Zoledronic acid concentrate d / prig.r-ra d / ifusion 4mg, 5ml No. 1

• Bone metastases in malignant solid tumors (prostate cancer, breast cancer and others) and multiple myeloma, including to reduce the risk of pathological fractures, spinal cord compression.

• Hypercalcemia due to malignant tumors.

Bone metastases in malignant solid tumors and multiple myeloma:

Adults and elderly patients

The recommended dose is 4 mg by intravenous drip, for at least 15 minutes every 3-4 weeks. Before the introduction of the drug, the concentrate (contents of 1 bottle) is diluted with 100 ml of an infusion solution that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution).

Patients should also be additionally prescribed calcium by mouth at a dose of 500 mg per day and vitamin D by mouth at a dose of 400 IU per day.

Hypercalcemia due to malignant tumors:

Adults and elderly patients

In hypercalcemia (concentration of serum calcium corrected for albumin? 12 mg / dL or 3 mmol / L), the recommended single dose of the drug is 4 mg. To ensure adequate hydration of the patient, it is recommended to administer saline before, simultaneously or after the infusion of zoledronic acid.

Patients with impaired renal function

Hypercalcemia due to malignant tumors:

The decision to treat patients with severe renal impairment with zoledronic acid should be made only after a careful assessment of the risk of using the drug and the expected benefit of therapy. Patients whose serum creatinine concentration is <400 ?mol / L or <4.5 mg / dL does not require dosage adjustment.

Bone metastases of common malignant tumors and multiple myeloma:

The dose of zoledronic acid depends on the baseline creatinine clearance calculated using the Cockcroft-Gault formula. It is not recommended to take zoledronic acid in patients with severe renal impairment (creatinine clearance values ??<30 ml / min).

After the start of therapy, the concentration of serum creatinine should be determined before the introduction of each dose of the drug. If renal dysfunction is detected, the next administration of zoledronic acid should be postponed. Renal dysfunction is defined by the following parameters:

For patients with a normal baseline serum creatinine concentration (<1.4 mg / dl) - an increase in creatinine concentration by 0.5 mg / dl;

For patients with an altered baseline serum creatinine concentration (> 1.4 mg / dL), an increase in creatinine concentration by 1 mg / dL.

Therapy with zoledronic acid is resumed only after the level of creatinine reaches values ??within ± 10% of the initial value, at the same dose that was used before the interruption of treatment.

Preparation of solution for infusion

A solution for infusion is prepared from a concentrate of 4 mg / 5 ml (contents of 1 bottle) under aseptic conditions. Before the administration of the drug, the concentrate (the contents of 1 bottle or a smaller volume, if required) is diluted with 100 ml of a solution for infusion that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution). It is advisable to use the prepared zoledronic acid solution immediately after preparation. The solution unused immediately can be stored in aseptic conditions in a refrigerator at a temperature of + 2-8 ? C for no more than 24 hours. Before administration, the solution should be kept indoors until it reaches room temperature.

The total time between the dilution of the concentrate, storage of the preparation of the solution under aseptic conditions in the refrigerator at a temperature of + 2-8 ? C and the end of the administration of the drug should not exceed 24 hours.

Zoledronic acid solution should not be mixed with any other medicinal products. The drug should not be mixed with any solutions containing calcium and any other divalent cations, such as Ringer's solution. A separate infusion set should always be used to administer zoledronic acid solution.

Active substance:

Zoledronic acid monohydrate 4,264 mg in terms of zoledronic acid 4,000 mg

Excipients: Mannitol 220,000 mg, Sodium citrate dihydrate 24,000 mg, Water for injection up to 5 ml.

• Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.

• Severe renal dysfunction (CC less than 30 ml / min).

• Pregnancy and lactation.

• Childhood (efficacy and safety have not been established)

Carefully:

Use the drug with caution in patients with mild and moderate renal impairment (CC> 30 ml / min).

Caution should be exercised when used simultaneously with other drugs that can cause hypocalcemia (for example, aminoglycosides, calcitonin, 'loop' diuretics) due to the risk of a synergistic effect leading to severe hypocalcemia.

The drug should be used with caution in conjunction with other drugs with nephrotoxic potential.

It should be used with caution in conjunction with anti-angiogenic drugs due to the increased risk of developing osteonecrosis of the jaw.

Observe caution when used in patients with severe liver dysfunction due to the limited data on the use of the drug in patients of this category.

Pregnancy and lactation:

The use of the drug Zoledronic acid during pregnancy is contraindicated.

Zoledronic acid may have adverse effects on the fetus. In animal studies, toxic effects on reproductive function have been identified. There is no data on the use of the drug during pregnancy in humans.

If pregnancy occurs during bisphosphonate therapy, there is a possible risk of intrauterine fetal malformations (for example, skeletal anomalies and other anomalies). The dependence of the risk on the magnitude of the time interval between the cessation of bisphosphonate therapy and the moment of conception, the route of administration and the characteristics of a particular drug is unknown.

Women of reproductive age should be warned about the need to use reliable contraceptive methods during treatment with Zoledronic acid.

It is not known whether zoledronic acid passes into breast milk. The use of the drug Zoledronic acid during breastfeeding is contraindicated.

In animal studies, zoledronic acid suppressed fertility at a dose of 0.1 mg / kg per day. There is no evidence of the effect of zoledronic acid on human fertility.

Pharmacodynamics

Zoledronic acid is a highly effective bisphosphonate that selectively acts on the bone. The drug inhibits bone resorption by acting on osteoclasts.

The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. The exact molecular mechanism behind the inhibition of osteoclast activity is still unclear. Zoledronic acid has no undesirable effects on bone formation, mineralization and mechanical properties.

In addition to the inhibitory effect on bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug in bone metastases:

In vivo: inhibition of osteoclastic resorption of bone tissue, altering the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells; anti-angiogenic activity. Suppression of bone resorption is clinically accompanied, among other things, by a pronounced decrease in pain.

In vitro: inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity, synergistic cytostatic effect with anticancer drugs; antiadhesive / invasive activity.

Zoledronic acid, suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer, and also reduces the penetration of human breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and has an anti-angiogenic effect in animals.

In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone lesions, zoledronic acid prevents the development of pathological fractures, compression of the spinal cord, reduces the need for radiation therapy and surgery, and reduces tumor hypercalcemia. The drug is able to restrain the progression of pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic foci than with osteolytic ones.

In patients with multiple myeloma and breast cancer with at least one bone focus, the efficacy of zoledronic acid at a dose of 4 mg is comparable to that of pamidronate at a dose of 90 mg.

In patients with tumor hypercalcemia, the effect of zoledronic acid is characterized by a decrease in the level of calcium in the blood serum and the excretion of calcium by the kidneys. The average time to normalize calcium levels is about 4 days. By the 10th day, the calcium concentration is normalized in 87-88% of patients. The mean time to relapse (albumin-corrected serum calcium level of at least 2.9 mmol / L) is 30-40 days. No significant differences were observed between the efficacy of zoledronic acid at doses of 4 and 8 mg in the treatment of hypercalcemia.

Studies show no significant differences in the frequency and severity of adverse events observed in patients treated with zoledronic acid 4 mg and 8 mg, pamidronate 90 mg, or placebo for both the treatment of bone metastases and hypercalcemia.

Pharmokinetics

Pharmacokinetic parameters do not depend on the dose of the drug.

After the start of the infusion of zoledronic acid, the serum concentration increases rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% of the peak after 24 hours with a consistently prolonged period of low concentrations not exceeding 0.1% of maximum before re-infusion on day 28. Zoledronic acid, administered intravenously, is excreted by the kidneys in three stages: a rapid two-phase elimination of the drug from the systemic circulation with half-lives of 0.24 h and 1.87 h and a prolonged phase with a terminal half-life of 146 h. every 28 days. Zoledronic acid is not metabolized and is excreted by the kidneys unchanged. During the first 24 hours, 39 ± 16% of the administered dose is found in the urine.The rest of the drug is mainly associated with bone tissue. Then, the reverse release of zoledronic acid from the bone tissue into the systemic circulation and its excretion by the kidneys occurs slowly. The total plasma clearance of the drug is 5.04 ± 2.5 l / h and does not depend on the dose of the drug, gender, age, race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 minutes leads to 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 race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 minutes results in a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect the area under the concentration-time curve (AUC).the race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 minutes results in a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect the area under the concentration-time curve (AUC).

Pharmacokinetic studies in patients with hypercalcemia or impaired liver function have not been performed. According to data obtained in vitro, zoledronic acid does not inhibit isozymes of the cytochrome P450 system and does not undergo biotransformation, which suggests that the state of liver function does not significantly affect the pharmacokinetics of zoledronic acid. Less than 3% of the drug dose is excreted through the intestines.

Renal clearance of zoledronic acid positively correlates with creatine clearance and is 75 ± 33% of creatinine clearance, averaging 84 ± 29% (range 22-143 ml / min). In patients with a creatinine clearance of 20 ml / min (severe renal failure) or 50 ml / min (moderate renal failure), the calculated clearance of zoledronic acid is 37% and 72%, respectively, of the zoledronate clearance value in patients with a creatinine clearance of 84 ml / min. Pharmacokinetic data in patients with severe renal impairment (creatinine clearance (CC) less than 30 ml / min) are limited.

A low affinity of zoledronic acid to the cellular components of the blood has been shown, the binding to plasma proteins is low (about 56%) and does not depend on the concentration of zoledronic acid.

Drug interactions

With the simultaneous use of other commonly used drugs with zoledronic acid (antineoplastic agents, diuretics, antibiotics, analgesics), no clinically significant interactions were noted.

According to data obtained in in vitro studies, zoledronic acid does not have significant binding to plasma proteins and does not inhibit isozymes of the cytochrome P450 system. However, special clinical studies to study drug interactions have not been conducted.

It is recommended to be careful while using bisphosphonates with aminoglycosides, calcitonin, loop diuretics, since the simultaneous administration of these drugs causes a more prolonged decrease in plasma calcium concentration.

Caution is necessary with the simultaneous use of zoledronic acid with drugs that potentially have nephrotoxic effects. It should also be borne in mind the likelihood of developing hypomagnesemia.

Patients with multiple myeloma may have an increased risk of renal impairment with intravenous administration of bisphosphonates such as zoledronic acid in combination with thalidomide.

Pharmaceutical interactions and compatibility issues

Do not mix diluted zoledronic acid with infusion solutions containing calcium ions, such as Ringer's solution.

When using glass vials, infusion systems and bags of various types made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for the administration of zoledronic acid, no signs of incompatibility with zoledronic acid were found.

Overdose

In acute overdose of the drug (limited data), renal dysfunction, including renal failure, changes in the electrolyte composition, including the concentration of calcium, phosphate and magnesium in the blood plasma, were noted. A patient who has received a dose of the drug in excess of the recommended one should be under constant supervision. In the event of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Side effects

Disturbances from the blood and lymphatic system: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely pancytopenia.

Nervous system disorders: often - headache, paresthesia; infrequently - dizziness, dysgeusia, hypesthesia, hyperesthesia, tremor; very rarely - convulsions, kinesthesia and tetany (developing due to hypocalcemia).

Mental disorders: often - sleep disturbance; infrequently - a feeling of anxiety; rarely - confusion.

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

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

Disturbances from the respiratory system, chest and mediastinal organs: sometimes - shortness of breath, cough; rarely, interstitial lung disease.

Skin and subcutaneous tissue disorders: sometimes - itching, rash (including erymatous and macular), increased sweating.

Musculoskeletal and connective tissue disorders: often - bone pain, myalgia, arthralgia, generalized pain, joint stiffness; infrequently - jaw necrosis, muscle cramps.

Disturbances from the heart and blood vessels: sometimes - a pronounced increase or decrease in blood pressure; rarely - bradycardia; arrhythmia (developing due to hypocalcemia).

Renal and urinary tract disorders: often - renal dysfunction; sometimes - acute renal failure, hematuria, proteinuria.

Immune system disorders: sometimes - hypersensitivity reactions; rarely - angioedema.

Laboratory and instrumental data: very often - hypophosphatemia; often - an increase in serum concentrations of creatinine and urea, hypocalcemia; sometimes - hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.

General disorders and disorders at the injection site: often - acute phase reaction, fever, flu-like syndrome (including general malaise, chills, feeling of malaise, 'hot flashes'), peripheral edema, asthenia; infrequently - reactions at the injection site (pain, irritation, swelling, induration, redness), chest pain, weight gain; rarely, arthritis and joint swelling as a symptom of an acute phase reaction.

It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma who are sensitive to acetylsalicylic acid, cases of bronchospasm were observed, however, this phenomenon was not observed when using zoledronic acid.

In the treatment of patients with bisphosphonates in clinical practice, rare cases of osteonecrosis of the jaw have been described (usually after tooth extraction or other dental intervention). A clear causal relationship for the development of osteonecrosis has not been established.

Adverse events according to spontaneous reports and literature reports (frequency unknown)

Immune system disorders: anaphylactic reaction / shock.

Nervous system disorders: drowsiness.

Violations of the organ of vision: episcleritis, scleritis and inflammatory diseases of the orbit.

Cardiac disorders: atrial fibrillation.

Vascular disorders: A decrease in blood pressure leading to fainting or circulatory collapse, mainly in patients with risk factors.

Disturbances from the respiratory system, chest and mediastinal organs: bronchospasm.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: sudden severe limitation of joint mobility and / or severe and sometimes disabling pain in bones, joints and / or muscles, atypical subtrochanteric and diaphyseal fractures of the femur.