Zometa concentrate 4mg/5ml vial 1pc

Composition

Active ingredient:  

zoledronic acid monohydrate;

Auxiliary substances:  

mannitol,

sodium citrate,

water for injection,

nitrogen

Pharmacological action

Zometa – inhibiting bone resorption.

Pharmacodynamics

Zoledronic acid is a highly effective bisphosphonate that has a selective effect on bone. The drug suppresses bone resorption by affecting osteoclasts.

The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. The exact molecular mechanism responsible for inhibiting 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, which changes the microenvironment of the bone marrow, leading to a decrease in the 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 pro-apoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive/anti-invasive activity.

Zoledronic acid, 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 and animal endothelial cells and 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, spinal cord compression, reduces the need for radiation therapy and surgical interventions, and 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 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 effect of Zometa is characterized by a decrease in the level of calcium in the blood serum and excretion of calcium in the urine. The average time to normalization of calcium levels is about 4 days. By day 10, the calcium concentration normalizes in 87-88% of patients.

The average time to relapse (adjusted for albumin serum calcium level-at least 2.9 mmol / l) is 30-40 days. There were no significant differences between the effectiveness of Zometa at doses of 4 and 8 mg in the treatment of hypercalcemia.

Studies did not show significant differences in the frequency and severity of adverse events observed in patients treated with Zometa 4 or 8 mg, pamidronate 90 mg, or placebo in both the treatment of bone metastases and hypercalcemia.

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 of zoledronic acid in 64 patients. Pharmacokinetic parameters do not depend on the dose of the drug.

After the start of Zometa infusion, serum concentrations increase rapidly, peaking at the end of the infusion, followed by a rapid decrease of 10% after 4 hours and less than 1% after 24 hours, with a consistently prolonged period of low concentrations not exceeding 0.1% of the maximum until repeated infusion on day 28.

Zoledronic acid administered intravenously is excreted by the kidneys in 3 stages: rapid two-phase elimination of the drug from the systemic circulation with a T_1/2 of 0.24 hours and 1.87 hours and a long phase with a final T_1/2of 146 hours. No accumulation of the drug was observed with repeated injections every 28 days.

Zoledronic acid does not undergo systemic metabolism and is excreted unchanged by the kidneys. During the first 24 hours in the urine is detected (39±16)% of the administered dose. The remaining amount of the drug is mainly bound to bone tissue.

Then, slowly, zoledronic acid is released back from the bone tissue into the systemic circulation and excreted by the kidneys. 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 minutes leads to a 30% decrease in the concentration of zoledronic acid at the end of the infusion, but does not affect the AUC.

Pharmacokinetic studies in patients with hypercalcemia or hepatic insufficiency 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 drug dose is excreted in the 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.

Population analysis showed that in patients with a creatinine clearance of 20 ml/min (severe renal insufficiency) or 50 ml/min (moderate renal insufficiency), the calculated clearance of zoledronic acid was 37 and 72%, respectively, of the clearance of zoledronate in patients with a creatinine clearance of 84 ml/min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (creatinine clearance

Low affinity of zoledronic acid to blood components is shown. Binding to plasma proteins is low (about 50%) and does not depend on the Zometa concentration.

Indications

Bone metastases of common malignant tumors (prostate cancer, breast cancer) and myeloma, including to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia due to the tumor, and reduce the need for radiation therapy or bone surgery; hypercalcemia due to a malignant tumor.

Use during pregnancy and lactation

The drug Zometa is contraindicated for use during pregnancy and lactation (breastfeeding).

Contraindications

• hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug;
• pregnancy;
• lactation (breastfeeding).

Side effects

From the side of hematopoietic organs:  often-anemia, sometimes-thrombocytopenia, leukopenia; rarely-pancytopenia.

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

From the side of the visual organs:  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.

Respiratory system disorders:  sometimes-shortness of breath, cough.

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

Musculoskeletal disorders:  often-bone pain, myalgia, arthralgia, generalized pain; sometimes-muscle cramps.

From the cardiovascular system:  sometimes-a marked increase or decrease 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 the side of laboratory parameters:  very often — hypophosphatemia; often-increased serum creatinine and urea concentrations, hypocalcemia; sometimes-hypomagnesemia, hypokalemia; rarely-hyperkalemia, hypernatremia.

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

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

Interaction

No clinically significant interactions were observed when other commonly used medications (antitumor agents, diuretics, antibiotics, analgesics) were co-administered with Zometa.

According to data obtained in vitro studies, zoledronic acid has no significant binding to plasma proteins and does not inhibit cytochrome P450 enzymes. However, no specific clinical studies have been conducted to investigate drug interactions.

Caution is recommended when using bisphosphonates and aminoglycosides simultaneously, since the simultaneous effect of these drugs is manifested by an increase in the duration of a decrease in the concentration of calcium in blood plasma.

Caution is necessary when concomitantly using Zometa with drugs that potentially have a nephrotoxic effect.

You should also keep in mind the likelihood of developing hypomagnesemia.

Patients with multiple myeloma may have an increased risk of developing impaired renal function with intravenous bisphosphonates, such as Zometa, in combination with thalidomide.

Pharmaceutical interaction

Diluted Zometa solution should not 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 Zometa use, no signs of incompatibility with Zometa were found.

How to take, course of use and dosage

Intravenous, drip; duration of infusion — not less than 15 minutes. The frequency of appointments is every 3-4 weeks. For bone metastases of common malignant tumors and myeloma, the recommended dose of the drug is 4 mg for adults and elderly patients. Before use of the drug, dilute the concentrate (contents of 1 fl. ) in 100 ml of an infusion solution that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution).

Patients should also be additionally prescribed oral calcium at a dose of 500 mg / day and oral vitamin D at a dose of 400 IU / day.

For hypercalcemia caused by a malignant tumor (calcium concentration with albumin correction ≥12 mg/dl or 3 mmol/L), adults and elderly patients, the recommended dose of the drug is 4 mg. To ensure adequate hydration of the patient, it is recommended to administer saline solution before, in parallel or after the infusion of Zometa.

The decision to treat Zometa hypercalcemia due to a malignant tumor in patients with severe renal impairment should be made only after careful assessment of the risk of using the drug and the expected benefit of therapy. Patients who have a serum creatinine concentration of

In 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. It is not recommended to use Zometa in patients with severe renal impairment (creatinine clearance <30 ml / min).

Overdose

Symptoms: in acute overdose of the drug (limited data), impaired renal function (including renal failure), changes in the electrolyte composition (including concentrations of calcium, phosphates and magnesium in blood plasma) were noted.

A patient who has received the drug at a dose exceeding the recommended dose should be constantly monitored.

Treatment: if hypocalcemia occurs with clinically significant manifestations, an infusion of calcium gluconate is indicated.

Special instructions

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

Use in patients with impaired renal function. When deciding whether to use 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 make a conclusion about whether the potential benefit of the drug use prevails over the possible risk.

Before each use of Zometa, the serum creatinine concentration should be determined. At the beginning of treatment with the drug in patients with bone metastases with mild to moderate renal dysfunction, it is recommended to use Zometa in reduced doses.

In patients who develop impaired renal function during therapy with Zometa, you can continue therapy with the drug only after the creatinine concentration returns to values that are within 10% of the initial value.

Considering the possibility of renal impairment when using bisphosphonates, including Zometa, as well as the lack of comprehensive data on the clinical safety of the drug in patients with severe renal impairment (serum creatinine concentration ≥400 mmol/l or ≥4.5 mg/dl — in patients with hypercalcemia due to a malignant tumor and ≥265 mmol/l or ≥3.0 mg/dl — in patients with malignant tumors with bone metastases) 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 this cohort of patients is not recommended.

Make sure that the patient is adequately hydrated before the infusion. If necessary, it is recommended to administer saline solution before, in parallel or after the infusion of Zometa. Hyperhydration 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, short-term additional use of appropriate substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function in this category of patients is necessary.

When deciding whether to treat patients with bone metastases with Zometa in order to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of Zometa treatment.

There are isolated reports of impaired renal function associated with the use of bisphosphonates. Risk factors for such complications include dehydration, previous renal failure, repeated use of Zometa or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid use of the drug.

Despite the fact that the risk of the above-described 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 deterioration of 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 the recommended doses, although less often.

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

Cases of osteonecrosis of the jaw in cancer patients on the background of antitumor treatment, including bisphosphonates (including Zometa), are described. Many patients showed signs of a local infectious and inflammatory process, including osteomyelitis.

In clinical practice, the most common development of osteonecrosis of the jaw was observed in patients with advanced breast cancer and myeloma, as well as in the presence of dental diseases (including after tooth extraction, periodontal diseases, unsatisfactory 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 perform appropriate preventive procedures, as well as recommend strict compliance with oral hygiene rules.

During the treatment of these patients, dental operations should be avoided as much as possible. There is no evidence that discontinuing bisphosphonate treatment prior to dental intervention reduces the risk of osteonecrosis of the jaw. A patient’s treatment plan 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 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, most patients had no symptoms. In several patients, symptoms recurred when therapy was resumed or another bisphosphonate was prescribed.

Zometa contains the same active ingredient as Aclasta — zoledronic acid. Patients receiving Zometa therapy should not receive Aclasta at the same time.

Use in pediatrics. The efficacy and safety of Zometa in pediatric practice have not yet been established.

Influence on the ability to drive motor vehicles and manage mechanisms

The effect of Zometa on the ability to drive vehicles and work mechanisms has not been studied.

Form of production

Concentrate for preparation of solution for infusions

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Zoledronic acid

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution