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primobolan enanthate

Zoledronic acid belongs to the highly effective bisphosphonates, selective effect on bone. The drug suppresses bone resorption by acting on osteoclasts.The selective effect primobolan enanthate of bisphosphonates on bone is based on the high affinity for mineralized bone. The exact molecular mechanism for the inhibition of osteoclastic activity is still unclear. Zoledronic acid has no adverse effect on the formation, mineralization and bone mechanical properties.In addition to inhibitory effect on bone resorption zolendronovaya acid has antitumor properties providing efficacy in bone metastases:

  • In vivo: inhibition of osteoclastic primobolan enanthate bone resorption modifying bone marrow microenvironment resulting in a reduction of tumor cell growth; anti-angiogenic activity.Inhibition of bone resorption clinically including accompanied by a marked reduction of pain.
  • In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity, synergistic cytostatic effect with protivoopuhlevymi drugs; anti-adhesive / invasive activity. ®

 

Zoledronic acid, inhibiting proliferation and inducing apoptosis, has a direct anticancer effect against the human myeloma and breast cancer cells, but also reduces the penetration of breast cancer cells through a human extracellular matrix that indicates the presence of Her antimetastatic properties. Also, zoledronic acid inhibits proliferation of human endothelial cells and has an anti-angiogenic effect in animals.

Patients with prostate cancer and other solid tumors with metastatic bone lesions Zometa ® prevent the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, reduces tumor hypercalcaemia. The drug can inhibit the progression of pain. The therapeutic effect is less pronounced in patients with osteoblastic centers than osteolytic. In patients with multiple myeloma and breast cancer in the presence of at least one bone hearth efficiency Zometa ® 4 mg is comparable with pamidronate 90 mg.

Patients with tumor hypercalcemia effect Zometa ® is characterized by a decrease in the level of calcium in the blood serum and excretion of calcium in the urine. The median time to normalization of calcium level is about 4 days. By the 10 th day of the calcium concentration to normal in 87-88% of patients. The median time to relapse (corrected for albumin serum calcium level at least 2.9 mmol / l) is 30-40 days. No significant differences between the effectiveness of Zometa ® at doses of 4 and 8 mg for treatment of hypercalcemia is observed.

Studies reveal no significant differences in the incidence and severity of adverse events observed in patients treated with Zometa ® at doses of 4 mg, 8 mg, pamidronate in a dose of 90 mg or a placebo in the treatment of bone metastases and hypercalcaemia.

Pharmacokinetics
Data on the pharmacokinetics of bone metastases were obtained after single and repeated 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients. Pharmacokinetic parameters are independent of dose.

After initiation of the infusion Zometa ® serum concentrations increased rapidly, reaching a peak at the end of infusion, followed by a rapid decrease in the concentration of 10% after 4 hours and less than 1% of the peak after 24 hours successively prolonged period of low concentrations not exceeding 0.1% of the maximum to re-infusion on day 28.

Zoledronic acid is infused intravenously, excreted by the kidneys in three phases: rapid biphasic elimination of the drug from the systemic circulation with half-lives of 0.24 hours and 1.87 hours, and long phase with a finite half-life of 146 hours, not mentioned drug accumulation after repeated administration every 28 days.. Zoledronic acid is not metabolized and excreted by the kidneys unchanged. During the first 24 hours in the urine detected 39 ± 16% of the administered dose. The remainder of the drug is mainly associated with bone tissue. Then reverse the release of zoledronic acid are fast enough from the bone into the systemic circulation and its excretion by the kidneys. The total plasma clearance of the drug is 5.04 ± 2.5 l / h and independent of dose, sex, age, race and weight of the patient. Increasing the infusion time from 5 minutes to 15 reduces the zoledronic acid concentration of 30% at the end of infusion, but no effect on AUC.

Pharmacokinetic studies in patients with hypercalcemia or failure of liver function have not been conducted. According to data obtained in vitro, zoledronic acid inhibits the enzyme and human P450 biotransformation, which suggests that the state of the liver any essential way affect the pharmacokinetics of zoledronic acid. Since feces derived less than 3% of the dose of the drug.

The renal clearance of zoledronic acid was positively correlated with creatine clearance and is 75 ± 33% of the creatinine clearance, averaging 84 ± 29% (range 22-143 mL / min) in the 64 patients included in the study. population analysis showed that patients with a creatinine clearance of 20 ml / min (severe renal failure) or 50 ml / min (moderate renal insufficiency) calculated clearance of zoledronic acid is 37% and 72% respectively of the value of the clearance zoledronic acid in patients with a creatinine clearance of patients 84 ml / min. Limited pharmacokinetic data obtained for patients with severe renal impairment (creatinine clearance less than 30 mL / min).

Results Zoledronic acid low affinity to blood components, plasma protein binding is low (about 56%) and independent of the concentration of Zometa ® .

Indications for use.

 

  • Bone metastases common cancers (prostate cancer, breast cancer), and myeloma, including reducing the risk of pathologic fractures, spinal cord compression, hypercalcemia due to tumors and to reduce the need for radiotherapy or surgical intervention on the bone.
  • Hypercalcemia due to malignancy.

 

Contraindications

 

  • Hypersensitivity to zoledronic acid, other bisphosphonates, or any other components of the drug.
  • Pregnancy and lactation.

 

Precautions
When deciding on the use of  in patients with hypercalcemia due to malignancy, on the background of renal function, it is necessary to evaluate the condition of the patient primobolan enanthate and make the conclusion that prevails whether the potential benefits of the introduction of the drug over the possible risk.

Before each dose Zometa ® should be determined in the serum creatinine concentration. At the beginning of treatment in patients with bone metastases with mild renal dysfunction and moderate severity, recommended Zometa ® at lower doses. In patients who have kidney dysfunction appeared during therapy Zometa ®, drug therapy can be continued only after the concentration of creatinine returns to the values that are within 10% of the initial value.

Given the possibility of renal impairment in the application of bisphosphonates, including Zometa ® , as well as due to lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration> 400 mmol / L or> 4.5 mg / dL in patients with hypercalcemia due to malignancy and> 265 umol / l or> 3.0 mg / dL in patients with malignant tumors with metastases in the bone) and the presence of very limited pharmacokinetic data in patients with baseline severe renal impairment (creatinine clearance <30 mL / min ), the use of Zometa ® in these patients is not recommended.

Dosage and administration: Bone metastases common malignant tumors and multiple myeloma: Adults and elderly patients The recommended dose is 4 mg. Before administration of the drug diluted concentrate (contents of 1 vial) 100 ml of a solution for infusion containing no calcium (0.9% sodium chloride solution or 5% dextrose). Zometa administered intravenously; infusion duration – at least 15 minutes. The multiplicity of purposes – every 3-4 weeks.

 

Cautions
Before infusion should ensure adequate hydration of the patient. If necessary, we recommend the introduction of saline before, in parallel or after the infusion of Zometa ® Avoid overhydration patient because of the risk of complications to the cardiovascular system.

After the introduction of Zometa ® requires constant monitoring of the concentration of calcium, phosphorus, magnesium and creatinine in serum. With the development of hypocalcemia, hypophosphatemia, or hypomagnesemia may be necessary in the short-term additional administration of the substances concerned. Patients with untreated hypercalcemia usually has renal impairment, therefore careful monitoring of renal function in these patients.

When deciding on the treatment of Zometa ® patients with bone metastases, to reduce the risk of pathologic fractures, spinal cord compression, hypercalcemia due to tumors and to reduce the need for radiotherapy or surgical intervention on the bone, it should be appreciated that the therapeutic effect after 2-3 months after initiation of treatment Zometa ® .

There are some reports of impaired renal function during treatment with bisphosphonates. Risk factors for the occurrence of such complications include dehydration, previous renal failure, multiple doses of Zometa or other bisphosphonates, as well as use of nephrotoxic drugs, and too rapid introduction of the drug. Although the risk of complications is reduced above provided administration Zometa ® 4 mg for at least 15 minutes, the possibility of renal function is maintained.

Increased serum creatinine concentration is also observed in some patients during long-term use of Zometa ® at recommended doses, although less frequently.

Since there are limited clinical data on the use of the drug in patients with severe hepatic failure patients, it is not primobolan enanthate possible to give specific guidance for this category of patients.

Cases of osteonecrosis of the jaw in cancer patients on the background of anti-tumor treatment including bisphosphonates. Many patients had signs of local infection-inflammation, including osteomyelitis.Prior to treatment with bisphosphonates is necessary to provide dental examination and appropriate preventive treatments in patients with risk factors (concomitant therapy – chemotherapy, radiation therapy, corticosteroid treatment, concomitant diseases – anemia, coagulopathy, infection with diseases of the oral cavity, poor oral hygiene).

During treatment, these patients should, if possible, to avoid dental procedures. There is no evidence that the interruption of treatment with bisphosphonates before dental surgery reduces the risk of osteonecrosis of the jaw. The treatment plan specific patient should be based on an individual assessment of risk / benefit ratio.

The efficacy and safety of Zometa ® in pediatric patients has not yet been established.

Form release
Concentrate for solution for infusion 4 mg / 5 ml colorless plastic bottles. 1 bottle with instruction on use in carton box.

Storage
at temperatures no higher than 30 ° C.
The drug should be stored out of reach of children.

Shelf life.
3, the
drug should not be used after the expiration date printed on the package.

Patients should also appoint an additional calcium oral dose of 500 mg per day and vitamin D oral dose of 400 ME per day.

Hypercalcemia due to malignancy:
Adults and elderly patients If hypercalcemia (calcium concentration correction in the level of albumin> 12 mg / dL or 3 mmol / l), the recommended dose is 4 mg. Before administration of the drug diluted concentrate (contents of 1 vial) 100 ml of a solution for infusion containing no calcium (0.9% sodium chloride solution or 5% dextrose). Zometa administered intravenously once; infusion duration – at least 15 minutes. To ensure adequate hydration of the patient is recommended prior to the introduction of saline, in parallel or after the infusion of Zometa.

Patients with impaired renal function
hypercalcemia due to malignancy:
A decision on the treatment of Zometa in patients with severe renal impairment should be taken only after careful evaluation of the risk of the drug and the expected benefits of therapy. Patients whose serum creatinine concentration is <400 micromoles / liter or <4.5 mg / dl, no correction is required dosing regime.

Bone metastases are common malignant tumors and multiple myeloma:

Zometa dose depends on the baseline creatinine clearance calculated according to the formula Cockcroft-Gault. Zometa is not recommended in patients with severe renal impairment (creatinine clearance values <30 mL / min).

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