Expiration date: 11/2025

The composition and form of issue:

Concentrate for preparation of solution for infusion 5 ml (1 FL.)

of zoledronic acid monohydrate 4,264 mg

(corresponding to 4 mg of zoledronic acid anhydrous)

auxiliary substances: mannitol, sodium citrate, water for injections, nitrogen

in vials of 5 ml in a cardboard pack 1 bottle.

Description pharmaceutical form:

Clear, colorless liquid.

Feature:

Biphosphonate. Inhibitor of bone resorption.

Pharmacokinetics:

Data on the pharmacokinetics in bone metastases 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.

After the start of infusion of Zometa, serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid reduction in the concentration of 10% after 4 h and less than 1% after 24 h with a consistently prolonged period of low concentrations not exceeding 0.1% of the maximum before re-infusion on the 28th day.

Zoledronic acid, injected and excreted by the kidneys in 3 phases: rapid biphasic elimination of the drug from the systemic circulation with a T1/2 of 0.24 h and h of 1.87 and a long phase with a finite T1/2, amounting to 146 h No observed drug accumulation after repeated administration every 28 days.

Zoledronic acid is not subject to systemic metabolism and is excreted by the kidneys unchanged. During the first 24 h in the urine detected (39±16)% of the administered dose. The remainder of the drug is mainly associated with bone tissue. Then slowly reverse the release of zoledronic acid from bone tissue into the systemic circulation and its renal excretion. The total plasma clearance of the drug is (5,04±2,5) l/h and is independent of dose, sex, age, race and body mass of the patient. The increase in infusion time from 5 to 15 min leads to reduction of the concentration of zoledronic acid at 30% at the end of the infusion, but does not affect AUC.

Pharmacokinetic studies in patients with hypercalcemia or with impairment of liver function was carried out. According to the data obtained in vitro, zoledronic acid inhibits the enzyme P450 human and not biotransformation, suggesting that the condition of the liver in any significant way does not affect the pharmacokinetics of zoledronic acid. The feces derived less than 3% of the dose.

The renal clearance of zoledronic acid correlates positively with creatinine clearance and is (75±33)% of Cl creatinine, averaging (84±29)% (range 22-143 ml/min) in the 64 patients included in the study. The analysis of population showed that patients with a creatinine Cl of 20 ml/min (renal failure, severe), or 50 ml/min (renal failure of moderate severity) was calculated clearance of zoledronic acid — 37 and 72%, respectively, from the values of clearance of zoledronic in patients with Cl creatinine 84 ml/min. Limited pharmacokinetic data were obtained for patients with renal insufficiency, severe (creatinine Cl <30 ml/min).

The low affinity of zoledronic acid to components of the blood. The plasma protein binding is low (about 50%) and does not depend on the concentration of Zometa.

Description pharmacological action:

Zoledronic acid is a highly effective bisphosphonates, with selective effects on bone. The drug inhibits bone resorption by acting on osteoclasts.

Selective action of bisphosphonates on bone tissue is based on high affinity for mineralized bone. The exact molecular mechanism for the inhibition of the activity of the osteoclasts is still unclear. Zoledronic acid does not render undesirable influence on formation, mineralization and mechanical properties of bone.

In addition to inhibitory actions on bone resorption, zoledronic acid possesses antitumor properties, provides efficacy in bone metastases:

in vivo: inhibition of osteoclastic bone resorption, altering the microenvironment of the bone marrow, leading to decreased growth of tumor cells antiangiogenic activity. The suppression of bone resorption is also accompanied by a clinically apparent reduction of pain.

in vitro: inhibition of osteoblast proliferation, direct cytostatic and proportionsa activity, synergistic cytostatic effect with anticancer drugs anti-adhesive/antiinvasive activity.

Zoledronic acid, inhibiting the proliferation and inducing apoptosis, exerts direct antitumor activity against cells of the human myeloma and cancer of the breast, and also reduces the penetration of cancer cells breast tumor through the extracellular matrix, indicating whether it has antimetastatic properties. In addition, zoledronic acid inhibits proliferation of endothelial cells of humans and animals, exerts antiangiogenic effect.

Patients with breast cancer, prostate cancer and other solid tumors with metastatic lesions of bones zometa prevents the development of pathological fractures, spinal cord compression, reduces the need for radiotherapy 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 foci of osteoblastic than osteolytic. In patients with multiple myeloma and breast cancer in the presence of at least one bone lesion efficacy of Zometa at a dose of 4 mg is comparable to pamidronate at a dose of 90 mg.

Patients with malignant hypercalcemia action of Zometa is characterized by a decrease in the level of calcium in blood serum and excretion of calcium in the urine. The average time to normalization of the calcium level is about 4 days. The 10th day of calcium concentration normal at 87-88% of patients. Mean time to relapse (adjusted for the albumin level of the serum calcium — not less than 2.9 mmol/l) is 30-40 days. Significant differences between the effectiveness of Zometa in doses 4 and 8 mg in the treatment of hypercalcemia not observed.

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

Indications:

• bone metastases common malignant tumors (prostate cancer, breast cancer) and multiple myeloma, including reducing the risk of pathological fractures, spinal cord compression, hypercalcemia due to tumor and reduce the need for radiation therapy or surgical interventions on the bone
  
• hypercalcemia caused by malignant tumor.
  

Contraindications:

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

Application of pregnancy and breast-feeding:

The drug zometa is contraindicated during pregnancy and lactation (breastfeeding).

Side effects:

Information about the frequency of adverse reactions with the use of Zometa at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with the use of Zometa, usually mild and transient, similar to those reported with other bisphosphonates.

At/in the introduction is usually noted the development of flu-like syndrome is almost 9% of patients, but there was bone pain, fever, General malaise, chills.

Occasionally (approximately 3% of patients) have been reported arthralgia and myalgia.

Frequently (approximately 20% of patients) decrease renal excretion of calcium was accompanied by a sharp decrease in the concentration of phosphorus, which is asymptomatic and not require treatment. Approximately 3% of patients the calcium concentration in the serum was reduced to hypocalcemia (without clinical manifestations).

There are reports of such reactions from the gastrointestinal tract after the on/in infusion of Zometa, such as nausea (5.8%) and vomiting (2.6 percent).

Local site reactions infusion site such as redness or swelling and/or pain, were observed in less than 1% of patients.

Anorexia was observed in 1.5% of patients treated with the Zometa at a dose of 4 mg.

There were several cases of rash or pruritus (less than 1%).

As with other bisphosphonates, cases of conjunctivitis in approximately 1%.

There are reports of impaired renal function (2.3%) are, however, other risk factors these patients may also have value.

Based on the summary analysis of controlled studies reported on the development of severe anemia (hemoglobin <8.0 g/DL) in 5.2% of patients receiving Zometa at a dose of 4 mg, compared with 4.2% receiving placebo.

Adverse reactions are listed below according to the organs and systems, indicating the frequency of their occurrence. Criteria frequency: very often — &ge1/10 often — &ge1/100 but <1/10 sometimes &ge1/1000 and <1/100 rare &ge1/10000, but <1/1000 very rare <1/10000, including individual messages.

On the part of the blood: often — anemia, sometimes — thrombocytopenia, leukopenia rare — pancytopenia.

From the peripheral nervous system and Central nervous system: often — headache sometimes — dizziness, paresthesia, disorders of taste sensations, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders, rarely — confusion.

From the side of organs of vision: often — conjunctivitis sometimes blurring of the vision very rarely uveitis, episcleritis.

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

The respiratory system: sometimes — shortness of breath, cough.

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

From the side of musculoskeletal system: often — pain in bones, myalgia, arthralgia, generalised pain and sometimes muscle spasms.

Of the cardiovascular system: sometimes- pronounced increase or decrease in blood pressure, rarely — bradycardia.

From the urinary system: often — violation of kidney function and sometimes acute renal failure, hematuria, proteinuria.

The immune system: sometimes — hypersensitivity reactions rarely — angioedema.

From the laboratory parameters: very often — hypophosphatemia often — increased serum concentrations of creatinine and urea, sometimes hypocalcemia — hypomagnesemia, hypokalemia rare — hyperkalemia, hypernatremia.

Local reactions: pain, irritation, swelling, education infiltrates at the injection of the drug.

Other: often — fever, flu-like symptoms (including malaise, chills, painful condition, heat), sometimes — asthenia, peripheral oedema, pain in chest, weight gain.

It should be borne in mind that the use of other bisphosphonates in patients with bronchial asthma who are sensitive to acetylsalicylic acid, there have been cases of bronchospasm, however, the application of Zometa this phenomenon was not observed.

In clinical studies with the use of zoledronic acid (at a dose of 4 mg every 3-4 weeks) in patients with oncological diseases, increase the frequency of fibrillary was not observed.

The therapy Intake in clinical practice reported adverse events regardless of causal relationship with the drug: in the treatment of patients bifosfonatami (including Intake) in clinical practice, described rare cases of osteonecrosis of the jaw (usually after tooth extraction or other dental procedures).

In very rare cases, on the background of the use of Zometa was observed a decrease in blood pressure leading to syncope or circulatory collapse (primarily in patients with risk factors) development of drowsiness, bronchoconstriction, atrial fibrillation, anaphylactic reactions/shock, and urticaria.

Drug interactions:

While the use of Intake of other commonly used drugs (anticancer agents, diuretics, antibiotics, analgesics) any clinically significant interactions are not marked.

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

We recommend caution when concomitant use of bisphosphonates and aminoglycosides, since the simultaneous action of these drugs is manifested by increased duration of reducing the concentration of calcium in the blood plasma.

Caution is needed in concomitant use with Zometa drugs potentially nephrotoxic effects.

It should also be borne in mind the likelihood of developing hypomagnesemia.

In patients with multiple myeloma may increase the risk of developing impaired renal function at/in the introduction of bisphosphonates, such as zometa, in combination with thalidomide.

Pharmaceutical interaction

Diluted Zometa solution must not be mixed with infusion solutions containing calcium (e.g. ringer solution).

When used for injection Zometa glass vials, infusion systems and bags of different types, made of PVC, polyethylene and polypropylene (prefilled with 0.9% sodium chloride solution or 5% dextrose solution), any signs of incompatibility with the Intake not detected.

Method of application and dose:

In/in, drip, duration of infusion not less than 15 min. the Multiplicity of purposes — every 3-4 weeks. Bone metastases in common malignant tumors and multiple myeloma adults and elderly patients the recommended dose is 4 mg Before administration of the drug diluted concentrate (1 FL content.) in 100 ml of solution for infusion, containing calcium (0.9% sodium chloride solution or 5% dextrose solution).

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

With hypercalcemia due to malignant tumor (concentration of calcium correction for albumin level &ge12 mg/DL or 3 mmol/l), adults and elderly patients the recommended dose is 4 mg. To ensure adequate hydration of the patient is recommended the introduction of a physiological solution prior to, concurrently or after infusion of Zometa.

A treatment cycle with zometa hypercalcemia caused by malignant tumor, in patients with severe renal impairment should be taken only after a thorough risk assessment of the drug and the expected benefits of therapy. Patients who have a creatinine concentration in the serum is <400 µmol/l or <4.5 mg/DL, does not require correction of dosing regimen.

Bone metastases in common malignant tumors and multiple myeloma Zometa dose depends on baseline creatinine clearance, calculated according to the formula of Cockcroft-Gault. Not recommended to Zometa in patients with severe renal impairment (Cl creatinine values &le30 ml/min).

The recommended dose in patients with mild or moderate impaired renal function (values Cl creatinine 30-60 ml/min) given below.

The initial value of Cl creatinine, ml/min	The recommended dose of Zometa
>60	4 ?? (5 ml concentrate)
50–60	3,5 ?? (4,4 ml concentrate)
40–49	3,3 ?? (4,1 ml concentrate)
30–39	3,0 ?? (3,8 ml concentrate)

After the start of therapy Intake should be the determination of the concentration of serum creatinine before each dose of the drug. When violations of the kidney another infusion of Zometa should be postponed. Violations of kidney function are defined by the following parameters:

- for patients with normal baseline values of creatinine (<1.4 mg/DL) — increasing the concentration of serum creatinine 0.5 mg/DL.

- for patients with deviations of baseline creatinine (>1.4 mg/DL) — increasing the concentration of serum creatinine per 1 mg/DL.

Therapy Intake only resume once the level of creatinine reaches values in the range of 10% from the initial value, the same dose that was used prior to the interruption of treatment.

Rules for preparation of solution for infusions

From concentrate 4 mg/5 ml (contents of 1 FL.) prepare a solution for infusion. The solution should be prepared under aseptic conditions. Before the introduction of the drug diluted concentrate (1 FL content. or less, if required) in 100 ml of solution for infusion, containing calcium (0.9% sodium chloride solution or 5% dextrose solution). The prepared solution Zometa preferably used immediately after preparation. From unused solution can be stored in the refrigerator at 2-8 °C for no more than 24 hours Before the introduction of the solution should be kept indoors until they reach room temperature.

The total time between dilution of the concentrate, storage of the prepared solution in the refrigerator at 2-8 °C and end of administration of the drug should not exceed 24 hours.

Solution with Zometa should not be mixed with any other drugs. The zometa should not be mixed with any solutions containing calcium or any other divalent cations such as normal saline and ringer's lactate. The prepared solution of zoledronic acid should be entered using a separate system for on/in infusions.

Overdose:

Symptoms: in acute drug overdose (limited data) had impaired renal function (including renal failure), changes of the electrolyte composition (including concentrations of calcium, phosphate and magnesium in blood plasma). The patient who received the drug in doses exceeding recommended, should be under constant surveillance.

Treatment: in the event of hypocalcemia with clinically significant manifestations shown holding infusion of calcium gluconate.

Special instructions:

Application for violations of liver function. Because there are limited clinical data on the drug in patients with severe hepatic impairment, it is not possible to give specific recommendations for this category of patients.

Application for violations of renal function. When deciding on the use of Zometa in patients with hypercalcemia due to malignant tumor, against violations of kidney function, it is necessary to evaluate the patient's condition and concluded that prevails whether the potential benefits of drug administration over possible risks.

Before each injection of Zometa should determine the concentration of creatinine in serum. At the beginning of treatment patients with bone metastasis who have renal dysfunction mild and moderate severity is recommended to Zometa in low doses. In patients who have impaired renal function appeared during therapy Intake, you can continue therapy with the drug only after the creatinine concentration returns to values that are within 10% from the initial value.

Given the possibility of renal dysfunction with use of bisphosphonates, including Zometa and due to the lack of comprehensive data on the clinical safety of the drug in patients with severe renal impairment (creatinine concentration in serum &ge400 µmol/l or &ge4. 5 mg/DL — in patients with hypercalcemia due to malignant tumor &ge265 µmol/l or &ge3,0 mg/DL — patients with malignant tumors with bone metastases) and the presence of very limited pharmacokinetic data in patients with baseline severe renal impairment (Cl creatinine&le30 ml/min), the use of Zometa in this patient population is not recommended.

Before infusion, ensure adequate hydration of the patient. If necessary, that the introduction of the saline solution before, concurrently or after infusion of Zometa. You should avoid over-hydration of the patient because of the risk of occurrence of complications in the cardiovascular system.

After the introduction of Zometa requires constant monitoring of the concentration of calcium, phosphorus, magnesium and creatinine in the serum. With the development of hypocalcemia, hypophosphatemia or hypomagnesemia may be necessary in the short-term additional administration of the respective substances. Patients with untreated hypercalcemia usually there is dysfunction of the kidneys, so careful monitoring of renal function in these patients.

When deciding on the treatment Intake of patients with bone metastases to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia due to tumor and reduce the need for radiation therapy or surgical interventions on bones, should take into account that the therapeutic effect occurs in 2-3 months after the start of treatment Intake.

There are isolated reports of impaired renal function on the background of the use of bisphosphonates. The risk factors for such complications include dehydration, pre-renal failure, multiple doses of Zometa or other bisphosphonates as well as use of nephrotoxic drugs, and too rapid administration of the drug. Despite the fact that the risk of the above complications is reduced with the introduction of Zometa at a dose of 4 mg over at least 15 min, possibility of renal dysfunction persists.

There have been cases of deterioration of renal function, progression to kidney failure and the need for hemodialysis during the first or single use of Zometa.

Increased serum concentrations of creatinine also occur in some patients with long-term use of Zometa at recommended doses, although less frequently.

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

Described cases of osteonecrosis of the jaw in cancer patients following antineoplastic treatment, including bisphosphonates (including Zometa). Many patients had signs of local infectious - inflammatory process, including osteomyelitis.

In clinical practice, the most often the development of osteonecrosis of the jaw was observed in patients with advanced breast cancer and multiple myeloma, as well as the presence of dental diseases (including tooth extraction, in periodontal disease, poor prosthesis). Known risk factors of osteonecrosis of the jaw are cancer related cancer treatment (including chemotherapy, radiotherapy, corticosteroids), comorbidities (including anemia, coagulopathy, infection, previous disease of the mouth).

Before prescribing bisphosphonates to patients with cancer should carry out a dental examination and perform appropriate preventive treatments, and to recommend strict observance of rules of hygiene of the oral cavity.

During treatment these patients should, if possible, avoid dental surgeries. There is no evidence that interruption of treatment bisphosphonates before dental surgery reduces the risk of osteonecrosis of the jaw. Treatment plan individual patient should be based on individual assessment of risk/benefit.

In clinical practice, it was reported infrequent cases of strong and in some cases invalidusername pains in the bones, joints and muscles on the background of the use of bisphosphonates, including zoledronic acid.

These symptoms developed during the period from 1 day to several months after starting treatment. After cessation of treatment in most patients, the symptoms passed. In several patients the symptoms recurred with the resumption of therapy or another bisphosphonate.

Zometa contains the same active substance as the Aklast — zoledronic acid. Patients receiving treatment Intake, should not receive at the same time Aklast.

Use in Pediatrics. The efficacy and safety of Zometa in pediatric patients has so far not been established.

Effects on ability to drive vehicles and management mechanisms

The study of the effect of Zometa on the ability to drive vehicles and working machines was carried out.