are listed below on bodies and systems with the indication of frequency of their emergence. Criteria of frequency: very often (≥1/10), it is frequent (≥1/100, <1/10), sometimes (≥1/1,000, <1/100), is rare - (≥1/10,000, <1/1,000), is very rare (<1/10,000), including separate messages.

From bodies of a hemopoiesis: often – anemia, sometimes - thrombocytopenia, a leukopenia; seldom - a pancytopenia.

From a nervous system: often - a headache; sometimes - dizziness, feeling of alarm, paresthesia, a tremor, disturbances of flavoring feelings, a hypesthesia, a hyperesthesia, frustration of a dream; seldom - confusion of consciousness.

From an organ of sight: often - conjunctivitis; sometimes – a sight illegibility; very seldom - a uveitis, an episcleritis.

From digestive tract: often - nausea, vomiting, anorexia; sometimes - diarrhea, a lock, abdominal pains, dyspepsia, stomatitis, dryness in a mouth.

From respiratory system: sometimes - short wind, cough.

From skin and skin appendages: sometimes - an itch, rash (including erimatozny and makulezny), the increased perspiration.

From a musculoskeletal system: often - ostealgias, a mialgiya, an arthralgia, generalized pains; sometimes - muscular spasms.

From cardiovascular system: sometimes – the expressed increase or a lowering of arterial pressure; seldom - bradycardia.

From an urinary system: often - renal failures; sometimes - an acute renal failure, a hamaturia, a proteinuria.

From immune system: sometimes - hypersensitivity reactions; seldom - a Quincke's disease.

Local reactions: pain, irritation, puffiness, formation of infiltrate in a drug injection site.

Disturbances of laboratory indicators: very often - a hypophosphatemia; often - increase in serumal concentration of creatinine and urea, a hypocalcemia; sometimes – a hypomagnesiemia, a hypopotassemia; seldom - a hyperpotassemia, a hypernatremia.

Others: often – the grippopodobny syndrome (including a febricula, a fever, disease state, heat), fever, sometimes - an adynamy, peripheral hypostases; thorax pain, increase in body weight. At treatment of patients of a bisfosfonatama, including zoledronovy acid, cases of development of an osteonecrosis of a jaw were sometimes noted (usually after extraction of tooth or other dental intervention).

Seldom or never, the lowering of arterial pressure against the background of therapy by zoledronovy acid led to a faint or a circulator collapse.

Interaction with other medicines:

As solvents it is impossible to use solutions, calciferous or any bivalent cations, in particular Ringer's solution of a lactate.

At simultaneous use with antineoplastic medicines, diuretics, antibiotics, analgetics of clinically significant interactions it is noted.

Bisfosfonata and aminoglycosides exert the unidirectional impact on concentration of calcium in blood serum therefore at their co-administration the risk of development of a hypocalcemia and hypomagnesiemia increases.

It is recommended to be careful at simultaneous use of zoledronovy acid with the drugs which are potentially possessing nephrotoxic action. At patients with a multiple myeloma increase in risk of development of renal failures at intravenous administration of bisfosfonat in a combination with a thalidomide is possible.

Drug should not be mixed with other medicines.

Contraindications:

- Hypersensitivity to the zoledronovy acid, other bisfosfonata or any other components which are a part of drug.
- The expressed renal failure (clearance of creatinine ≤ 30 ml/min.).
- Pregnancy and period of feeding by a breast.
- Children's and teenage age (safety and efficiency of use are not established).

With care:

- at a renal failure,
- at the expressed liver failure (there are no data on use),
- at patients with bronchial asthma, sensitive to acetylsalicylic acid

Overdose:

At accidental overdose of drug the patient has to be under constant observation of the doctor. In case of the hypocalcemia which is followed by clinical manifestations performing infusion of calcium of a gluconate is shown.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 4 mg / 5 ml and 5 mg / 6,25 ml. On 5 ml of the concentrate containing 4 mg of zoledronovy acid, and 6,25 ml of the concentrate containing 5 mg of zoledronovy acid in the bottles of dark glass with a capacity of 10 ml which are hermetically corked by traffic jams from rubber and caps aluminum-plastic. 1 фл. with drug in a plastic or cardboard pad place in a cardboard pack.