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

Composition

Active ingredient:

zoledronic acid monohydrate;

Auxiliary substances:

d-mannitol;

sodium citrate dihydrous;

Solvent in ampoule:

water for injection 5 ml;

Solvent in a polymer container:

sodium chloride 9.0 g;

water for injection.

Pharmacological 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

Pharmacokinetic parameters do not depend on the dose. After the start of the infusion, the serum concentration increases rapidly, reaching Cmax at the end of the infusion, followed by a rapid decrease in concentration: by 10% after 4 hours and to 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: stages 1 and 2 — rapid elimination of the drug from the systemic circulation, with T 1/2 — 0.24 hours and 1.87 hours, respectively, and stage 3-long, with T 1/2 — 146 hours. No accumulation of the drug was observed 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 Cl and is 42-108% of Creatinine Cl, which averages 55-113%. In patients with severe (Cl creatinine ≤20 ml/min) and moderate renal insufficiency (Cl creatinine from 20 to 50 ml/min), the clearance of zoledronic acid is 37 and 72%, respectively, of the drug clearance values in patients with Cl creatinine ≥84 ml/min.

Indications

Hypercalcemia (serum albumin-adjusted calcium concentration ≥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-related hypercalcemia, and reduce the need for radiation therapy).

Use during pregnancy and lactation

Contraindicated in pregnancy. Breast-feeding should be discontinued for the duration of treatment.

Contraindications

• hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug;
• severe renal failure (creatinine clearance less than 30 ml / min);
• pregnancy and lactation;
• children and adolescents (safety and efficacy of the drug have not been established).

With caution:  impaired renal function; severe hepatic insufficiency (no data on use); patients with bronchial asthma, sensitive to acetylsalicylic acid.

Side effects

From the side of hematopoietic organs:  often-anemia; sometimes-thrombocytopenia, leukopenia; rarely-pancytopenia.

Nervous system disorders:  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.

Respiratory system disorders:  sometimes-shortness of breath, cough.

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

Musculoskeletal disorders:  often-bone pain, myalgia, arthralgia, generalized pain; sometimes-muscle cramps.

From the CCC side:  sometimes-a marked increase or decrease Blood pressure; rarely-bradycardia.

From the urinary 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, infiltrate formation at the injection site.

Other services:  often — fever, flu-like syndrome (including general malaise, chills, pain, fever), sometimes-asthenia, peripheral edema; chest pain, weight gain.

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. With the development of hypocalcemia, hypophosphatemia or hypomagnesemia, short-term additional use of appropriate substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function in this category of patients is necessary. When deciding whether to treat patients with bone metastases with zoledronic acid, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.

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. Despite the fact that the risk of the above-described complications is reduced if zoledronic acid is administered at a dose of 4 mg for at least 15 minutes, the possibility of impaired renal function remains. There have been cases of deterioration of renal function, progression of renal failure and the need for hemodialysis with the first or single use of zoledronic acid.

The drug should not be mixed with other drugs.

How to take, course of use and dosage

Intravenous, drip, for at least 15 minutes.

Overdose

Symptoms:  acute overdose of zoledronic acid may lead to impaired renal function, including renal failure, changes in the electrolyte composition, including the concentration of calcium, phosphates and magnesium in the blood plasma. In case of accidental overdose, the patient should be constantly monitored.

Treatment:  in case of hypocalcemia accompanied by clinical manifestations, calcium gluconate infusions are indicated.

Special instructions

Make sure that the patient is adequately hydrated before the infusion. If necessary, the use of saline solution before, during or after the infusion of zoledronic acid is recommended. Hyperhydration of the patient should be avoided because of the risk of CVD complications.

After use of the drug, it is necessary to constantly monitor the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum.

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.

Influence on the ability to drive a car and other mechanisms. Studies of the effect of the drug on the ability to drive vehicles and work with complex mechanisms have not been conducted. In case of side effects from the central nervous system, it is recommended to avoid activities that require increased attention and speed of mental and motor reactions.

Form of production

Lyophilizate for infusion solution preparation

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C

Expiration date

Lyophilizate — 3 years, reconstituted solution-24 hours, solvent (water for injection) — 5 years, solvent (0.9% sodium chloride infusion solution) – 3 years. The expiration date of the kit is set by default

Active ingredient

Zoledronic acid

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

Adult Doctor’s prescription