Resorba, lyophilizate 4 mg in kit

Pharmgroup: bone resorption inhibitor – bisphosphonate.
Pharmacological action: The drug Resorba belongs to a new class of highly effective bisphosphonates with selective action on bone tissue. It suppresses the activity of osteoclasts, has no undesirable effect on the formation, mineralization and mechanical properties of the bone tissue. The selective action of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue, but the exact molecular mechanism providing inhibition of osteoclast activity is still unknown. It also has direct antitumor properties that provide effectiveness in bone metastases.
In vitro it was found that zoledronic acid, by inhibiting cell proliferation and inducing apoptosis, has a direct antitumor effect on myeloma and breast cancer cells, reducing their risk of metastasis. Inhibition of osteoclast resorption of bone tissue, which changes bone marrow microenvironment, leads to reduction of tumor cell growth; anti-angiogenic and anti-tumor activity is noted.
Zoledronic acid also inhibits proliferation of human endothelial cells. In tumor-induced hypercalcemia it reduces serum calcium concentration.
Pharmacokinetics: Pharmacokinetic parameters are not dose-dependent. After the start of infusion, serum concentrations increase rapidly, reaching maximum concentration (Cmax) at the end of infusion, followed by a rapid decrease in concentration by 10% after 4 h and by less than 1% of Cmax after 24 h with a further long period of low concentrations not exceeding 0.1% of Cmax, before re-infusion on day 28.
Plasma protein binding is 56%. It is not metabolized.
It is excreted unchanged by the kidneys in 3 phases: Phase 1 and Phase 2 – rapid drug withdrawal from systemic blood flow, with half-life of 0.24 h and 1.87 h respectively, and Phase 3 – prolonged, with half-life of 146 h. No drug cumulation was noted with Resorb in repeated injections every 28 days. During the first 24 h, 23-55% of the drug is detected in the urine. The rest of the drug is bound to the bone tissue, after which it is slowly released back into the systemic bloodstream and excreted by the kidneys; less than 3% is excreted with the feces. Total plasma clearance is 2.54-7.54 l/h. It does not depend on the drug dose, sex, age, race and body weight of the patient. Increasing infusion duration from 5 to 15 min leads to a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect AUC.
Renal clearance correlates positively with creatinine clearance (CK) and is 42-108% of CK, which is on average 55-113%. In patients with severe (CK 20 ml/min) and moderate renal impairment (CK 50 ml/min), zoledronic acid clearance is 37 and 72%, respectively, of the drug clearance values in patients with CK 84 ml/min.

Indications

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

Pharmacological effect

Pharmaceutical group: bone resorption inhibitor – bisphosphonate.
Pharmaceutical action: Rezorba belongs to a new class of highly effective bisphosphonates that have a selective effect on bone tissue. Suppresses the activity of osteoclasts and does not have undesirable effects 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 remains unclear. It also has direct antitumor properties, ensuring effectiveness in bone metastases.
In vitro, it was found that zoledronic acid, by suppressing proliferation and inducing cell 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 alters the bone marrow microenvironment, leads to decreased tumor cell growth; antiangiogenic and analgesic activity is noted.
Zoledronic acid also inhibits the proliferation of human endothelial cells. In case of hypercalcemia caused by a tumor, it reduces the concentration of calcium in the blood serum.
Pharmacokinetics: Pharmacokinetic parameters do not depend on dose. Once the infusion is started, serum concentrations increase rapidly, reaching a maximum concentration (Cmax) at the end of the infusion, followed by a rapid decrease in concentrations of 10% after 4 hours and to less than 1% of Cmax after 24 hours, followed by a prolonged period of low concentrations not exceeding 0.1% of Cmax, until re-infusion on day 28.
Communication with plasma proteins – 56%. Not metabolized.
It is excreted unchanged by the kidneys in 3 stages: phases 1 and 2 – rapid elimination of the drug from the systemic circulation, with half-life periods of 0.24 hours and 1.87 hours, respectively, and phase 3 – long-term, with a half-life of 146 hours. No accumulation of the drug Rezorba was observed with repeated administrations every 28 days. During the first 24 hours, 23-55% is found in 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 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 infusion duration from 5 to 15 minutes resulted in a 30% decrease in zoledronic acid concentration at the end of infusion but had no effect on AUC.
Renal clearance positively correlates with creatinine clearance (CC) and amounts to 42-108% of creatinine clearance, which averages 55-113%. In patients with severe (creatinine clearance 20 ml/min) and moderate renal failure (creatinine clearance 50 ml/min), the clearance of zoledronic acid is 37 and 72%, respectively, of the drug clearance in patients with creatinine clearance 84 ml/min.

Special instructions

Before infusion, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer saline before, in parallel with, or after the infusion of zoledronic acid. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.
After administration of the drug Rezorba, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary.
Renal function should be closely monitored during zoledronic acid therapy. Risk factors for renal dysfunction include dehydration, previous renal 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 cases of bronchospasm have been reported when prescribing other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, but such cases have not yet been reported with the use of zoledronic acid.
During treatment with bisphosphonates, including zoledronic acid, cases of the development of osteonecrosis of the jaw have been described in cancer patients, and therefore, before starting treatment with bisphosphonates, it is necessary to provide a dental examination and, in the case of risk factors (anemia, coagulopathies, infections, poor hygiene or oral diseases, concomitant chemotherapy or radiation therapy, treatment with corticosteroids), to carry out appropriate preventive procedures. During treatment with zoledronic acid, patients with risk factors should, if possible, avoid dental surgery.

Active ingredient

Zoledronic acid

Composition

1 fl.:
– zoledronic acid monohydrate 4.26 mg, which is resp. content of zoledronic acid anhydrous 4 mg
Excipients: D-mannitol – 220 mg, sodium citrate dihydrate – 27.34 mg (in terms of sodium citrate anhydrous – 24 mg).
Solvent in ampoule: water for injection – 5 ml.
Solvent in container: sodium chloride solution for infusion 0.9% – 100 ml.

Contraindications

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components of the drug.
Severe renal failure (creatinine clearance < 30 ml/min).
Pregnancy and breastfeeding.
Children and adolescents (safety and effectiveness have not been established).
With caution: in case of impaired renal function, severe liver failure (no data on use), in patients with bronchial asthma who are sensitive to acetylsalicylic acid.

Side Effects

Adverse reactions are listed below by organ and system, indicating the frequency of their occurrence. Frequency criteria: very often (≥1/10), often (≥1/100, From the hematopoietic organs: often – anemia, sometimes – thrombocytopenia, leukopenia; rarely – pancytopenia.
From the nervous system: often – headache; sometimes – dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely – confusion.
From the organs 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 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 – renal dysfunction; 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 concentrations of creatinine and urea, hypocalcemia; sometimes – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatremia.
Local reactions: pain, irritation, swelling, formation of infiltrate at the site of drug administration.
Other: often – fever, flu-like syndrome (including general malaise, chills, pain, fever), sometimes – asthenia, peripheral edema; chest pain, weight gain.
When patients were treated with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw (usually after tooth extraction or other dental surgery) have sometimes been reported.
In very rare cases, a decrease in blood pressure during therapy with zoledronic acid has led to fainting or circulatory collapse.

Interaction

Solutions containing calcium, in particular Ringer’s solution, should not be used as solvents.
When used simultaneously with antitumor drugs, diuretics, antibiotics, analgesics, no clinically significant interactions were noted.
Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, therefore, when administered simultaneously, the risk of developing hypocalcemia and hypomagnesemia increases.
Caution is necessary when using zoledronic acid concomitantly with drugs that have a potential nephrotoxic effect.
In patients with multiple myeloma, there may be an increased risk of developing renal dysfunction when administered intravenously with bisphosphonates in combination with thalidomide.
The drug should not be mixed with other drugs.

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.

Manufacturer

Pharm-Sintez, Russia