Expiration date: 05/2025

The composition and form of issue:

Concentrate for solution for infusion. 1 ml contains active substance:

of zoledronic acid monohydrate, 0,85 mg

(meets of zoledronic acid anhydrous and 0.80 mg) 

excipients: 

D-mannitol 44,0 mg

sodium citrate dihydrate 5.5 mg

(corresponds to the sodium citrate anhydrous and 4.8 mg) 

water for injection to 1.0 ml

in dark glass bottles of 5 ml (contains 4 mg of zoledronic acid) or 6.25 mg (containing 5 mg of zoledronic acid) in cardboard packs of 1 vial.

Description pharmaceutical form:

Clear, colorless liquid.

Pharmacokinetics:

Pharmacokinetic parameters are not dose-dependent.

After the start of infusion, the concentration in serum increases rapidly, reaching Cmax at end of infusion, followed by a rapid reduction in the concentration of 10% after 4 h and less than 1% of Cmax after 24 h with a further long period of low concentrations not exceeding 0.1% of Cmax until re-infusion on the 28th day.

The plasma protein binding is 56%. Plasma clearance does not depend on the dose, sex, age, race and body mass of the patient. Is not subjected to metabolism.

From 20 to 50% excreted by kidneys unchanged in 3 stages: 1 and 2 phases — rapid excretion of the drug from the systemic blood circulation with a T1/2 — 0.24 to 1.87 h, respectively and a long 3-phase T1/2 — h 146

Not marked drug accumulation after repeated administration every 28 days. During the first 24 h in the urine detected 23-55 % of the administered dose. The remainder of the drug binds to bone tissue, after which there is a slow release back into the systemic circulation and renal excretion of the bowel is less than 3% of zoledronic acid. Increasing the length of infusion from 5 to 15 min leads to reduction of the concentration of zoledronic acid at 30% at the end of the infusion, but does not affect AUC. The renal clearance of zoledronic acid correlates positively with Cl creatinine is 42-108% of Cl creatinine average 55-113%. In patients with severe (creatinine Cl &le20 ml/min) and moderate (Cl creatinine 20-50 ml/min) renal impairment the clearance of zoledronic acid is 37 and 72% respectively from the values of clearance of the drug in patients with Cl creatinine >84 ml/min.

Description pharmacological action:

The drug Rezoklastin FS belongs to a new class of highly effective bisphosphonates with selective effect on bone tissue. Zoledronic acid suppresses osteoclast activity, does not render undesirable influence on formation, mineralization and mechanical properties of bone tissue. Selective action of bisphosphonates on bone tissue is based on high affinity for mineralized bone, but the exact molecular mechanism for the inhibition of the activity of the osteoclasts is still unclear. Zoledronic acid in addition to inhibitory actions on bone resorption, has direct anti-tumor properties, provides efficacy in bone metastases.

Established In vitro, zoledronic acid, inhibiting the proliferation and inducing apoptosis of cells, has direct antitumor effects on myeloma cells and breast cancer, reduces the risk of metastasis. Osteoclastic inhibition of bone resorption leads to a reduction of tumor cell growth observed anti-angiogenic and analgesic activity. Zoledronic acid also inhibits the proliferation of endothelial cells in humans. If hypercalcemia is caused by a tumor, reduces the concentration of calcium in the blood serum.

With the use of zoledronic acid in patients with postmenopausal osteoporosis (value of T-criterion of mineral bone density of the femoral neck of -2.5 less) was a statistically significant reduction in the risk of vertebral fractures, as well as reducing the risk of developing one or more new (re) of vertebral fractures.

In the treatment of zoledronic acid in patients with bone Paget's disease was a statistically significant, rapid and lasting therapeutic response, and normalization of bone metabolism and concentration of alkaline phosphatase in the blood plasma.

The drug is also highly effective in patients who received prior treatment with oral bisphosphonates. It is established that the majority of patients with the use of zoledronic acid therapeutic response was maintained for the entire period of treatment (about 2 years).

In patients with postmenopausal osteoporosis and bone Paget's disease zoledronic acid does not affect the qualitative state of normal bone, does not violate the processes of bone remodeling and mineralization and promotes the preservation of normal trabecular architecture of the bone.

Indications:

• hypercalcemia (concentration of albumin-adjusted serum calcium &ge12 mg/DL or 3 mmol/l) induced by malignant tumors
  
• metastatic bone lesions with malignant solid tumors and multiple myeloma (to reduce the risk of pathological fractures, spinal cord compression hypercalcemia due to tumor and reduce the need for radiation therapy)
  
• form of primary postmenopausal osteoporosis
  
• form of senile primary osteoporosis
  
• secondary osteoporosis
  
• bone Paget's disease.
  

Contraindications:

• hypersensitivity of zoledronic acid, other bisphosphonates or any other components included in the composition of the drug
  
• expressed kidney failure (Cl creatinine — &le30 ml/min)
  
• pregnancy
  
• the breast-feeding period
  
• childhood and adolescence (safety and efficacy have not been established).
  

Caution should be applied under the following conditions:

• violation of kidney function
  
• severe hepatic insufficiency (no data use)
  
• bronchial asthma (in the patients with hypersensitivity to acetylsalicylic acid).
  

Side effects:

Adverse reactions are listed below according to the organs and systems, indicating the frequency of their occurrence. Criteria frequency: very often — &ge1/10 often — &ge1/100, <1 10="" ge1="" 1000="" 1="" 100="" 10000="" p="">

On the part of the blood: often — anemia, sometimes — thrombocytopenia, leukopenia rare — pancytopenia.

From the nervous system: often — headache sometimes — dizziness, anxiety, paresthesia, tremor, disorders of taste sensations, hypoesthesia, hyperesthesia, sleep disorders, rarely — confusion.

On the part of the organ of vision: often — conjunctivitis sometimes — blurred vision very rare — uveitis, episcleritis.

From the digestive tract: often — nausea, vomiting, anorexia and sometimes diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

The respiratory system: sometimes — shortness of breath, cough.

The skin and skin appendages: sometimes — itching, rash (including erythematous and maculato), excessive sweating.

From the side of musculoskeletal system: often — pain in bones, myalgia, arthralgia, generalised pain and sometimes muscle spasms.

Of the cardiovascular system: sometimes- pronounced increase or decrease in blood pressure, rarely — bradycardia.

From the urinary system: often — violation of kidney function and sometimes acute renal failure, hematuria, proteinuria.

The immune system: sometimes — hypersensitivity reactions rarely — angioedema.

Local reactions: pain, irritation, swelling, education infiltrates at the injection of the drug.

Violations of laboratory parameters: very often — hypophosphatemia often — increased serum concentrations of creatinine and urea, sometimes hypocalcemia — hypomagnesemia, hypokalemia rare — hyperkalemia, hypernatremia.

Other: often — grippopodobnyy syndrome (including General malaise, chills, painful condition, heat), fever, sometimes — asthenia, peripheral oedema, pain in chest, weight gain.

When treating patients with bisphosphonates, including zoledronic acid, sometimes there were cases of developing osteonecrosis of the jaw (usually after tooth extraction or other dental procedures). In very rare cases, decrease in blood pressure during therapy of zoledronic acid led to syncope or circulatory collapse.

Drug interactions:

As solvents cannot be used solutions containing calcium, or any divalent cation, in particular a solution of ringer's lactate.

While the use of anticancer drugs, diuretics, antibiotics, analgesics clinically significant interactions are not marked.

Bisphosphonates and aminoglycosides have a unidirectional influence on the calcium concentration in the serum, so their concurrent use increases the risk of hypocalcemia and hypomagnesemia.

We recommend caution when coadministration of zoledronic acid with drugs, with potentially nephrotoxic effects.

In patients with multiple myeloma may increase the risk of developing impaired renal function at/in the introduction of bisphosphonates in combination with thalidomide.

The drug should not be mixed with other drugs.

Method of application and dose:

In/in, drip, for at least 15 min.

With hypercalcemia due to malignant tumors (concentration of calcium correction for albumin level &ge12 mg/DL or 3 mmol/l), the recommended dose Rezoklastin FS is 4 mg, once. The infusion is carried out under conditions adequate hydration of the patient.

When metastatic bone lesions with malignant solid tumors and multiple myeloma the recommended dose is 4 mg every 3-4 weeks. It is recommended to additionally assign inside the calcium in the dose of 500 mg/day and vitamin D at a dose of 400 IU/day.

In postmenopausal and senile form of osteoporosis is primary to increase mineral bone density, prevent fractures of the vertebral bodies and other bones of the skeleton, the recommended dose is 5 mg 1 time per year.

In secondary osteoporosis, the recommended dose Rezoklastin FS is 5 mg 1 time per year. If the intake of calcium and vitamin D from food is not enough, one should also prescribe calcium and vitamin D. the Duration of the drug determined by the physician individually depending on the patient's condition.

For the treatment of bone Paget's disease it is recommended that a single on/in the introduction of the drug in a dose of 5 mg. In view of the fact that the bone Paget's disease is characterized by a high level of bone metabolism, all patients with this disease are advised to take daily calcium and vitamin D during the first 10 days after administration of zoledronic acid.

Re-treatment of zoledronic acid on bone Paget's disease. After the first administration of the drug is observed for a long period of remission. Currently, specific data on re-treatment of bone Paget's disease is not available. However, repeated injection may be considered in case of detection of patients with disease recurrence on the basis of the following criteria: absence of normalization of the activity of alkaline phosphatase of blood serum, increase its activity in the dynamics and the presence of clinical signs of bone Paget's disease, detected during a medical examination after 12 months after the first dose of zoledronic acid.

Patients with impaired renal function

Hypercalcemia caused by malignant tumors. The decision about the treatment of zoledronic acid in patients with severe renal dysfunction should only be taken after careful evaluation of risk/benefit. When the concentration of creatinine in serum <400 4="" 5="" p="">

Metastatic bone lesions with malignant solid tumors and multiple myeloma. The dose of zoledronic acid in patients with impaired renal function depends on the initial level of Cl creatinine calculated by the formula of Cockcroft-Gault. In severe renal impairment (Cl creatinine <30 cl="" 30="" 60="" p="">

Table

The recommended dose of zoledronic acid depending on the values Cl creatinine

The initial value of Cl creatinine, ml/min	The recommended dose of zoledronic acid, mg
50–60	3,5
40–49	3,3
30–39	3,0

The concentration of serum creatinine should be determined before each dose of the drug. When violations of the kidney another infusion of zoledronic acid should be postponed. Violations of kidney function are defined by the following parameters:

- for patients with normal baseline creatinine values (<1,4 i> is the increase in the concentration of creatinine in serum by 0.5 mg/DL

- for patients with deviations of baseline creatinine (>1.4 mg/DL) — increase of creatinine concentration in serum by 1 mg/DL.

Therapy of zoledronic acid resumes only after the creatinine concentration will reach values above the initial value not more than 10%, the same dose that was used prior to the interruption of treatment.

Instructions for the preparation of the solution

The solution is prepared under aseptic conditions. Before the introduction of the drug is diluted (contents of 1 vial of 4 mg/5 ml or 5 mg/6,25 ml, depending on the recommended dose) in a 100 ml solution for infusion not containing calcium (0.9% sodium chloride solution or 5% dextrose solution).

The prepared solution Rezoklastin FS preferably used immediately after preparation. Unused solution can be stored in the refrigerator at 2 to 8 °C for no longer than 24 h Before introduction of the solution should be kept indoors until they reach room temperature. The prepared solution of zoledronic acid should be entered using a separate system for on/in infusions.

Overdose:

Symptoms: accidental overdose of drug, the patient should be under constant medical supervision. In the event of hypocalcemia, accompanied by clinical manifestations, shown holding infusion of calcium gluconate.

Treatment: the conduct infusion of calcium gluconate.

Special instructions:

Before infusion to exclude the presence of dehydration in the patient. If necessary, that the introduction of saline before, during, or after infusion of zoledronic acid. You should avoid over-hydration of the patient because of the risk of occurrence of complications in the cardiovascular system.

When deciding on the application Rezoklastin FS in patients with hypercalcemia due to malignant tumor, against violations of kidney function, it is necessary to evaluate the patient's condition and conclude that the ratio of potential benefits and possible risks of treatment. After the introduction of the drug requires constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in serum.

The therapy of zoledronic acid should be monitored closely for kidney function. The risk factors of impaired renal function include dehydration, pre-renal failure, multiple doses of zoledronic acid or other bisphosphonates as well as use of nephrotoxic drugs, and too rapid administration of the drug.

It should be borne in mind that when you assign other bisphosphonates to patients with bronchial asthma, hypersensitive to acetylsalicylic acid, there have been cases of bronchospasm, however, the use of zoledronic acid, such cases are not yet registered.

In cancer patients, on the background of treatment with bisphosphonates, including zoledronic acid, described the development of osteonecrosis of the jaw, therefore before treatment it is necessary to provide a dental examination and in case of presence of risk factors (anemia, coagulopathy, infection, poor hygiene or diseases of the oral cavity associated with chemotherapy or radiation therapy, corticosteroid treatment) to carry out appropriate preventive procedures. The treatment of zoledronic acid to patients with risk factors, if possible, avoid dental surgeries. To reduce the frequency of adverse reactions after infusion Rezoklastin FS, patients should be prescribe paracetamol or ibuprofen immediately after drug administration.

Effects on ability to drive vehicles and other mechanisms. Use caution when driving and other mechanisms.

Expiration date:

The solvent is 4 years.