Rezorba

General characteristics. Structure:

Active ingredient: 4,26 mg of zoledronovy acid of monohydrate (that corresponds to 4 mg of zoledronovy acid anhydrous).

Excipients: D-Mannitolum, sodium citrate anhydrous.

Solvent in the amupul: water for injections.

Solvent in a container polymeric: sodium chloride of 0,9%, water for injections.

Drug of the last generation in therapy of a resorption of a bone tissue. Drug possesses selective effect on a bone tissue and is applied at treatment of bone metastasises of solid tumors, at a multiple myeloma, the hypercalcemia caused by a malignant tumor.

Pharmacological properties:

Pharmacodynamics. Zoledronovy acid belongs to the highly effective bisfosfonatam which are selectively operating on a bone tissue. Drug suppresses a resorption of a bone tissue, influencing osteoclasts. The selection action of bisfosfonat on a bone tissue is based on high affinity to the mineralized bone tissue. The exact molecular mechanism providing inhibition of activity of osteoclasts still remains obscure.

Zoledronovy acid does not make undesirable impact on formation, a mineralization and mechanical properties of a bone.

In addition to an inhibiting effect on a bone resorption, zoledronovy acid has the antineoplastic properties providing efficiency of drug at metastasises in bones.

In vivo: inhibits a resorption of a bone tissue osteoclasts, changes a marrow microenvironment, leads to decrease in growth of tumor cells; shows antiangiogenic activity. Suppression of a bone resorption clinically is followed, including, the expressed decrease in pain.

In vitro: inhibits proliferation of osteoblasts, shows direct cytostatic and pro-apoptotic activity, synergistic cytostatic эффектс antineoplastic drugs; abhesive and anti-invasive activity. 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 of the person 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, a prostate cancer 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 from an osteoliticheskma.

At patients with a multiple myeloma and a breast cancer in the presence of at least one bone center efficiency of zoledronovy acid in a dose of 4 mg is comparable with pamidronovy acid in a dose of 90 mg.

At patients with a tumoral hypercalcemia effect of drug is characterized by decrease in level of calcium in blood serum and calcium removal by kidneys. Average time before normalization of level 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 (the serum calcium level corrected on albumine 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.

Researches do not reveal significant distinctions concerning frequency and weight of the undesirable phenomena observed at the patients who were hit zoledronovy acid in doses of 4 mg, 8 mg, pamidronovy acid in a dose of 90 mg or placebo as at treatment of metastasises in bones, and a hypercalcemia.

Pharmacokinetics. Data on pharmacokinetics at metastasises in a bone 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. After the beginning of infusion serumal concentration quickly increase, reaching peak at the end of infusion, bystry reduction of concentration by 10% after 4 hours and for less than 1% of peak after 24 hours with consistently prolonged period of low concentration of not exceeding 0.1% from maximum before repeated infusion for the 28th day further follows.

The Zoledronovy acid entered intravenously is removed by kidneys in three stages: bystry two-phase removal of drug from system circulation with elimination half-lives - 0.24 h and 1.87 h and a long phase with the final elimination half-life making 146 h. Cumulation of drug at repeated introductions is noted each 28 days. Zoledronovy acid is not exposed to metabolism and is removed by kidneys in an invariable look.

Zoledronovy acid does not inhibit isoenzymes of system of P450 cytochrome at the person. During the first 24 h in urine 39±16% of the entered dose are found. Other amount of drug generally contacts a bone tissue. Then slowly there is the return release of zoledronovy acid from a bone tissue in a system blood stream and its removal by kidneys. The general plasma clearance of drug makes 5.04±2,5 l/h and does not depend on a dose of drug, a sex, age, race and body weight of the patient. Increase in time of infusion from 5 minutes to 15 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.

Pharmacokinetic researches at patients with a hypercalcemia or insufficiency of function of a liver were not moved.

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 does not influence a little significantly pharmacokinetics of zoledronovy acid. Through intestines less than 3% of a dose of drug are removed.

The renal clearance of zoledronovy acid positively correlates with clearance of creatinine and makes 75±33% of clearance of the creatinine averaging 84±29% (range of 22-143 ml/min.) at 64 patients included in a research.

The analysis of population showed that at patients with heavy renal (clearance of creatinine of ≤20 ml/min.) or a moderate renal failure (clearance of creatinine of 20-50 ml/min.) the calculated clearance of zoledronovy acid makes 37% and 72% respectively of values of clearance of a zoledronat at patients with clearance of creatinine ≥ 84 ml/min. Limited pharmacokinetic data are obtained for patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.).

Low affinity of zoledronovy acid to blood components, linkng with proteins of plasma low is shown (about 56%) and does not depend on concentration of drug.

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)

Route of administration and doses:

Intravenously kapelno within at least 15 minutes. At bone metastasises and the osteolytic centers at a multiple myeloma the recommended dose 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 400ME in days.

At the hypercalcemia (concentration of calcium with correction on albumine level ≥ 12 mg/dl or 3mmol/l) caused by malignant tumors the recommended dose makes 4 mg, once. Infusion is carried out on condition of adequate hydration of the patient.

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.

Bone metastasises of widespread malignant tumors and multiple myeloma. The dose of zoledronovy acid 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 (value of clearance of creatinine of 30-60 ml/min.) are given below.

Reference value of KK (ml/min.)	The recommended dose of zoledronovy acid
> 60	4,0 mg
50 - 60	3,5 mg
40 - 49	3,3 mg
30 - 39	3,0 mg

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 content of creatinine in blood serum on 1 mg/dl.

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

The instruction for preparation of solution for infusions: solution is prepared in aseptic conditions; 4 mg dissolve in 5 ml of water for injections, carefully stir up before full dissolution. The received solution with a necessary dose dissolve 0,9% of solution of sodium of chloride or 5% of solution of a dextrose in 100 ml. Not to use solutions, calciferous. It is desirable to use the prepared solution directly after preparation. Unused solution can be stored in the refrigerator at a temperature of +2-80 From no more than 24 h. The solution stored in the refrigerator before introduction should be warmed to room temperature.

Features of use:

Before infusion it is necessary to be convinced of adequate hydration 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.

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.

Against the background of treatment of a bisfosfonatama, including zoledronovy acid, at oncological patients cases of development of an osteonecrosis of a jaw are described in this connection prior to treatment of a bisfosfonatama it is necessary to provide dental inspection and in case of existence of risk factors (anemia, coagulopathies, infections, the bad hygiene or diseases of an oral cavity accompanying himio-or radiation therapy, treatment by corticosteroids) 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.

Features of a medical use of medicine pregnant women, women during breastfeeding, children. Use during pregnancy and breastfeeding is contraindicated. Use of drug at children's and teenage age as safety and efficiency of use are not established is contraindicated.

Influence on ability to drive the car and other mechanisms. The research of influence of drug on ability to manage vehicles and to work with difficult mechanisms was not conducted. In case of side effects from TsNS it is recommended to avoid activity, the requiring special attention and speed of mental and motor reactions.

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, paresthesias, disturbances of flavoring feelings, a hypesthesia, a hyperesthesia, a tremor, feeling of alarm, frustration of a dream; seldom - confusion of consciousness.

From organs of sight: often - conjunctivitis; sometimes - "blurring" of sight; 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 secretory system: often - renal failures; sometimes - an acute renal failure, a hamaturia, a proteinuria.

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

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.

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

Others: often - fever, the grippopodobny syndrome (including a febricula, a fever, disease state, heat), 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, in particular Ringer's solution.

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. At development of a hypocalcemia, hypophosphatemia or hypomagnesiemia there can be a need for short-term additional administration of the corresponding substances. Patients with not treated 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 metamtaza it is necessary to take into account that the therapeutic effect occurs in 2-3 months after an initiation of treatment zoledronovy acid.

Care is necessary 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.

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.

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 less than 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, the expressed liver failure (there are no data on use), at patients with bronchial asthma, sensitive to acetylsalicylic acid.

Overdose:

At acute overdose of zoledronovy acid renal failures, including a renal failure, changes of electrolytic structure, including concentration of calcium, phosphates and magnesium in a blood plasma are possible. At accidental overdose the patient 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:

In the dry, protected from light place, at a temperature not above 25 °C. The recovered solution: at a temperature from 5 to 25 °C. To store in the place, unavailable to children.

Period of validity: lyophilisate - 3 years, the recovered solution - 24 h, solvent ("Water for injections") – 5 years, solvent ("Sodium chloride solution for infusions of 0,9%") – 3 years. The period of validity of a set is established on a component with the smallest period of validity.

Issue conditions:

According to the recipe

Packaging:

The lyophilisate containing 4,0 mg of zoledronovy acid (in terms of anhydrous substance), in bottles of dark neutral glass with a capacity of 10 ml, hermetically corked by traffic jams from rubber and closed by aluminum-plastic caps.

On 5 ml of solvent ("Water for the injections") in ampoules of neutral glass having a tension ring for opening either with a point of a break or without it.

On the 100th solvent ("Sodium chloride solution for infusions of 0,9%") in containers from polyvinylchloride for infusion solutions of single use of KPIR with two sterile ports. One container is placed in a bag from polyethylene or polyethylene - a polyamide film.

1 bottle with drug and 1 ampoule with solvent ("Water for injections") in a blister strip packaging. 1 blister strip packaging together with a knife for opening of ampoules or the scarificator ampoule and the application instruction in a cardboard pack.

1 blister strip packaging together with a knife for opening of ampoules or the scarificator an ampoule, 1 container in a bag with solvent ("Sodium chloride solution for infusions of 0,9%") and the application instruction in a cardboard pack.

When packaging solvent ("Water for injections") or in ampoules with a break point the knife or the scarificator ampoule do not put in the import ampoules having a tension ring for opening.