Блазтера®

General characteristics. Structure:

Lyophilisate for preparation of solution for infusions
in the form of flat cake, separate units or powder of white or almost white color.
1 фл.
zoledronovy acid monohydrate - 4.264 mg,
what corresponds to the content of zoledronovy acid of 4 mg
Excipients: Mannitolum, sodium citrate (for finishing pH), water for and (before lyophilizing).
Bottles of colourless glass (1) – a pack cardboard.

Pharmacological properties:

Inhibitor of a bone resorption. Zoledronovy acid belongs to highly effective bisfosfonata which possess selective effect on a bone tissue. Drug suppresses a resorption of a bone tissue, affecting 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 bone metastasises. Zoledronovy acid, suppressing proliferation and inducing 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 at animals showed antiangiogenic action. At patients with cancer of a 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 removal of calcium with urine. 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 (the concentration of calcium of serum corrected on albumine not less than 2.9 mmol/l) makes 30-40 days. Significant distinctions between efficiency of zoledronovy acid in doses 4 i8 the mg at treatment of a hypercalcemia is not observed.

Pharmacokinetics. Pharmacokinetic parameters do not depend on a drug dose.
Absorption and distribution
After the beginning of infusion concentration in blood serum quickly increases, reaching Cmax at the end of infusion, bystry reduction of concentration by 10% in 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 follows further. 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.
Communication with proteins of plasma – 56%. Low affinity of zoledronovy acid to blood components is noted.
Metabolism and removal
Is not exposed to metabolism.
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, st1/2-0.24ch and 1.87 h respectively, and the 3rd phase – long, 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% 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; with a stake it is removed
less than 3%. The general plasma clearance – 2.54 7.54 l/h. It does not depend on a drug dose,
sex, age, race and body weight of the patient.
Pharmacokinetics in special clinical cases
The renal clearance positively correlates with KK and makes 42-108% of KK averaging 55-113%. At patients with a renal failure of heavy degree (KK of 20 ml/min.) and moderate degree (KK of 50 ml/min.) the clearance of zoledronovy acid makes 37 and 72% respectively of values of clearance of drug at patients at KK of 84 ml/min.

Indications to use:

The hypercalcemia (concentration corrected on albumine serumal кальция_ 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, reduction of the hypercalcemia caused by a tumor and decrease in need for performing radiation therapy).

Route of administration and doses:

The drug is administered in/in kapelno within not less than 15 min.
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 dose makes 4 mg.
Before infusion it is necessary to check concentration of creatinine in blood serum. Correction of the mode of dosing with a renal failure of easy or moderate degree (concentration of serumal creatinine <400 µmol/l or <4.5 mg/dl) is not required from patients.
Infusion is carried out on condition of adequate hydration of the patient (introduction of 0.9% of solution of sodium of chloride before, at the same time or after infusion of zoledronovy acid). Repeated administration of drug in a dose of 4 mg is shown in case of an aggravation of symptoms after clear effect (that is achievements of concentration of calcium ions in blood serum of 2.7 mmol/l and below) or in case of a refrakternost to the first introduction. The interval between the first and repeated introduction has to be not less than 1 week for effect assessment.
In need of repeated administration of zoledronovy acid concentration of creatinine of blood serum should be defined before each infusion.
At a multiple myeloma and metastatic damage of bones at solid tumors Blaztera's dose depends on the initial KK calculated by Kokroft's formula.
The recommended doses at patients with renal failures of easy or moderate degree
(KK 30 values "60 ml/min.) are given below.
Reference value> 60 4.0 mg
KK (ml/min.) of 50-60 3.5 mg
The recommended dose of 40-49 3.3 mg
Blasters of 30-39 3.0 mg

After the beginning of therapy it is necessary to carry out by zoledronovy acid definition of concentration of serumal creatinine before introduction of each dose of drug.
At identification of renal failures the next administration of drug should be postponed.
Renal failures are determined by the following parameters:
- for patients with normal reference values of creatinine (<1.4 mg/dl) – increase
on 0.5 mg/dl.
- for patients with deviations of initial level of creatinine (> 1.4 mg/dl) – increase on 1 mg/dl.
Therapy by zoledronovy acid is resumed only after the level of creatinine reaches values within 10% of initial size, in the same dose which was applied before treatment interruption.
To patients it is necessary to appoint zoledronovy acid in addition to therapy calcium inside in a dose of 500 mg/days and vitamin D inside in a dose of 400 ME/days.
The instruction for preparation of solution for infusions
Solution is prepared in aseptic conditions. Bottle contents (4 mg of zoledronovy acid) are dissolved in 5 ml of water for injections and carefully stirred 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.
It is desirable to use the prepared solution directly after preparation. Unused solution can be stored in the refrigerator at a temperature of 2 "8 °C of no more than 24 h.
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 of 2-8 °C and the end of administration of drug should not exceed 24 h.
Solution of zoledronovy acid should not be mixed with any other medicines or with solutions, calciferous or any other bivalent cations, such as Ringer's solution. Always it is necessary to use separate system for infusions.

Features of use:

Treatment by zoledronovy acid needs to be carried out under control of the doctor having experience of use of bisfosfonat. 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. Before each administration of zoledronovy acid it is necessary to define concentration of creatinine in serum. In an initiation of treatment drug of the patients with bone metastasises having renal failures of weak and average degree of manifestation recommends to apply zoledronovy acid in reduced doses. If the renal failure appeared during therapy by zoledronovy acid, it is possible to continue therapy by drug only after concentration of creatinine returns to values which are in limits of 10% of initial size.
Before infusion it is necessary to be convinced of adequate hydration of the patient. If necessary introduction of 0.9% of solution of sodium of chloride 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 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 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 metastasises of solid tumors it is necessary to take into account that the therapeutic effect occurs through 2 "3 months after an initiation of treatment. 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 belong 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 minutes, the possibility of a renal failure remains.
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. As there are limited clinical data on use of drug for patients with a heavy liver failure, it is not possible to make specific recommendations for this category of patients.
Jaw osteonecrosis cases at oncological patients against the background of the antineoplastic treatment including bisfosfonata are described. At many patients signs of local infectious and inflammatory process, including osteomyelitis took place.
Prior to treatment of a bisfosfonatama it is necessary to provide dental inspection and the corresponding preventive procedures at patients with risk factors (the accompanying therapy chemotherapy, radiation therapy, treatment of GKS; associated diseases – anemia, coagulopathies, an infection, the available oral cavity disease; bad hygiene of a mouth).
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 to dental interventions
risk of an osteonecrosis of a jaw. Treatment planning of the specific patient has to be based on individual assessment of a ratio risk/advantage.

Side effects:

The undesirable reactions connected using zoledronovy acid usually slight. Criteria of frequency of side reactions:
very often (_1/10), it is frequent (_1/100, <1/10), sometimes
(_1/1000, <1/100), it is rare (_1/10000, <1/1000), is very rare (<1/10000, including separate messages).
From bodies of a hemopoiesis: often – anemia, sometimes – thrombocytopenia, a leukopenia; seldom – a pancytopenia.
From TsNS and peripheral 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 an organ of sight: often – conjunctivitis; sometimes – a sight illegibility; very seldom – a uveitis, an episcleritis.
From the alimentary system: often – nausea, vomiting, anorexia; sometimes – diarrhea, a lock, abdominal pains, dyspepsia, stomatitis, dryness in a mouth.
From respiratory system: sometimes – short wind, cough.
Dermatological reactions: sometimes – an itch, rash (including erythematic and macular), the increased perspiration.
From a musculoskeletal system: often – ostealgias, a mialgiya, an arthralgia, generalized pains; sometimes – muscular spasms.
From outside сердечно&сосудистой systems: sometimes – the expressed increase in the ABP; seldom – bradycardia.
From an urinary system: often – renal failures; sometimes – an acute renal failure, a hamaturia, a proteinuria.
Allergic reactions: sometimes – hypersensitivity reactions; seldom – a Quincke's disease.
From 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, fervescence); sometimes – an adynamy, peripheral hypostases; thorax pain, increase in body weight. At treatment of patients of a bisfosfonatama in clinical practice exceptional cases of development of an osteonecrosis of a jaw are described (usually after extraction
tooth or other dental intervention). The accurate causal relationship of development of an osteonecrosis is not established.

Interaction with other medicines:

At simultaneous use with zoledronovy acid of other often used medicines (antineoplastic means, diuretics, antibiotics, analgetics) of any clinically significant interactions it is noted.
According to the data obtained in the researches in vitro
zoledronovy acid has no considerable linkng with proteins of plasma and does not inhibit isoenzymes of system of P450 cytochrome.
It is recommended to be careful at simultaneous use of bisfosfonat and aminoglycosides as simultaneous effect of these drugs is shown by increase in duration of decrease in concentration of calcium in a blood plasma.
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 disturbances is possible
functions of kidneys at in introduction of bisfosfonat, such as zoledronovy acid, to combinations with a thalidomide.
Pharmaceutical interaction
Divorced solution of zoledronovy acid cannot be mixed with the infusion solutions containing calcium ions, for example, Ringer's solution.

Contraindications:

– initial heavy renal failure
(KK <30 ml/min.);
– pregnancy;
– period of a lactation (breastfeeding);
– children's and teenage age (safety and efficiency of use were not studied);
– hypersensitivity to zoledronovy acid, other bisfosfonata or any
to other components which are a part of drug.
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 use of zoledronovy acid for patients with bronchial asthma, sensitive to acetylsalicylic acid (at use of other bisfosfonat bronchospasm cases were noted).

PREGNANCY AND LACTATION
Drug is contraindicated to use at pregnancy and in the period of a lactation.

Overdose:

Symptoms: strengthening of symptoms of a hypocalcemia. Treatment: administration of calcium of a gluconate.

Storage conditions:

Drug should be stored in dry, protected from light, the place, unavailable to children, at a temperature not above 25 °C. A period of validity – 2 years.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for infusions. On 4 mg in the bottles from colourless glass corked by brombutilovy traffic jams and which are pressed out by aluminum caps with safety plastic covers of orange color. On 1 bottle in a cardboard pack.