Zometa concentrate for solution for infusion bottle 5 ml
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Active ingredients
Zoledronic acid
Release form
Solution
Composition
Active ingredient: Zoledronic acid (Acidum zoledronicum) Active ingredient concentration (mg): 4
Pharmacological effect
Inhibitor of bone tissue resorption. Bisphosphonate. Zeredronic acid is a highly effective bisphosphonate with a selective effect on 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 that inhibits the activity of osteoclasts is still unexplained. Zoledronic acid does not have an undesirable effect 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 bone resorption that changes the bone marrow microenvironment leading to reduced growth of tumor cells; antiangiogenic activity. Suppression of bone resorption is also clinically accompanied by a marked reduction in pain. In vitro: inhibition of osteoblast proliferation, direct cytotoxic and proapoptotic activity, synergistic cytostatic effect with anticancer drugs; antiadhesive / invasive activity. Zoledronic acid, by suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer, and also reduces the penetration of breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelium cells and in animals has an antiangiogenic effect. In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone damage, Zometa prevents the development of pathological fractures and spinal cord compression, reduces the need for radiation therapy and surgical interventions, reduces tumor hypercalcemia.The drug is able to restrain the progression of pain. 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 center, the effectiveness of Zometa at a dose of 4 mg is comparable to pamidronate at a dose of 90 mg. In patients with tumor hypercalcemia, the effect of Zometa is characterized by a decrease in serum calcium and calcium excretion in urine. 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 average time to relapse (albumin-corrected serum calcium level is not less than 2.9 mmol / l) is 30-40 days. There were no significant differences between the effectiveness of Zometa in doses of 4 and 8 mg in the treatment of hypercalcemia. The studies did not reveal significant differences in the incidence and severity of adverse events observed in patients who received Zomet in doses of 4 mg, 8 mg, pamidronate in a dose of 90 mg or placebo in the treatment of bone metastases and hypercalcemia.
Pharmacokinetics
Data on pharmacokinetics for bone metastases were obtained after a single and repeated 5 and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients. Pharmacokinetic parameters do not depend on the dose of the drug. After the start of the infusion of Zometa, serum concentrations increase 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% after 24 hours with successively prolonged periods of low concentrations , not exceeding 0.1% of the maximum before re-infusion on day 28. Zolendronic acid, introduced into / in, is excreted by the kidneys in 3 stages: rapid two-phase elimination of the drug from the systemic circulation with T1 / 2 0.24 h and 1.87 h and long phase with a finite T1 / 2 was 146 hours. There was no drug accumulation after repeated administration every 28 dney.Zoledronovaya acid is not metabolised systemically and excreted by the kidneys in unchanged form. During the first 24 hours, 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is mainly associated with bone tissue. Then, slowly, the back release of zendronic acid from the bone tissue into the systemic circulation and its excretion by the kidneys occurs. The total plasma clearance of the drug is 5.04 ± 2.5 l / h and does not depend on the dose of the drug, sex, age, race, or body weight of the patient.An increase in the infusion time from 5 to 15 minutes leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but does not affect the AUC. Pharmacokinetic studies in patients with hypercalcemia or liver failure were not conducted. According to data obtained in vitro, zolendronic acid does not inhibit the human P450 enzyme and does not undergo biotransformation, this 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 with feces. The renal clearance of zoledronic acid correlates positively with creatinine clearance and is 75 ± 33% of QC, reaching an average of 84 ± 29% (range 22-143 ml / min) in 64 patients included in the study . Population analysis showed that in patients with CC 20 ml / min (severe renal failure) or 50 ml / min (moderately severe renal failure), the calculated clearance of zoledronic acid is 37% and 72%, respectively, of the value of clearance of zoledronate in patients with CC 84 ml / min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (CC less than 30 ml / min). Low affinity of zoledronic acid to blood components has been shown. Plasma protein binding is low (about 50%) and does not depend on Zometa concentration.
Indications
bone metastases of common malignant tumors (prostate cancer, breast cancer) and myeloma, including to reduce the risk of pathological fractures, compression of the spinal cord, hypercalcemia caused by a tumor, and reducing the need for radiotherapy or surgical interventions on the bones, hypercalcemia due to a malignant tumor.
Contraindications
hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug; pregnancy; lactation (breastfeeding).
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
Zometa's drug is contraindicated for use during pregnancy and lactation (breastfeeding).
Dosage and administration
In / in, drip; duration of infusion - not less than 15 minutes.The multiplicity of appointments - every 3-4 weeks. For bone metastases of common malignant tumors and multiple myeloma in adults and elderly patients, the recommended dose is 4 mg. Before the introduction of the drug diluted concentrate (1 fl.) In 100 ml of solution for infusion, not containing calcium (0.9% sodium chloride solution or 5% dextrose solution).
Side effects
From the side of blood-forming organs: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely, pancytopenia. From the peripheral nervous system and central nervous system: often - headache; sometimes - dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; seldom - confusion of consciousness. From the organs of vision: often - conjunctivitis; sometimes blurred vision; very rarely - uveitis, episcleritis. From the digestive system: often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth. On the part of the respiratory system: sometimes - shortness of breath, cough. Dermatological reactions: sometimes - itching, rash (including erythematous and macular), increased sweating. muscular 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 urinary system: often - impaired renal function; sometimes - acute renal failure, hematuria, proteinuria. From the immune system: sometimes - hypersensitivity reactions; rarely - angioedema. From laboratory parameters: very often - hypophosphatemia; often - increased serum concentrations of creatinine and urea, hypocalcemia; sometimes - hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatraemia.
Overdose
Symptoms: in acute overdose of the drug (limited data), renal impairment (including renal failure), changes in electrolyte composition (including concentrations of calcium, phosphate and magnesium in plasma) were noted. The patient who received the drug in a dose exceeding the recommended dose should be under constant observation. Treatment: if hypocalcemia occurs with clinically significant manifestations, calcium gluconate infusion is indicated.
Interaction with other drugs
With the simultaneous use of other commonly used drugs (anti-tumor drugs, diuretics, antibiotics, analgesics) with Zometa, 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 cytochrome P450 enzymes. Nevertheless, special clinical studies on the study of drug interactions have not been conducted. It is recommended that caution be taken with simultaneous use of bisphosphonates and aminoglycosides, since the simultaneous effect of these drugs is manifested by an increase in the duration of the decrease in plasma calcium concentration. action. It should also be borne in mind the likelihood of developing hypomagna ui. In patients with multiple myeloma, there may be an increased risk of developing renal dysfunction when IV is injected with bisphosphonates, such as Zometa, in combination with thalidomide. When used for the introduction of Zometa glass bottles, infusion systems and bags of different types, made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with a 0.9% solution sodium chloride or 5% dextrose), no signs of incompatibility with Zomet were detected.
special instructions
When deciding on the use of Zometa in patients with hypercalcemia caused by a malignant tumor, on the background of renal dysfunction, it is necessary to assess the patient’s condition and to conclude whether the potential benefit of the drug over the possible risk prevails. in serum. At the beginning of drug treatment in patients with bone metastases with impaired renal function of weak and moderate severity, it is recommended to use Zomet in low doses. In patients who have impaired renal function during Zomet therapy, drug therapy can be continued only after the creatinine concentration returns to values that are within the initial value of ± 10%. Considering the possibility of impaired renal function when using bisphosphonates, includingZometa, and also due to the lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration ≥400 µmol / l or ≥4.5 mg / dl in patients with hypercalcemia due to a malignant tumor and ≥265 µmol / l ≥3.0 mg / dl in patients with malignant tumors with bone metastases) and the availability of very limited pharmacokinetic data in patients with initial severely impaired renal function (CC ≤ 30 ml / min), the use of Zometa in this group of patients is not It is recommended. Before infusion it is necessary to be convinced of adequate hydration of the patient. If necessary, the introduction of saline is recommended before, in parallel or after infusion of Zometa. Overhydration of the patient should be avoided due to the risk of complications of the cardiovascular system. After the introduction of Zometa, constant monitoring of serum calcium, phosphorus, magnesium and creatinine levels is necessary. With the development of hypocalcemia, hypophosphatemia, or hypomagnesaemia, it may be necessary to short-term additional administration of the relevant substances. Patients with untreated hypercalcemia, as a rule, have impaired renal function, therefore careful monitoring of renal function is necessary in this category of patients. When deciding on the treatment of patients with bone metastases with Zomet to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia caused by tumor, and reducing the need for radiotherapy or surgery on the bone, it should be taken into account that the therapeutic effect occurs 2-3 months after n There are separate reports of renal dysfunction during the use of bisphosphonates. The risk factors for such complications include dehydration, previous renal failure, repeated administration of Zometa or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Despite the fact that the risk of the above-described complications is reduced, provided that Zometa is administered at a dose of 4 mg for at least 15 minutes,the possibility of impaired renal function is preserved. There have been cases of deterioration of renal function, progression of renal failure and the need for hemodialysis with the first or one-time use of Zometa. Increased serum creatinine concentrations are also observed in some patients with long-term use of Zometa in recommended doses, although less often. There are limited clinical data on the use of the drug in patients with severe liver failure, not representing It is possible to give specific recommendations for this category of patients. Cases of osteonecrosis of the jaw in cancer patients against the background of antitumor treatment, including bisphosphonates (including Zomet) are described. Many patients showed signs of local inflammatory process, including osteomyelitis. In clinical practice, the development of osteonecrosis of the jaw was most often observed in patients with advanced breast cancer and myeloma, as well as in the presence of dental diseases (including after tooth extraction , with periodontal diseases, unsatisfactory fixation of dentures). The known risk factors for osteonecrosis of the jaw are: cancer, cancer-related treatment (including chemotherapy, radiation therapy, corticosteroids), comorbidities (including anemia, coagulopathy, infection, previous oral disease). Before administering bisphosphonates to patients with oncological diseases, a dental examination should be carried out and appropriate prophylactic procedures should be carried out, as well as strict adherence to the rules of oral hygiene should be recommended. t avoid dental surgery if possible. There is no evidence that interrupting treatment with bisphosphonates prior to dental interventions reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual assessment of the risk / benefit ratio. In clinical practice, infrequent cases of severe and in some cases disabling pain in bones, joints and muscles have been reported during the use of bisphosphonates, which include zoledronic acid. These symptoms developed during the period from 1 day to several months from the start of treatment. After discontinuation of treatment, most patients had symptoms.In several patients, the symptoms recurred when the therapy was resumed or a different bisphosphonate was prescribed. Something contains the same active ingredient as Aclasta - zoledronic acid. Patients receiving Zomet therapy should not receive Aclasta at the same time. Use in pediatrics Efficacy and safety of using Zometa in pediatric practice has not yet been established. Impact on ability to drive vehicles and control mechanisms Study of the influence of Zomets on the ability to drive vehicles and working mechanisms has not been carried out.