Zometa conc. for preparation. solution for infusions 4 mg / 5 ml bottle 1 pc. pack (Zolendronovaya acid)

Release form

Concentrate for solution for infusion

Packing

1 vial

Pharmacological action

Zometa - inhibiting bone resorption.

Pharmacodynamics

Zoledronic acid is a highly effective bisphosphonate that has 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 provides inhibition of osteoclast activity is still unclear. Zoledronic acid does not adversely affect 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, changing the microenvironment of bone marrow, leading to a decrease in tumor cell growth 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 antitumor drugs anti-adhesive / anti-invasive activity.

Zoledronic acid, inhibiting 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 its antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human and animal endothelial cells, has an antiangiogenic effect.

In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone lesions Zometa prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, reduces tumor hypercalcemia. The drug is able to inhibit 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 lesion, 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 action 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 concentration of calcium is normalized in 87–88% of patients. The average time to relapse (albumin-corrected serum calcium level of at least 2.9 mmol / l) is 30–40 days. Significant differences between the effectiveness of Zometa in doses of 4 and 8 mg in the treatment of hypercalcemia are not observed.

Studies do not reveal significant differences in the frequency and severity of adverse events observed in patients receiving Zometa at doses of 4 or 8 mg, pamidronate at a dose of 90 mg or placebo in the treatment of bone metastases and hypercalcemia.

Pharmacokinetics

Pharmacokinetics for bone metastases were obtained after a single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg zoledronic acid in 64 patients. Pharmacokinetic parameters are not dependent on the dose of the drug.

After the start of the Zometa infusion, 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 less than 1% after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1 % of maximum to re-infusion on day 28.

Zoledronic acid administered iv is excreted by the kidneys in 3 stages: rapid two-phase excretion of the drug from the systemic circulation with T1 / 2 0.24 hours and 1.87 hours and a long phase with a final T1 / 2 of 146 hours. Not noted cumulation of the drug with repeated administrations every 28 days.

Zoledronic acid does not undergo systemic metabolism and is excreted unchanged by the kidneys. During the first 24 hours, (39 ± 16)% of the administered dose is detected in the urine. The remaining amount of the drug is mainly associated with bone tissue. Then, the reverse release of zoledronic acid from the bone tissue into the systemic circulation and its excretion by the kidneys slowly 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, gender, age, race and body weight of the patient. An increase in the infusion time from 5 to 15 min 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 have not been conducted. According to in vitro data, zoledronic acid does not inhibit the human P450 enzyme and does not undergo biotransformation, which suggests that the state of liver function does not significantly affect the pharmacokinetics of zoledronic acid. Less than 3% of the dose is excreted with feces.

Renal clearance of zoledronic acid positively correlates with creatinine clearance and is (75 ± 33)% of Cl creatinine, reaching an average of (84 ± 29)% (range - 22–143 ml / min) in 64 patients included in the study. A population analysis showed that in patients with Cl creatinine 20 ml / min (severe renal failure) or 50 ml / min (moderate renal failure), the calculated clearance of zoledronic acid is 37 and 72%, respectively, of the zoledronate clearance in patients with Cl creatinine 84 ml / min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (Cl creatinine

. Low affinity of zoledronic acid for blood components was 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 due to the tumor, and to reduce the need for radiation therapy or surgical interventions on the bone hypercalcemia caused by a malignant tumor.

Contraindications

hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug

pregnancy

lactation (breastfeeding).

Use during pregnancy and lactation

The drug Zometa is contraindicated in pregnancy and lactation (breastfeeding).

Special instructions

Use for impaired liver function. Since there are limited clinical data on the use of the drug in patients with severe liver failure, it is not possible to give specific recommendations for this category of patients.

Use for impaired renal function. When deciding on the use of Zometa in patients with hypercalcemia due to a malignant tumor, against the background of impaired renal function, it is necessary to assess the patient's condition and conclude that the potential benefit of the drug is more likely to prevail.

Serum creatinine concentration should be determined before each administration of Zometa. At the beginning of drug treatment for patients with bone metastases with impaired renal function of mild to moderate severity, it is recommended to use Zomet in low doses. In patients in whom renal dysfunction appeared during Zometa therapy, it is possible to continue drug therapy only after the creatinine concentration returns to values ​​that are within 10% of the initial value.

Given the possibility of impaired renal function with the use of bisphosphonates, including Zometa, and also due to the lack of comprehensive data on the clinical safety of the drug in patients with severe renal impairment (serum creatinine concentration 400 Ојmol / L or 4.5 mg / dl - in patients with hypercalcemia due to malignant tumor and 265 Ојmol / l or 3.0 mg / dl - in patients with malignant tumors with bone metastases) and the availability of very limited pharmacokinetic data in patients with initial severe renal impairment (Cl creatinine 30 ml / min), use of Zometa in this group bo Flax is not recommended.

Before infusion, ensure adequate hydration of the patient. If necessary, it is recommended that physiological saline be administered before, in parallel, or after Zometa infusion. Overhydration of the patient should be avoided due to the risk of complications from the cardiovascular system.

After the introduction of Zometa, constant monitoring of the concentration of calcium, phosphorus, magnesium and creatinine in the blood serum is necessary. With the development of hypocalcemia, hypophosphatemia or hypomagnesemia, there may be a need for a short additional administration of the appropriate substances. Patients with untreated hypercalcemia, as a rule, have impaired renal function, therefore, careful monitoring of renal function in this category of patients is necessary.

When deciding on the treatment of Zometa with patients with bone metastases in order to reduce the risk of pathological fractures, spinal cord compression, tumor hypercalcemia, and reducing the need for radiation therapy or surgical interventions on the bones, it should be borne in mind that the therapeutic effect occurs 2-3 months after the start of treatment with Zometa.

There are some reports of impaired renal function with the use of bisphosphonates. Risk factors for the occurrence of 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 complications is reduced if Zometa 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 impaired renal function, progression of renal failure and the need for hemodialysis with the first or single use of Zometa.

An increase in serum creatinine concentrations is also observed in some patients with prolonged use of Zometa at recommended doses, although less frequently.

Since there is limited clinical data on the use of the drug in patients with severe hepatic impairment, it is not possible to give specific recommendations for this category of patients.

Cases of osteonecrosis of the jaw in cancer patients with antitumor treatment, including bisphosphonates (including Zomet), are described. Many patients had signs of a local infectious and inflammatory process, including osteomyelitis.

In clinical practice, the development of jaw osteonecrosis 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, periodontal disease, poor fixation of dentures). Known risk factors for osteonecrosis of the jaw are cancer, concomitant cancer treatment (including chemotherapy, radiation therapy, corticosteroids), concomitant diseases (including anemia, coagulopathy, infection, previous oral disease).

Before prescribing bisphosphonates, patients with cancer should undergo a dental examination and appropriate preventive procedures, as well as recommend strict adherence to oral hygiene rules.

During treatment of these patients, dental surgery should be avoided whenever possible. There is no evidence that interrupting treatment with bisphosphonates before dental interventions reduces the risk of jaw osteonecrosis. 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 the development of severe and, in some cases, disabling pain in bones, joints and muscles have been reported with the use of bisphosphonates, which include zoledronic acid.

These symptoms developed over a period of 1 day to several months from the start of treatment. After discontinuation of treatment, the symptoms disappeared in most patients. In several patients, symptoms recurred when therapy was resumed or another bisphosphonate was prescribed.

Zometa contains the same active substance as Aklast - zoledronic acid. Patients receiving Zometa therapy should not receive Aklast at the same time.

Use in pediatrics. Efficiency and safety of use of Zometa in pediatric practice have not yet been established.

Influence on the ability to drive vehicles and control mechanisms

A study of the influence of Zometa on the ability to drive vehicles and operating mechanisms has not been conducted.

Composition of

1 vial (5 ml) contains:

Active ingredient:

zoledronic acid 4 mg.

Excipients:

mannitol,

sodium citrate,

d / i water,

nitrogen.

Dosage and Administration

Intravenously, drip infusion duration - at least 15 minutes Multiplicity of appointment - every 3-4 weeks. With bone metastases of common malignant tumors and myeloma, for adults and elderly patients, the recommended dose of the drug is 4 mg. Before the introduction of the drug, the concentrate (contents of 1 vial) is diluted in 100 ml of calcium-free infusion solution (0.9% sodium chloride solution or 5% dextrose solution).

Patients should also be given calcium orally at a dose of 500 mg / day and vitamin D orally at a dose of 400 IU / day.

In case of hypercalcemia due to a malignant tumor (calcium concentration with correction for albumin level? 12 mg / dl or 3 mmol / l), the recommended dose of the drug is 4 mg for adults and elderly patients. To ensure adequate hydration of the patient, it is recommended that physiological saline be administered before, in parallel, or after Zometa infusion.

The decision to treat Zometa hypercalcemia due to a malignant tumor in patients with severe renal impairment should be made only after a thorough assessment of the risk of the drug and the expected benefits of therapy. For patients with a serum creatinine concentration of

. For bone metastases of common malignant tumors and myeloma, the dose of Zometa depends on the initial level of creatinine clearance calculated using the Cockcroft-Gault formula. Zometa is not recommended for use in patients with severe impaired renal function (creatinine Cl values? 30 ml / min).

Side effects of

From the hemopoietic organs: often anemia, sometimes thrombocytopenia, leukopenia rarely pancytopenia.

From the peripheral nervous system and central nervous system: often - headache sometimes - dizziness, paresthesia, taste disturbances, hypesthesia, hyperesthesia, tremors, anxiety, sleep disorders rarely - confusion.

From the side of the organs of vision: often - conjunctivitis sometimes - blurred vision is very rare - uveitis, episcleritis.

From the digestive system: often - nausea, vomiting, anorexia, sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system: sometimes - shortness of breath, cough.

Dermatological reactions: sometimes - itching, rash (including erythematous and macular), excessive sweating.

From the musculoskeletal system: often - bone pain, myalgia, arthralgia, generalized pain, sometimes - muscle cramps.

From the cardiovascular system: sometimes - a marked increase or decrease in blood pressure rarely - bradycardia.

From the urinary system: often - impaired renal function, sometimes - acute renal failure, hematuria, proteinuria.

On the part of the immune system: sometimes - hypersensitivity reactions rarely - angioedema.

On the part of laboratory indicators: very often - hypophosphatemia often - increased serum concentrations of creatinine and urea, hypocalcemia sometimes - hypomagnesemia, hypokalemia rarely - hyperkalemia, hypernatremia.

Local reactions: pain, irritation, swelling, the formation of infiltrate at the injection site.

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

Drug Interactions

With the simultaneous use of other commonly used drugs (antitumor agents, diuretics, antibiotics, analgesics) with Zometa, no clinically significant interactions were noted.

According to data from in vitro studies, zoledronic acid has no significant binding to plasma proteins and does not inhibit the enzymes of the cytochrome P450 system. However, special clinical studies on the study of drug interactions have not been conducted.

Caution is advised when using bisphosphonates and aminoglycosides at the same time, since the simultaneous action of these drugs is manifested by an increase in the duration of a decrease in plasma calcium concentration.

Caution is necessary when using Zometa with drugs that potentially have nephrotoxic effects.

One should also bear in mind the likelihood of developing hypomagnesemia.

In patients with multiple myeloma, there may be an increased risk of developing renal dysfunction with iv administration of bisphosphonates, such as Zometa, in combination with thalidomide.

Pharmaceutical interactions

Diluted solution Zometa cannot be mixed with infusion solutions containing calcium ions (for example, Ringer's solution).

When using glass vials, infusion systems and bags of various types made of PVC, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for the introduction of Zometa, there were no signs of incompatibility with Zometa.

overdose

Symptoms: with acute drug overdose (limited data), kidney dysfunction (including renal failure), electrolyte composition changes (including calcium, phosphate, and magnesium concentrations in plasma).

The patient receiving the drug at a dose in excess of the recommended dose should be monitored continuously.

Treatment: with the occurrence of hypocalcemia with clinically significant manifestations, a glucose gluconate infusion has been shown.

Storage conditions

Keep out of the reach and sight of children at temperatures not exceeding 30 ° C.

Shelf life

3 years.

Terms and conditions

prescription

dosage form

infusion solution

Possible product names

Zometa conc. for preparation. solution for infusions 4 mg / 5 ml bottle 1 pc.

ZOMETA vial, 4 mg / 5 ml

ZOMETA 0.004 5ML FLOW I / O

ZOMETA 0.004 5ML FLAC END D / R-RA D / INF

ZOMETA 0.004 FLAK I / O



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