Zolendrovista (zoledronic acid) concentracted solution for infusions 4 mg/5 ml. 5 ml. vial №1

$125.00

Prevention of bone-related symptoms (pathological fractures, compression of the spine, complications after surgery and radiation therapy, or hypercalcaemia due to malignancy) in patients with malignancies. Treatment of hypercalcemia caused by a malignant tumor.

Category:

Description

Storage:

active substance: zoledronic acid;

5 ml of concentrate contain 4 mg of zoledronic anhydrous acid, which corresponds to 4.264 mg of zoledronic acid monohydrate;

Excipients: mannitol (E 421), sodium citrate dihydrate, water for injections.

Dosage form

Concentrate for solution for infusion.

Basic physical and chemical properties: transparent colorless solution.

Pharmacotherapeutic group

Agents that affect the structure and mineralization of bones. Bisphosphonates. ATX code M05B A08.

Pharmacological properties

Pharmacodynamics

Zoledronic acid belongs to a new class of bisphosphonates that have a specific effect on bone tissue. It is one of the most potent inhibitors of osteoclastic bone resorption known today.

The selective action of bisphosphonates on bones is based on their high affinity for mineralized bone tissue, but the molecular mechanism that leads to inhibition of osteoclastic activity has not yet been elucidated. Animal studies have shown that zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization and mechanical properties.

In addition to inhibiting osteoclastic bone resorption, zoledronic acid has a direct antitumor effect on cultured myeloma cells and human breast cancer by inhibiting cell proliferation and inducing apoptosis. This indicates that zoledronic acid may have antimetastatic properties. The following properties have been demonstrated in preclinical studies:

In vivo – inhibition of osteoclast bone resorption, which acts on the structure of the microcrystalline matrix of bone, which reduces tumor growth, antiangiogenic effect (action on blood vessels, which reduces the blood supply to the tumor), analgesic effect.

In vitro – inhibition of osteoblast proliferation, cytostatic action, proapoptostatic action on tumor cells, synergistic cytostatic effect with other antitumor drugs, antiadhesive and antiinvasive action.

Pharmacokinetics

Data on pharmacokinetics in 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 the infusion of zoledronic acid, plasma concentrations of the drug increase rapidly, reaching a peak at the end of the infusion, then there is a rapid decrease in concentration by 10% from the peak value after 4 hours and by <1% from the peak value after 24 hours. do not exceed 0.1% of the peak, until the second infusion on the 28th day. Zoledronic acid, administered intravenously, is excreted by the kidneys in 3 stages: rapid two-phase excretion of the drug from the systemic circulation with a half-life t½α = 0.24 hours and t½β = 1.87 hours and a long phase with a terminal half-life t½γ = 146 hours. No accumulation of the drug in plasma with repeated injections every 28 days. Zoledronic acid is not metabolized and excreted unchanged by the kidneys. During the first 24 hours, 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is mainly bound to bone tissue. Then slowly reverse release of zoledronic acid from bone tissue into the systemic bloodstream and its excretion by the kidneys. The total clearance of the drug in the body is 5.04 ± 2.5 l / h and does not depend on the dose of the drug, sex, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 min reduces the zoledronic acid concentration by 30% at the end of the infusion, but does not affect the plasma concentration-time curve (AUC).

The variability of the pharmacokinetic parameters of zoledronic acid in different patients was high, as in other bisphosphonates.

There are no data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and hepatic insufficiency. According to in vitro data, zoledronic acid does not inhibit the human enzyme P450 and is not biotransformed; According to experimental studies in animals, feces excrete less than 3% of the administered dose, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with renal clearance of 75 ± 33% creatinine clearance averaging 84 ± 29 ml / min (range 22-143 ml / min) in the 64 cancer patients enrolled in the study. Analysis of the patient group showed that in patients with a creatinine clearance of 20 ml / min (acute renal failure) and 50 ml / min (moderate renal failure), the relative clearance of zoledronic acid was 37% and 72%, respectively. However, pharmacokinetic data in patients with acute renal failure (<30 ml / min) are limited.

The low affinity of zoledronic acid with cellular components of blood is revealed.

Plasma protein binding is low, with unbound fraction ranging from 60% at 2 ng / ml to 77% at 2000 ng / ml zoledronic acid.

Special populations

Children

Limited pharmacokinetic data in children with severe osteogenesis are provided

the possibility to assume that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to that in adults when used in equivalent doses (mg / kg). Age, weight, sex, and creatinine clearance were not shown to affect systemic zoledronic acid exposure.

Clinical characteristics

Indication.

  • Prevention of symptoms associated with bone damage (pathological fractures, spinal cord compression, complications after surgery and radiation therapy, or hypercalcemia due to malignancy) in patients with late-stage malignancies.
  • Treatment of hypercalcemia caused by a malignant tumor.

Contraindication.

  • Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates or to any of the excipients.
  • Pregnancy or breastfeeding.
  • Features of application.

General

Prior to administration of ZolendroVista, adequate hydration should be performed in all patients, including patients with mild to moderate renal impairment.

Hyperhydration should be avoided in patients at risk of developing heart failure.

Standard metabolic parameters associated with hypercalcaemia, such as calcium, phosphate, and magnesium, should be closely monitored after initiation of the drug. If hypocalcaemia, hypophosphatemia, or hypomagnesemia occur, short-term corrective therapy may be required.

Untreated patients with hypercalcaemia usually have some renal impairment, so careful monitoring of renal function is required.

Patients receiving ZolendroVista therapy should not use other zoledronic acid-containing drugs at the same time and should not use any other bisphosphonates.

Renal dysfunction

When deciding whether to use the drug in patients with hypercalcaemia due to malignancy, the patient’s condition should be assessed against the background of renal dysfunction and a conclusion made as to whether the potential benefit of treatment outweighs the possible risk.

When deciding on the treatment of patients with bone metastases in order to prevent the symptoms associated with spinal diseases, it should be borne in mind that the effect of the drug begins to appear after 2-3 months.

There have been reports of renal dysfunction associated with the use of bisphosphonates. Factors that increase the possibility of renal impairment include dehydration, pre-existing renal impairment, repeated cycles of ZolendroVista or other bisphosphonates, as well as the use of nephrotoxic agents or infusion in a shorter time than recommended. Although the risk is reduced with ZolendroVista 4 mg for at least 15 minutes, deterioration in renal function is possible. Cases of deterioration in renal function, progression to renal failure and the need for dialysis have been observed in patients after administration of an initial dose or a single dose of zoledronic acid 4 mg.

Elevated serum creatinine is also observed in some patients who regularly take the drug in the recommended doses to prevent the symptoms associated with spinal diseases, although this is quite rare.

Serum creatinine levels should be assessed in patients before each dose of ZolendroVista. After initiation of treatment, lower doses of DilendroV are recommended for patients with bone metastases and women with early postmenopausal breast cancer during treatment with aromatase inhibitors (AIs) to prevent bone loss and bone fractures in mild or moderate renal impairment. table in the section “Method of administration and dosage”). In patients with impaired renal function during treatment, the drug can be resumed only when the creatinine level returns to the initial value within 10% of the initial value. When resuming therapy, ZolendroVist is used in the same dose as before the temporary cessation.

Due to the possible effect of bisphosphonates, including ZolendroVista, on renal function, due to the lack of detailed clinical safety data in patients with severe renal impairment, serum creatinine is ≥ 400 μmol / l or ≥ 4.5 mg / dl for patients with tumor-induced hypercalcaemia and serum creatinine is ≥ 265 μmol / l or ≥ 3 mg / dL for patients with bone metastases and in women with early postmenopausal breast cancer during treatment with aromatase inhibitors (AI). bone loss and bone fractures, respectively) and only limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 ml / min). The drug is not recommended for use in patients with severe renal insufficiency.

Liver dysfunction

There are no specific recommendations for patients with severe hepatic impairment, as only limited clinical data are available.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported, mainly in cancer patients receiving a regimen that included bisphosphonates, including zoledronic acid.

Many of these patients also received chemotherapy and corticosteroids. Most of the reported cases were related to dental procedures, such as tooth extraction. Many of the patients had signs of local infection, including osteomyelitis.

The start of treatment or a new course of treatment should be postponed if patients have unhealed open soft tissue lesions in the oral cavity, except in medical emergencies. Prior to initiating bisphosphonate therapy, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive dental treatment and individual benefit-risk assessment.

The following risk factors should be considered to assess the individual risks of developing osteonecrosis of the jaw:

– Bisphosphonate activity (higher risk for more active ingredients), route of administration (higher risk for parenteral administration) and cumulative dose.

– Cancer, comorbidities (eg, anemia, coagulopathy, infection), smoking.

– History of dental diseases, poor oral hygiene, periodontal diseases, invasive dental procedures and unsuitable dentures.

Prior to treatment with bisphosphonates, the oral cavity should be examined with appropriate dental prophylaxis.

Invasive dental procedures should be avoided whenever possible during treatment with these patients. Dental surgery may worsen the condition of patients who have developed osteonecrosis of the jaw during bisphosphonate therapy. There are no data in patients who require dental procedures to determine whether the risk of developing osteonecrosis of the jaw is reduced when discontinuing bisphosphonates. The treatment regimen for patients who develop osteonecrosis of the jaw should be developed in conjunction with a physician and a dentist or dental surgeon with experience in treating patients with osteonecrosis of the jaw. Consideration should be given to temporarily discontinuing zoledronic acid until the condition normalizes and risk factors are minimized.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal was observed when taking bisphosphonates, mainly during long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and / or local risk factors such as infection or injury. The possibility of osteonecrosis of the external auditory canal should be considered in patients who receive bisphosphonates and complain of symptoms from the hearing organs, including chronic ear infections.

Musculoskeletal pain

Severe, sometimes disabling pain in the bones, joints, and / or muscles of patients using bisphosphonates has been reported in post-marketing experience. However, such reports were isolated. This category of drugs includes zoledronic acid. The time to onset of symptoms ranged from one day to several months from the start of treatment. In most patients, after discontinuation of treatment, the severity of symptoms decreased. In this category of patients, recurrence of symptoms was noted if treatment was resumed with the same drug or other bisphosphonate.

Atypical fracture of the femur

Atypical subtrochanteric and diaphyseal fractures of the femur have been reported during bisphosphonate therapy, primarily in patients treated with osteoporosis for a long time. These transverse or short oblique fractures are possible anywhere along the thigh from just below the small acetabulum to just above the appendages. These fractures occur after minimal or no trauma, and some patients experience pain in the thigh or groin, often associated with radiological signs of a stress fracture, weeks or months before a complete hip fracture occurs. Fractures are often bilateral, so the second femur should be examined in patients receiving bisphosphonate therapy and who have suffered a fracture of the femur. Poor healing of such fractures has also been reported. Based on individual risk and benefit assessment, discontinuation of bisphosphonate therapy for patients with suspected atypical femoral fractures should be addressed.

During treatment with bisphosphonates, the patient should inform the physician of any pain in the pelvis, thigh, or groin, and any patient with such symptoms should be examined for incomplete femoral fracture.

Hypocalcemia

Hypocalcaemia has been reported in patients receiving zoledronic acid; cases of cardiac arrhythmias and neurological reactions (including seizures, numbness and tetany), secondary to severe hypocalcaemia; cases of severe hypocalcemia requiring hospitalization. In some cases, hypocalcemia can be life-threatening.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Pregnancy

There are no adequate data from the use of zoledronic acid in pregnant women. Reproductive studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Breastfeeding period

It is not known whether zoledronic acid is excreted in human milk.

Ability to influence the speed of reaction when driving a car or working with other mechanisms

Adverse drug reactions, such as dizziness and somnolence, may affect the ability to drive or use machines, so caution should be exercised when driving or operating complex machinery while using ZolendroVista.

Method of application and dosage

The drug should be administered only by a physician experienced in the intravenous administration of bisphosphonates.

Before administration, 5 ml of ZolendroVista concentrate containing 4 mg of zoledronic acid is diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The reconstituted solution for infusion is administered as a single intravenous infusion over at least 15 minutes.

ZolendroVista concentrate should not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer’s solution, and should be administered as a single intravenous infusion using a separate infusion system.

Prevention of symptoms associated with bone lesions in patients with late-stage malignancies

Adults and elderly patients

The recommended dose of zoledronic acid is 4 mg as an infusion every 3-4 weeks.

Patients also need daily calcium supplements at a dose of 500 mg and 400 IU of vitamin D per day.

When deciding on the treatment of patients with metastatic bone lesions for the prevention of symptoms associated with bone lesions, it should be borne in mind that the onset of the effect of treatment occurs after 2-3 months.

Atypical fracture of the femur

Atypical subtrochanteric and diaphyseal fractures of the femur have been reported during bisphosphonate therapy, primarily in patients treated with osteoporosis for a long time. These transverse or short oblique fractures are possible anywhere along the thigh from just below the small acetabulum to just above the appendages. These fractures occur after minimal or no trauma, and some patients experience pain in the thigh or groin, often associated with radiological signs of a stress fracture, weeks or months before a complete hip fracture occurs. Fractures are often bilateral, so the second femur should be examined in patients receiving bisphosphonate therapy and who have suffered a fracture of the femur. Poor healing of such fractures has also been reported. Based on individual risk and benefit assessment, discontinuation of bisphosphonate therapy for patients with suspected atypical femoral fractures should be addressed.

During treatment with bisphosphonates, the patient should inform the physician of any pain in the pelvis, thigh, or groin, and any patient with such symptoms should be examined for incomplete femoral fracture.

Hypocalcemia

Hypocalcaemia has been reported in patients receiving zoledronic acid; cases of cardiac arrhythmias and neurological reactions (including seizures, numbness and tetany), secondary to severe hypocalcaemia; cases of severe hypocalcemia requiring hospitalization. In some cases, hypocalcemia can be life-threatening.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding

Pregnancy

There are no adequate data from the use of zoledronic acid in pregnant women. Reproductive studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Breastfeeding period

It is not known whether zoledronic acid is excreted in human milk.

Ability to influence the speed of reaction when driving a car or working with other mechanisms

Adverse drug reactions, such as dizziness and somnolence, may affect the ability to drive or use machines, so caution should be exercised when driving or operating complex machinery while using ZolendroVista.

Method of application and dosage

The drug should be administered only by a physician experienced in the intravenous administration of bisphosphonates.

Before administration, 5 ml of ZolendroVista concentrate containing 4 mg of zoledronic acid is diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The reconstituted solution for infusion is administered as a single intravenous infusion over at least 15 minutes.

ZolendroVista concentrate should not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer’s solution, and should be administered as a single intravenous infusion using a separate infusion system.

Prevention of symptoms associated with bone lesions in patients with late-stage malignancies

Adults and elderly patients

The recommended dose of zoledronic acid is 4 mg as an infusion every 3-4 weeks.

Patients also need daily calcium supplements at a dose of 500 mg and 400 IU of vitamin D per day.

When deciding on the treatment of patients with metastatic bone lesions for the prevention of symptoms associated with bone lesions, it should be borne in mind that the onset of the effect of treatment occurs after 2-3 months.

Children

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations on how to use in children.

Instructions for preparing doses of zoledronic acid

For intravenous administration.

5 ml of drug concentrate containing 4 mg of zoledronic acid should be diluted in 100 ml of sterile 0.9% sodium chloride solution or 5% glucose for intravenous infusion.

Reduced doses of ZolendroVista are recommended for patients with mild or moderate renal impairment.

Instructions for preparing reduced doses of the drug:

Collect the appropriate volume of concentrate as follows:

  •  4.4 ml corresponds to 3.5 mg;
  •  4.1 ml corresponds to 3.3 mg;
  • 3.8 ml corresponds to 3 mg.

Adequate hydration of the patient should be provided before and after administration of ZolendroVista.

Children

The safety and efficacy of zoledronic acid in children have not been established.

Overdose

Clinical experience in the treatment of acute zoledronic acid overdose is limited. False use of zoledronic acid in a dose of up to 48 mg has been recorded. Patients who received the drug in excess of the recommended dose should be under constant medical supervision, as possible renal dysfunction (including renal failure), changes in serum electrolytes (including calcium, phosphate and magnesium) ). In case of hypocalcemia, infusion of calcium gluconate is indicated according to clinical indicators. Treatment is symptomatic.

Adverse reactions

Acute reactions, symptoms of which included bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint edema, have usually been reported within 3 days of zoledronic acid administration. These symptoms usually disappear within a few days.

The following important side effects have been identified with the use of zoledronic acid:

renal dysfunction, jaw necrosis, acute reactions, hypocalcemia, visual impairment, atrial fibrillation, anaphylaxis, interstitial lung disease.

Information on the frequency of adverse reactions when using zoledronic acid at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with zoledronic acid are similar to those reported with other bisphosphonates and may occur in approximately one-third of all patients.

Information on the following adverse reactions was collected during clinical trials, preferably after long-term treatment with zoledronic acid.

Adverse reactions are ranked under headings of frequency: very common (≥ 1/10), common (≥ 1/100, <1/10), uncomon (≥ 1/1000, <1/100), rare (≥ 1 / 10,000, <1/1000), very rare (<1/10000), unknown (cannot be estimated from the available data).

From the blood and lymphatic system:

often – anemia;

sometimes – thrombocytopenia, leukopenia;

rarely – pancytopenia.

From the nervous system:

often – headache;

sometimes – paresthesias, dizziness, taste disorders, hypoesthesia, hyperesthesia, tremor, drowsiness; very rarely – epileptic seizures, numbness and tetany (secondary to hypocalcemia).

From the psyche:

sometimes – anxiety, sleep disorders;

rarely – confusion of consciousness.

From the eyes:

often – conjunctivitis;

sometimes – blurred vision, scleritis and inflammation of the orbit;

rarely – uveitis;

very rarely – episcleritis.

From the gastrointestinal tract:

often – nausea, vomiting, anorexia;

sometimes – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system:

sometimes – dyspnea, cough, bronchoconstriction;

rarely – interstitial lung disease.

From the skin and subcutaneous tissues:

sometimes – itching, rash (including erythematous and macular rash), sweating.

From the musculoskeletal system, connective tissue:

often – bone pain, myalgia, arthralgia, generalized pain;

sometimes – muscle cramps, osteonecrosis of the jaw;

very rarely – osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates).

From the cardiovascular system:

sometimes – arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension, which causes syncope and circulatory collapse;

rarely – bradycardia, very rarely – cardiac arrhythmia (secondary to hypocalcemia).

From the kidneys and genitourinary system:

often – renal disorders;

sometimes – acute renal failure, hematuria, proteinuria;

rarely – acquired Fanconi syndrome.

From the immune system:

sometimes – hypersensitivity reactions;

rarely – angioneurotic edema.

General disorders and administration site conditions:

often – fever, flu-like condition (including fatigue, chills, malaise and hot flashes);

sometimes injection site reactions (including pain, irritation, swelling, hardening), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions / shock, urticaria;

rarely – arthritis and swelling of the joints as symptoms of an acute phase reaction.

Deviations of laboratory parameters:

very often – hypophosphatemia;

often – increased levels of creatinine and urea in the blood, hypocalcemia;

sometimes – hypomagnesemia, hypokalemia;

rarely – hyperkalemia, hypernatremia.

Renal dysfunction

Deterioration of renal function has been reported with zoledronic acid. Based on an analysis of the safety data obtained from registration studies of zoledronic acid for the prevention of adverse events associated with bone damage, in patients with common malignancies, the incidence of renal impairment considered to be related to zoledronic acid was as follows: multiple myeloma – 3.2%, prostate cancer – 3.1%, breast cancer – 4.3%, lung cancer and other solid tumors – 3.2%. Factors that may increase the risk of renal impairment include dehydration, previous renal impairment, repeated courses of zoledronic acid or other bisphosphonates, as well as concomitant use of other nephrotoxic agents or reduction of the recommended infusion time. Cases of deterioration of renal function, progression of renal failure and the need for hemodialysis during the first or single use of zoledronic acid at a dose of 4 mg have been reported.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been reported mainly in cancer patients who have used zoledronic acid. Many of these patients had local infections, including osteomyelitis. Most of the cases involved dental procedures such as tooth extraction. Osteonecrosis of the jaw has many identified risk factors, including diagnosed cancer, concomitant therapy (eg, chemotherapy, radiation therapy, corticosteroids) and comorbidities (eg, anemia, coagulopathy, infections, oral disease).

Although no causal relationship has been established, these patients are advised to avoid invasive dental procedures.

Atrial fibrillation

Efficacy and safety of zoledronic acid were observed in patients with postmenopausal osteoporosis, the overall incidence of atrial fibrillation was 2.5% in the group of patients receiving zoledronic acid 5 mg and 1.9% in the placebo group. The cause of the increased incidence of atrial fibrillation is unknown.

Acute phase reactions

These side effects include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea and arthralgia, as well as arthritis with associated swelling of the joints, which may occur within the first 3 days after infusion. This reaction is called “flu-like” syndrome, or “after receiving the drug” syndrome.

Atypical fractures of the femur

Reactions such as have been reported rarely during post-marketing experience

acute subtrochanteric and diaphyseal fractures of the femur (adverse reaction to bisphosphonates).

Side effects caused by hypocalcemia

Hypocalcemia is an important identified risk when using the drug according to registered indications. Clinical and post-marketing data suggest an association between zoledronic acid therapy, reports of hypocalcaemia and the development of secondary cardiac arrhythmias. There is also evidence of an association between hypocalcaemia and secondary neurological responses, including seizures, numbness, and tetany.

Expiration date

3 years.

After dilution: from a microbiological point of view, the drug should be used immediately.

If not used immediately, store within 24 hours at 2-8 ºC after opening.

The cooled solution should be brought to room temperature before administration.

Storage conditions

Does not require special storage conditions. Keep out of reach of children.

Incompatibility

The drug concentrate should be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate should not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer’s solution, and should be administered as a single infusion using a separate infusion system.

Studies with glass vials, as well as several types of infusion bags and infusion systems made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution), showed no incompatibility with the above materials.

Packaging

5 ml of concentrate for solution for infusion in a vial with a rubber stopper and an aluminum cap. 1 vial in a cardboard box.