Rezorba lyophilisate for infusion solution 4mg + water for injection 5ml + sodium chloride 100ml, pack

Composition

of 1 fl. : – zoledronic acid monohydrate 4.26 mg, which corresponds to content of zoledronic acid anhydrous 4 mgsupport substances: D-mannitol – 220 mg, sodium citrate dihydrate-27.34 mg (in terms of sodium citrate anhydrous-24 mg). Solvent in ampoule: d/i water-5 ml. Solvent in container: sodium chloride solution for infusions 0.9% – 100 ml

Pharmacological action

Pharmaceutical group: bone resorption inhibitor-biphosphonate. Pharmaceutical action: The drug Rezorba belongs to a new class of highly effective bisphosphonates that have a selective effect on bone tissue. 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 that provides inhibition of osteoclast activity is still unclear. It also has direct antitumor properties that provide effectiveness in bone metastases. In vitro, it was found that zoledronic acid suppresses cell proliferation and induces apoptosis, has a direct antitumor effect on myeloma and breast cancer cells, and reduces the risk of their metastasis. Inhibition of osteoclastic bone resorption, which changes the bone marrow microenvironment, leads to a decrease in the growth of tumor cells; antiangiogenic and analgesic activity is noted. Zoledronic acid also inhibits the proliferation of human endothelial cells. When hypercalcemia is caused by a tumor, it reduces the concentration of calcium in the blood serum. Pharmacokinetics: The pharmacokinetic parameters are dose-independent. After the start of the infusion, the serum concentration increases rapidly, reaching a maximum concentration (Cmax) at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% of Cmax after 24 hours, followed by a long period of low concentrations not exceeding 0.1% of Cmax, until repeated infusion on day 28. Binding to plasma proteins is 56%. It is not metabolized. It is excreted unchanged by the kidneys in 3 stages: phase 1 and 2 – rapid elimination of the drug from the systemic circulation, with a half – life of 0.24 hours and 1.87 hours, respectively, and phase 3 – long, with a half – life of 146 hours. There was no accumulation of Resorb with repeated injections every 28 days. During the first 24 hours,23-55% is detected in the urine. The remaining amount of the drug binds to bone tissue, after which it is slowly released back into the systemic circulation and excreted by the kidneys; less than 3% is excreted in the feces. Total plasma clearance is 2.54 – 7.54 l/h. It does not depend on the dose of the drug, gender, age, race, or body weight of the patient. Increasing the duration of the infusion from 5 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 AUC. Renal clearance is positively correlated with creatinine clearance (creatinine clearance) and is 42-108% of the mean creatinine clearance of 55-113%. In patients with severe (creatinine clearance 20 ml/min) and moderate renal insufficiency (creatinine clearance 50 ml/min), the clearance of zoledronic acid is 37 and 72%, respectively, of the drug clearance values in patients with creatinine clearance 84 ml/min.

Indications

• osteolytic, osteoblastic and mixed bone metastases of solid tumors;
• osteolytic foci in multiple myeloma;
• hypercalcemia caused by a malignant tumor.

Contraindications

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug. Severe renal insufficiency (creatinine clearance Pregnancy and lactation. Children and adolescents (safety and efficacy of the drug have not been established). With caution: with impaired renal function, severe hepatic insufficiency (no data on use), in patients with bronchial asthma, sensitive to acetylsalicylic acid.

Side effects

Adverse reactions are listed below by organ and system, with an indication of the frequency of their occurrence. Frequency criteria: very common (≥1/10), common (≥1/100, From the hematopoietic organs: often-anemia, sometimes-thrombocytopenia, leukopenia; rarely-pancytopenia. From the nervous system: often-headache; sometimes-dizziness, paresthesia, taste disorders, hypesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely-confusion. From the side of the visual organs: 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 erymatous and macular), increased sweating. From the musculoskeletal system: often-bone pain, myalgia, arthralgia generalized pain; sometimes-muscle cramps. From the cardiovascular system: sometimes-a pronounced increase or decrease in blood pressure; rarely-bradycardia. From the excretory system: often-impaired renal function; sometimes-acute renal failure, hematuria, proteinuria. From the immune system: sometimes-hypersensitivity reactions; rarely-angioedema. Violations of laboratory parameters: very often – hypophosphatemia; often-increased serum creatinine and urea concentrations, hypocalcemia; sometimes-hypomagnesemia, hypokalemia; rarely-hyperkalemia, hypernatremia. Local reactions: pain, irritation, swelling, infiltration at the injection site. Others: often-fever, flu-like syndrome (including general malaise, chills, pain, fever), sometimes-asthenia, peripheral edema; chest pain, weight gain. Patients treated with bisphosphonates, including zoledronic acid, have occasionally developed osteonecrosis of the jaw (usually after tooth extraction or other dental intervention). In very rare cases, lowering blood pressure during zoledronic acid therapy resulted in syncope or circulatory collapse.

Interaction

Solutions containing calcium, in particular Ringer’s solution, should not be used as solvents. When used concomitantly with antitumor drugs, diuretics, antibiotics, and analgesics, no clinically significant interactions were observed. Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, so when they are administered simultaneously, the risk of hypocalcemia and hypomagnesemia increases. Caution should be exercised when zoledronic acid is co-administered with drugs that may have a potentially nephrotoxic effect. Patients with multiple myeloma may have an increased risk of developing impaired renal function with intravenous bisphosphonates in combination with thalidomide. The drug should not be mixed with other medicines.

How to take, course of use and dosage

Intravenous drip for at least 15 minutes. For bone metastases and osteolytic foci in multiple myeloma, the recommended dose is 4 mg of Rezorba, every 3-4 weeks. Additionally, it is recommended to prescribe inside calcium at a dose of 500 mg per day and vitamin D at a dose of 400 IU per day. For hypercalcemia (calcium concentration with albumin correction ≥ 12 mg/dl or 3 mmol/L) caused by malignant tumors, the recommended dose is 4 mg, once. Rezorba infusion is performed under the condition of adequate hydration of the patient. In postmenopausal and senile forms of primary osteoporosis, the recommended dose is 4 mg, once a year, to increase bone mineral density and prevent fractures of the vertebral bodies and other skeletal bones. If dietary intake of calcium and vitamin D is insufficient, patients with osteoporosis should be additionally prescribed calcium and vitamin D supplements. The duration of use of the drug is determined by the doctor individually, depending on the patient’s condition (ci) with postmenopausal or senile primary osteoporosis. In secondary osteoporosis, in order to increase bone mineral density, prevent fractures of the vertebral bodies and other skeletal bones, the recommended dose is 4 mg of Rezorba, once a year. If the intake of calcium and vitamin D from food is insufficient, patients with secondary osteporosis should be additionally prescribed calcium and vitamin D supplements. The duration of use of the drug is determined by the doctor individually, depending on the patient’s condition, the etiology of secondary osteoporosis. Patients with impaired renal function: Hypercalcemia caused by malignant tumors: The decision to treat patients with severe renal impairment with zoledronic acid should be made only after careful assessment of the risk / benefit ratio. If the serum creatinine concentration is < 400 mmol / l orBone metastases of common malignant tumors and myeloma disease: The dose of zoledronic acid depends on the initial level of creatinine clearance (CC) calculated by the Cockcroft-Gault formula. In severe renal impairment (CC

Overdose

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

Special instructions

Before the infusion, make sure that the patient is adequately hydrated. If necessary, the use of saline solution before, in parallel or after the infusion of zoledronic acid is recommended. Hyperhydration of the patient should be avoided due to the risk of complications from the cardiovascular system. After use of Rezorba, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary. Renal function should be carefully monitored during zoledronic acid therapy. Risk factors for impaired renal function include dehydration, previous renal failure, repeated use of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid use of the drug. It should be borne in mind that when prescribing other bisphosphonates to patients with asthma sensitive to acetylsalicylic acid, cases of bronchospasm have been noted, but such cases have not yet been reported with the use of zoledronic acid. During treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have been described in cancer patients. Therefore, before starting treatment with bisphosphonates, it is necessary to provide a dental examination and, if there are risk factors (anemia, coagulopathy, infections, poor hygiene or oral diseases, concomitant chemotherapy or radiation therapy, corticosteroid treatment), conduct appropriate preventive procedures. During treatment with zoledronic acid, patients with risk factors should avoid dental surgery if possible.

Form of production

Lyophilizate for preparation of solution for infusions.

Active ingredient

Zoledronic acid

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

Adult Doctor’s prescription