Resoclastin FS - instructions for use, dose, side effects, contraindications

1 ml of concentrate contains: active substance: Zoledronic acid monohydrate - 0.85 mg (corresponding to zoledronic acid anhydrous) 0.80 mg; Excipients: D-Mannitol 44.0 mg, Sodium citrate dihydrate 5.5 mg (corresponding to sodium citrate anhydrous) 4.8 mg, Water for injection up to 1.0 ml

1 bottle contains 5 ml (4 mg of zoledronic acid) or 6.25 ml (5 mg of zoledronic acid) of the concentrate.

Description:

Transparent colorless liquid.

Pharmacotherapeutic group:Bone resorption inhibitor - bisphosphonate.

ATX: & nbsp

M.05.B.A.08 Zoledronic acid

Pharmacodynamics:

The drug "Resoclastin FS" refers to a new class of highly effective bisphosphonates that have a selective effect on bone tissue. Zoledronic acid inhibits the activity of osteoclasts, does not have an undesirable effect on the formation, mineralization and mechanical properties of bone tissue. The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue, but the exact molecular mechanism providing inhibition of osteoclast activity is still unclear. Zoledronic acid In addition to the inhibitory effect on bone resorption, it has direct antitumor properties that provide efficacy in bone metastases.

In vitro determined that zoledronic acid, suppressing proliferation and inducing apoptosis of cells, has a direct antitumor effect on myeloma cells and breast cancer, reduces the risk of their metastasis.Inhibition of osteoclastic bone resorption leads to a decrease in the growth of tumor cells; there is an anti-angiogenic and analgesic activity. Zoledronic acid suppresses also the proliferation of human endothelial cells. With hypercalcemia caused by a tumor, reduces the concentration of calcium in the blood serum.

The use of zoledronic acid in patients with postmenopausal osteoporosis (T-criterion of bone mineral density of the femoral neck less than-2.5) showed a statistically significant reduction in the risk of vertebral fractures, as well as a reduced risk of developing one or more new (repeated) vertebral fractures. In the treatment of zoledronic acid in patients with Paget's bone disease, a statistically significant, rapid and prolonged therapeutic response was observed, normalization of the bone metabolism level and concentration of AP in the blood plasma.

The drug is also highly effective in patients who received previous treatment with oral bisphosphonates. It has been established that in most patients with zoledronic acid the therapeutic response is maintained throughout the treatment period (about 2 years).

In patients with postmenopausal osteoporosis and bone disease Paget zoledronic acid does not affect the quality of normal bone, does not disrupt the processes of bone remodeling and mineralization and contributes to the preservation of normal trabecular bone architectonics.

Pharmacokinetics:

Pharmacokinetic parameters do not depend on the dose. After the start of infusion, serum concentration increases rapidly, reaching a maximum concentration (C_max) at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and at less than 1% of C_max after 24 hours with a further long period of low concentrations not exceeding 0.1% of C_max, until repeated infusion for 28 days.

The connection with plasma proteins is 56%. Plasma clearance does not depend on the dose of the drug, sex, age, race and body weight of the patient. Not exposed to metabolism. From 20 to 50% is excreted by the kidneys unchanged in 3 stages: 1 and 2 phases - rapid removal of the drug from the systemic blood flow with a half-life (T1) - 0.24 h and 1.87 h, respectively; and a prolonged 3 phase with T1 - 146 hours. No cumulation of the drug was observed with repeated injections every 28 days. During the first 24 hours in urine, 23-55% of the administered dose is detected.The rest of the drug binds to the bone tissue, after which a slow reverse release into the systemic circulation and excretion by the kidneys occurs; intestine is excreted less than 3 % zoledronic acid. An increase in the infusion time from 5 to 15 minutes results in a 30% decrease in the concentration of zoledronic acid at the end of the infusion, but does not affect the area under the concentration-time curve (AUC). The renal clearance of zolendronic acid positively correlates with creatinine clearance (CC) and is 42-108% of the CK, averaging 55-113 %. In patients with severe (CK <20 ml / min) and moderate renal failure (CK 20 to 50 ml / min), the zoledronic acid clearance is 37% and 72%, respectively, of clearance values in patients with CK> 84 ml / min.

Indications:

Hypercalcemia (concentration of albumin corrected serum calcium> 12 mg / dl or 3 mmol / l), induced by malignant tumors.
Metastatic bone damage in malignant solid tumors and myeloma (to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia, and reduced need for radiotherapy).
Postmenopausal form of primary osteoporosis.
Senile form of primary osteoporosis.
Secondary osteoporosis.
Bone disease of Paget.

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.
Severe renal insufficiency (creatinine clearance << - 30 ml / min).
Pregnancy and lactation.
Child and adolescence (safety and efficacy not established).

Carefully:

With caution in the violation of kidney function, with severe hepatic insufficiency (no data on use), in patients with bronchial asthma, sensitive to acetylsalicylic acid.

Dosing and Administration:

Resoclastin FS is administered intravenously drip, for at least 15 minutes.

With hypercalcemia due to malignant tumors (calcium concentration with an albumin correction> 12 mg / dL or 3 mmol / L), the recommended dose of the drug is 4 mg, once. Infusion is performed under the condition of adequate hydration of the patient.

At metastatic defeat of bones with malignant solid tumors and myeloma disease the recommended dose of the drug is 4 mg, every 3-4 weeks. In addition, it is recommended to prescribe calcium in a dose of 500 mg per day and vitamin D at a dose of 400 IU per day.

In the postmenopausal and senile form of primary osteoporosis with the aim of increasing the mineral density of bone tissue, preventing vertebral fractures and other bones of the skeleton, the recommended dose Reso-Klastin FS is 5 mg, once a year.

With secondary osteoporosis recommended dose Reso-Klastin FS is 5 mg, once a year. If the intake of calcium and vitamin D in the body with food is not enough, patients with osteoporosis should additionally be prescribed calcium and vitamin D. Duration of the drug is determined by the doctor individually depending on the patient's condition.

For treatment of Paget's bone disease it is recommended a single intravenous administration of the drug in a dose of 5 mg. Since, Paget's bone disease is characterized by a high level of bone metabolism, it is recommended that all patients with this disease take a daily intake of calcium and vitamin D within the first 10 days after the administration of zoledronic acid.

Repeated treatment with zoledronic acid of Paget's bone disease. After the first administration of the drug, a long period of remission is observed. Currently, there is no specific data on re-treatment of Paget's bone disease. However, the possibility of re-introduction of the drug can be considered in case of detection of relapse of the disease in patients based on the following criteria: the lack of normalization of serum alkaline phosphatase activity, the increase in its activity in dynamics, and the presence of clinical signs of Paget's bone disease detected after a medical examination after 12 months after the administration of the first dose of zoledronic acid.

In patients with impaired renal function

Hypercalcemia due to malignant tumors:

The decision to treat zoledronic acid patients with severe renal dysfunction should only be taken after a thorough assessment of the risk / benefit ratio. When the serum creatinine concentration is <400 μmol / L or <4.5 mg / dl, correction of the dosing regimen is not required.

Metastatic bone damage in malignant solid tumors and myeloma:

The dose of zoledronic acid in patients with impaired renal function depends on the baseline creatinine clearance (CK) calculated by the Cockcroft-Gault formula. In severe disorders of kidney function (KK <30 ml / min), zoledronic acid is not recommended. Recommended doses for mild or moderate renal dysfunction (CC values of 30-60 ml / min) are given below.

The initial value of CS (ml / min)	The recommended dose of zoledronic acid
50-60	3.5 mg
40-49	3.3 mg
30-39	3.0 mg

Determination of the serum creatinine concentration should be determined before each dose of the drug is administered. In the detection of violations of kidney function, the next administration of zoledronic acid should be postponed. Impaired renal function is determined by the following parameters:

for patients with normal baseline creatinine values (<1.4 mg / dl) - an increase in serum creatinine by 0.5 mg / dl;
For patients with abnormalities of baseline creatinine (> 1.4 mg / dl) - increased serum creatinine concentration by 1 mg / dl.

Therapy with zoledronic acid is resumed only after the concentration of creatinine reaches values that exceed the baseline by no more than 10%, at the same dose that was used before the interruption of treatment.

Instructions for preparing a solution

The solution is prepared in aseptic conditions. Before administration, the preparation is diluted (the contents of 1 vial - 4 mg / -5-ml or 5 mg / 6.25 ml, depending on the recommended dose) in 100 ml of a solution for calcium-free infusions (0.9 % solution of sodium chloride or 5 % solution of dextrose). The prepared solution of Resoclastin FS preferably used immediately after preparation. Unused solution can be stored in the refrigerator at a temperature of 2 to 8 ° C for not more than 24 hours. Before administration, the solution should be left in the room until the room temperature is reached. The prepared zoledronic acid solution must be administered using a separate system for intravenous infusion.

Side effects:

Undesirable reactions are listed below for organs and systems, indicating the frequency of their occurrence. Frequency criteria: very often (≥1 / 10), often (≥1 / 100, <1/10), sometimes (≥1 / 1,000, <1/100), rarely - (≥1 / 10,000, <1 / 1,000 ), very rarely (<1 / 10,000), including individual messages.

From the hematopoiesis: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely - pancytopenia.

From the nervous system: often - headache; sometimes - dizziness, a sense of anxiety, paresthesia, tremor, taste disorders, hypoesthesia, hyperesthesia, sleep disorders; rarely confusion.

From the side of the organ of vision: often - conjunctivitis; sometimes - blurred vision; very rarely - uveitis, episcleritis.

From the gastrointestinal tract: often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system: sometimes - shortness of breath, cough.

From the skin and skin appendages: sometimes - itching, rash (including erythematous and macular), increased sweating.

From the musculoskeletal system: often - pain in the bones, myalgia, arthralgia, generalized pain; sometimes - muscle cramps.

From the cardiovascular system: sometimes - marked increase or decrease in blood pressure; rarely - aetiology.

From the urinary system: often - impaired renal function; sometimes - acute renal failure, hematuria, proteinuria.

From the immune system: sometimes - hypersensitivity reactions; rarely - angioedema.

Local reactions: pain, irritation, swelling, the formation of an infiltrate at the site of administration of the drug.

Violations of laboratory indicators: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; sometimes hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.

Other: often - influenza-like syndrome (including general malaise, chills, painful condition, fever), fever, sometimes - asthenia, peripheral edema; pain in the chest, weight gain. In the treatment of patients with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental intervention) have been observed. In very rare cases, a reduction in blood pressure with zoledronic acid therapy resulted in syncope or circulatory collapse.

Overdose:

In case of an accidental drug overdose, the patient should be under constant medical supervision. In the case of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Interaction:

Solvents that contain calcium or any divalent cations, such as Ringer's lactate solution, can not be used as solvents. With simultaneous use with antitumor drugs, diuretics, antibiotics, analgesics, clinically significant interactions have not been observed.Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, so when they are concurrently prescribed, the risk of hypocalcemia and hypomagnesemia increases. It is advisable to use caution while using zoledronic acid with drugs potentially having a nephrotoxic effect. In patients with multiple myeloma, there may be an increased risk of kidney dysfunction with intravenous bisphosphonate administration in combination with thalidomide. The drug should not be mixed with other drugs.

Special instructions:

Before the infusion, dehydration in the patient should be avoided. If necessary, the introduction of saline before, parallel or after infusion of zoledronic acid is recommended. It is necessary to avoid hyperhydration of the patient because of the risk of complications from the cardiovascular system.

When resolving the question of the use of resoclastin FS in patients with hypercalcemia caused by a malignant tumor, against a background of impaired renal function, it is necessary to assess the patient's condition and to draw a conclusion about the relationship between the potential benefit and the possible risk of treatment.After the administration of the drug, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary.

On the background of therapy with zoledronic acid should closely monitor the function of the kidneys. The risk factors for renal impairment include dehydration, previous kidney failure, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug.

It should be borne in mind that in the appointment of other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but with the use of zoledronic acid, such cases have not yet been documented.

Oncological patients treated with bisphosphonates, including zoledronic acid, described cases of osteonecrosis of the jaw, and therefore, before the treatment, it is necessary to provide a dental examination and if there are risk factors (anemia, coagulopathy, infection, poor hygiene or diseases of the oral cavity, concomitant chemo- or radiotherapy, corticosteroid treatment) to conduct appropriate preventive procedures.Against the background of treatment with zoledronic acid, patients with risk factors, whenever possible, should avoid dental surgical interventions. To reduce the incidence of adverse reactions after the infusion of Resoclastin FS, patients should be assigned paracetamol or ibuprofen immediately after the administration of the drug.

Effect on the ability to drive transp. cf. and fur:

Care must be taken when driving vehicles and other mechanisms.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 4 mg / 5 ml and 5 mg / 6.25 ml.

Packaging:

5 ml of a concentrate containing 4 mg of zoledronic acid and 6.25 ml of a concentrate containing 5 mg of zoledronic acid to dark-colored bottles with a capacity of 10 ml, hermetically sealed with rubber stoppers and aluminum-plastic caps.

1 bottle of the drug in a plastic or cardboard substrate, together with the instruction for use, is placed in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

Shelf life - 2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003578/10

Date of registration:29.04.2010

The owner of the registration certificate:F-SYNTHESIS, CJSC F-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

F-SYNTHESIS, CJSC Russia

Information update date: & nbsp18.10.2015

Illustrated instructions

Instructions

Resoclastin FS (Rezoklastin FS)