The drug Rezorba belongs to a new class of highly effective bicfosfonatov, which acts selectively on bone tissue. Inhibits osteoclast activity, has no adverse effect on the formation, mineralization and mechanical properties of bone. The selective action of bisphosphonates on bone is based on a high affinity for mineralized bone, but the precise molecular mechanism for the inhibition of osteoclastic activity is still unclear. Also has direct anti-tumor properties that provide efficacy in bone metastases.
In vitro found that zoledronic acid, inhibiting proliferation and inducing apoptosis, has a direct antitumor effect on myeloma cells and breast cancer, reduces the risk of metastasis. Inhibition of osteoclastic bone resorption modifying bone marrow microenvironment leads to a reduction of tumor cell growth; marked analgesic and anti-angiogenic activity.
zoledronic acid also inhibits the proliferation of human endothelial cells. Hypercalcemia caused by tumors, reduces the concentration of calcium in the blood serum.
The pharmacokinetic parameters are independent of dose. After initiation of the infusion of serum concentration increases rapidly, reaching Cmax at the end of infusion, followed by a rapid decrease in concentration: 10% – after 4 hours and to less than 1% of Cmax – 24 hours later with a further long period of low concentrations not exceeding 0.1% of Cmax, before re-infusion to the 28th day.
The connection to plasma proteins – 56%. Is not subject to metabolism.
excreted by the kidneys in unchanged form in 3 stages: 1st and 2nd stages – preparation rapid clearance from the systemic circulation, with a T1 / 2 – 0.24 h and 1.87 h, respectively, and the third stage – long, with a T1 / 2 -. 146 h There was no drug accumulation after repeated administration every 28 days. During the first 24 h found in the urine 23-55%. The remainder of the drug binds to bone tissue, followed by a slow reverse its release into the systemic circulation, and excretion by the kidneys; output from the feces of less than 3%. Total plasma clearance – 2,54-7,54 l / h. It does not depend on the dose of the drug, sex, age, race, and body weight. Increased infusion duration from 5 to 15 min results in a decrease of zoledronic acid concentration of 30% at the end of infusion, but does not affect the AUC.
Renal clearance was positively correlated with creatinine and Cl is 42-108% of Clkreatinina, averaging 55-113%. Patients with severe (Cl creatinine ≤20 ml / min) and moderate renal insufficiency (Cl creatinine of 20 to 50 ml / min) clearance zoledronic acid is 37 and 72% respectively of the values of the clearance of the drug in patients with creatinine Cl ≥84 mL / min.
Deystvuschee substance: zoledronic acid monohydrate;
Excipients: d-mannitol; sodium citrate dihydrate;
The solvent ampoule: water for injection 5 ml;
The solvent in the polymer container: 9.0 g of sodium chloride; water for injections.
hypercalcemia (corrected concentration of albumin in serum calcium ≥12 mg / dL or 3 mmol / L) induced by malignant tumors; Bone metastases of malignant sólidnyh tumors and multiple myeloma (to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia due to tumor and reduce the need for radiation therapy).
- hypersensitivity to zoledronic acid, other bisphosphonates or any other components within the drug;
- severe renal failure (Cl creatinine less than 30 ml / min);
- Pregnancy and lactation;
- childhood and adolescence (safety and efficacy have not been established).
With caution: renal impairment; severe hepatic failure (no data on the application); Patients with asthma are sensitive to aspirin.
From the side of hematopoiesis: often – anemia; sometimes – thrombocytopenia, leukopenia; rarely – pancytopenia
From the nervous system: often – headache; sometimes – dizziness, paraesthesia, dysgeusia, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely – confusion
From the side of view: often – conjunctivitis; sometimes – blurred vision; very rarely – uveitis, episcleritis
On the part of the digestive tract: often – nausea, vomiting, anorexia; sometimes – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth
With the respiratory system: sometimes – shortness of breath, cough
Skin and skin appendages: sometimes – itching, rash (including erythematous and macular), increased sweating
From the musculoskeletal system: often – bone pain, myalgia, arthralgia, generalized pain; sometimes – muscle cramps
From the CCC: sometimes – a marked increase or decrease in blood pressure; rarely – bradycardia
From the urinary system: often – renal dysfunction; sometimes – acute renal failure, hematuria, proteinuria
On the part of the immune system: sometimes – hypersensitivity reaction; rarely – angioedema
Violations laboratory parameters: often – hypophosphatemia; often – increased serum concentrations of creatinine and urea, hypocalcemia; sometimes – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatremia
Local reactions: pain, irritation, swelling, formation of infiltration at the site of injection
Other: often – fever, flu-like symptoms (including malaise, chills, painful condition, fever), sometimes – asthenia, peripheral edema; chest pain, weight gain.
How to accept, acceptance rate and dosage
intravenous drip, for at least 15 minutes.
In a dry place, protected from light at a temperature not higher than 25 ° C
The solvents can not be used, solutions containing calcium, particularly Ringer’s solution.
is not marked the simultaneous use of antitumour drugs, diuretics, antibiotics, analgesics clinically significant interactions.
Bisphosphonates and aminoglycosides have a one-way influence on the serum calcium concentration, so their simultaneous appointment increases the risk of hypocalcemia and hypomagnesemia. With the development of the hypocalcemia, hypomagnesemia or hypophosphatemia may be necessary to short the additional administration of the substances. Patients with untreated hypercalcemia, as a rule, there is impaired renal function, therefore, require careful monitoring of renal function in these patients. When deciding on treatment with zoledronic acid in patients with bone metastases should be taken into account that the therapeutic effect occurs within 2-3 months after initiation of treatment with zoledronic acid.
Caution is necessary while the use of zoledronic acid with drugs having potentially nephrotoxic effect. In patients with multiple myeloma, may increase the risk of renal dysfunction at / in the introduction of bisphosphonates in combination with thalidomide. Although the risk of complications is reduced above provided administration of zoledronic acid 4 mg for at least 15 min, the ability of renal function is maintained. Cases of deterioration of renal function, progression of renal failure and the need arises to hemodialysis in the first or single application of zoledronic acid.
The drug should not be mixed with other drugs.
should ensure adequate hydration of the patient prior to infusion. If necessary, it is recommended a physiological solution before, during or after infusion of zoledronic acid. Avoid overhydration of the patient because of the risk of complications from the CCC.
After administration requires constant monitoring of concentration of calcium, magnesium, phosphorus, and creatinine in the blood serum.
The therapy with zoledronic acid should be monitored closely for renal function. Risk factors for the occurrence of renal dysfunction include dehydration preceding renal failure, multiple doses 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 when assigning other bisphosphonates in patients with bronchial asthma, aspirin-sensitive, instances of bronchospasm were observed, but when using zoledronic acid, such cases are not yet registered.
The treatment with bisphosphonates, including zoledronic acid in cancer patients cases of osteonecrosis of the jaw described, in connection with which prior to treatment with bisphosphonates is necessary to provide dental examination, and if there are risk factors (anemia, coagulopathy, infection, poor hygiene or disease oral concomitant chemotherapy or radiation therapy, corticosteroid therapy) conduct appropriate preventive treatments. Against the background of treatment with zoledronic acid in patients with risk factors for dental surgical interventions should be avoided if possible.
Effect on ability to drive and other mechanisms. Studies of the effect of the drug on the ability to drive and work not carried out with complex mechanisms. In case of side effects TsNSrekomenduetsya avoid activities requiring increased attention and speed of mental and motor responses.
Pregnancy and lactation
is contraindicated in pregnancy. At the time of treatment should stop breastfeeding.
Symptoms for acute overdose of zoledronic acid may be impaired renal function, including renal failure, changes in the electrolyte composition, including the concentration of calcium, phosphate and magnesium in the blood plasma. In case of accidental overdose, the patient should be under constant supervision.
Treatment: In the event of hypocalcaemia, accompanied by clinical manifestations, shown holding infusion of calcium gluconate
The lyophilisate – 3 years reconstituted solution – 24 hours, the solvent (water for injection) – 5 years, solvent (sodium chloride solution for infusion 0.9%) – 3 years. The shelf life of the kit set components