Zoledronic acid - vista ac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLEDRONIC ACID-VISTA AC (ZOLEDRONIC ACID-VISTA AC)

Composition:

Active substance: zoledronic acid;

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

1 ml of concentrate contains 0.8529 mg of anhydrous zoledronic acid (in the form of zoledronic acid monohydrate);

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Drugs affecting bone structure and mineralization. Bisphosphonates. ATC code M05B A08.

Pharmacological Properties.

Pharmacodynamics.

Zoledronic acid belongs to a new class of bisphosphonates that specifically act on bone tissue. It is one of the most potent inhibitors of osteoclast-mediated bone resorption known to date.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone tissue; however, the molecular mechanism leading to inhibition of osteoclast activity has not yet been fully elucidated. Animal studies have shown that zoledronic acid inhibits bone resorption without negatively affecting bone formation, mineralization, or mechanical properties of bone.

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

In vivo — inhibition of osteoclast-mediated bone resorption acting on the microcrystalline matrix structure of bone, resulting in reduced tumor growth; antiangiogenic effect (action on blood vessels leading to reduced tumor blood supply); analgesic effect. In vitro — inhibition of osteoblastic proliferation; cytostatic effect; pro-apoptotic effect on tumor cells; synergistic cytostatic effect with other antineoplastic agents; anti-adhesive and anti-invasive effects.

Pharmacokinetics.

Pharmacokinetic data in patients with bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid administered to 64 patients. Pharmacokinetic parameters are independent of the drug dose.

After initiation of zoledronic acid infusion, plasma concentrations of the drug rapidly increase, reaching a peak at the end of the infusion. This is followed by a rapid decline in concentration to 10% of the peak value within 4 hours and to less than 1% of the peak value within 24 hours, with a subsequent prolonged period of low concentrations not exceeding 0.1% of the peak level until the next infusion on day 28. Intravenously administered zoledronic acid is eliminated by the kidneys in three phases: rapid biphasic elimination from systemic circulation with half-lives t½α = 0.24 hours and t½β = 1.87 hours, followed by a prolonged terminal phase with t½γ = 146 hours. No drug accumulation in plasma was observed with repeated administration every 28 days.

Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. Within the first 24 hours, 39 ± 16% of the administered dose is recovered in urine. The remainder of the drug is primarily bound to bone tissue. Subsequently, zoledronic acid is slowly released from bone back into systemic circulation and eliminated via the kidneys. Total systemic clearance of the drug is 5.04 ± 2.5 L/h and is independent of drug dose, sex, age, race, and body weight. Increasing the infusion duration from 5 to 15 minutes reduces the concentration of zoledronic acid by 30% at the end of infusion but does not affect the plasma concentration-time curve (AUC).

Inter-patient variability in the pharmacokinetic parameters of zoledronic acid was high, as observed with other bisphosphonates.

Pharmacokinetic data for zoledronic acid in patients with hypercalcemia and hepatic insufficiency are lacking. In vitro data indicate that zoledronic acid does not inhibit human cytochrome P450 enzymes and is not subject to biotransformation. Experimental animal studies show that less than 3% of the administered dose is excreted in feces, suggesting that hepatic function is unlikely to influence the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance. Renal clearance of zoledronic acid averages 75 ± 33% of creatinine clearance, which ranged from 22 to 143 mL/min (mean 84 ± 29 mL/min) in 64 oncology patients included in the study. Analysis of patient subgroups showed that relative clearance of zoledronic acid was 37% and 72% of normal in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 50 mL/min (moderate renal impairment), respectively. However, pharmacokinetic data in patients with severe renal impairment (< 30 mL/min) are limited.

Zoledronic acid has been shown to have low affinity for blood cellular components. Plasma protein binding is low, with unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.

Special Populations.

Children.

Limited pharmacokinetic data in children with severe forms of osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to that in adults when administered at equivalent doses (mg/kg). Age, body weight, sex, and creatinine clearance do not appear to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

• For the prevention of skeletal-related symptoms (pathological fractures, spinal cord compression, complications following surgical procedures or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced malignant neoplasms.
• For the treatment of hypercalcemia due to malignancy.

Contraindications.

Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates, or to any of the excipients of the medicinal product.

Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

During clinical studies, other medicinal products such as anticancer agents, antibiotics, and analgesics were frequently administered concomitantly with "Zoledronic Acid-Vista AS" without any clinically significant interactions being observed. According to in vitro study data, zoledronic acid does not significantly bind to plasma proteins and does not inhibit cytochrome P450 enzyme system enzymes. However, specific clinical studies investigating drug interactions have not been conducted.

Caution is recommended when administering bisphosphonates together with aminoglycosides, as they may have an additive effect, potentially leading to prolonged reduction in serum calcium levels. Caution is also recommended when using bisphosphonates concomitantly with loop diuretics, as additive effects may lead to hypocalcemia. Care should be taken when prescribing "Zoledronic Acid-Vista AS" together with other potentially nephrotoxic medicinal products. The possibility of developing hypomagnesemia during treatment should also be considered.

In patients with multiple myeloma, intravenous administration of bisphosphonates in combination with thalidomide increases the risk of renal impairment. Osteonecrosis of the jaw has been reported in patients receiving concomitant treatment with "Zoledronic Acid-Vista AS" and antiangiogenic medicinal products (which reduce tumor blood supply).

Special precautions for use.

Before administering the medicinal product "Zoledronic Acid-Vista AS", ensure adequate hydration of all patients, including those with mild to moderate renal impairment.

Avoid overhydration in patients at risk of developing heart failure. Standard metabolic parameters associated with hypercalcemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored after initiating therapy with "Zoledronic Acid-Vista AS". If hypocalcemia, hypophosphatemia, or hypomagnesemia occurs, short-term corrective therapy may be required.

Untreated patients with hypercalcemia usually have some degree of renal impairment; therefore, careful monitoring of renal function parameters is necessary.

Alternative medicinal products containing zoledronic acid as the active substance are available for the treatment of osteoporosis and Paget's disease. Patients receiving therapy with "Zoledronic Acid-Vista AS" must not concurrently receive other medicinal products containing zoledronic acid.

Patients receiving therapy with "Zoledronic Acid-Vista AS" must not use any other bisphosphonates.

Renal impairment.

When considering the use of the medicinal product in patients with malignancy-associated hypercalcemia and underlying renal impairment, the patient's condition should be evaluated and a decision made as to whether the potential benefit outweighs the possible risk.

When deciding on treatment of patients with bone metastases for prevention of skeletal-related events, it should be noted that the therapeutic effect becomes evident after 2–3 months. Renal dysfunction has been reported with bisphosphonate use. Factors increasing the risk of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of treatment with "Zoledronic Acid-Vista AS" or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion administered over a shorter duration than recommended. Although the risk is reduced when "Zoledronic Acid-Vista AS" is administered at a dose of 4 mg over no less than 15 minutes, deterioration of renal function is still possible. Cases of worsening renal function, progression to renal failure, and the need for dialysis have been observed in patients after administration of an initial or single 4 mg dose of zoledronic acid.

Elevated serum creatinine levels have also been observed in some patients receiving the medicinal product at recommended doses for prevention of skeletal-related events, although this occurs infrequently. Serum creatinine levels should be assessed in patients prior to each dose of "Zoledronic Acid-Vista AS". In patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, lower doses of "Zoledronic Acid-Vista AS" are recommended in cases of mild or moderate renal impairment (see table in the section "Dosage and administration"). In patients who develop renal impairment during treatment, the medicinal product may be resumed only when serum creatinine levels return to within 10% of baseline values. Upon resumption of therapy, "Zoledronic Acid-Vista AS" should be administered at the same dose as before the temporary interruption.

Due to the potential effect of bisphosphonates, including "Zoledronic Acid-Vista AS", on renal function, and in the absence of comprehensive clinical safety data in patients with severe renal impairment (defined as serum creatinine ≥ 400 μmol/L or ≥ 4.5 mg/dL in patients with tumor-induced hypercalcemia; serum creatinine ≥ 265 μmol/L or ≥ 3 mg/dL in patients with bone metastases and in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, respectively), and due to limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of "Zoledronic Acid-Vista AS" is not recommended in patients with severe renal impairment.

Hepatic impairment.

There are no specific recommendations for patients with severe hepatic impairment due to limited clinical data.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw has been reported primarily in oncology patients receiving treatment regimens that include bisphosphonates, including "Zoledronic Acid-Vista AS". Many of these patients were also receiving chemotherapy and corticosteroids. Most reported cases were associated with dental procedures such as tooth extraction. Many patients had signs of local infection, including osteomyelitis.

Initiation or resumption of treatment should be delayed in patients with unhealed open soft tissue lesions in the oral cavity, unless medically urgent. Prior to starting bisphosphonate therapy, patients with concomitant risk factors should undergo a dental examination with appropriate preventive dental treatment and individual benefit-risk assessment.

The following risk factors should be considered when assessing individual risk for developing osteonecrosis of the jaw:

• Potency of bisphosphonates (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose.
• Cancer, concomitant diseases (e.g., anemia, coagulopathy, infection), smoking.
• Concomitant therapies: chemotherapy, use of angiogenesis inhibitors, radiotherapy to the head and neck, corticosteroid therapy.
• Dental history (e.g., periodontal disease), poor oral hygiene, invasive dental procedures, and ill-fitting dentures. An oral examination with appropriate dental preventive measures should be performed before initiating bisphosphonate therapy.

All patients should be informed of the need to maintain good oral hygiene, undergo routine dental check-ups, and report symptoms such as tooth mobility, pain, swelling, or non-healing sores during bisphosphonate therapy. Invasive dental procedures should be avoided whenever possible during treatment. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data to suggest whether discontinuation of bisphosphonate therapy reduces the risk of developing osteonecrosis of the jaw in patients requiring dental procedures. The treating physician should make decisions based on individual benefit-risk assessment. Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration between the treating physician and a dentist or oral surgeon experienced in managing such cases. 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 has been observed with bisphosphonate use, primarily during long-term therapy. Risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and/or local risk factors such as infections or trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with symptoms related to the ear, including chronic ear infections. Sporadic cases of osteonecrosis in other bones, including the femur and pelvic bones, have been reported in adult oncology patients receiving bisphosphonate therapy.

Musculoskeletal pain.

During post-marketing surveillance, severe, sometimes incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been rare. This class of medicinal products includes "Zoledronic Acid-Vista AS" (zoledronic acid). The time to onset of symptoms ranged from one day to several months after starting treatment. In most patients, symptom severity decreased after discontinuation of the drug. Recurrence of symptoms was observed in some patients upon rechallenge with the same or another bisphosphonate.

Atypical femoral fractures.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur from slightly below the lesser trochanter to slightly above the condyles. These fractures occur with minimal or no trauma. Some patients experience thigh or groin pain, often associated with radiological signs of stress fracture, weeks or months before a complete femoral fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be evaluated in patients on bisphosphonate therapy who have sustained a femoral fracture. Poor healing of such fractures has also been reported. Based on individual assessment of risk and benefit, discontinuation of bisphosphonate therapy should be considered in patients suspected of having atypical femoral fractures.

Patients receiving bisphosphonate therapy should be advised to inform their physician of any pelvic, thigh, or groin pain. Any patient presenting with such symptoms should be evaluated for incomplete femoral fracture.

Hypocalcemia.

Hypocalcemia has been reported in patients receiving zoledronic acid. Cases of cardiac arrhythmias and neurological reactions (including seizures, hypoesthesia, numbness, and tetany) secondary to severe hypocalcemia have been documented. Cases of severe hypocalcemia requiring hospitalization have been reported. In some cases, hypocalcemia may be life-threatening. Caution should be exercised when zoledronic acid is used concomitantly with medicinal products that may cause hypocalcemia, as they may have a synergistic effect leading to severe hypocalcemia (see section "Interaction with other medicinal products and other forms of interaction"). Serum calcium levels should be checked and corrected if necessary before initiating therapy. Treatment of such patients should be adequately supplemented with calcium and vitamin D.

Important information about excipients.

Sodium.

"Zoledronic Acid-Vista AS" contains 24 mg of sodium per dose. Caution is advised when administering the medicinal product to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Pregnancy.

There are insufficient data on the use of zoledronic acid in pregnant women. Animal reproductive studies have shown reproductive toxicity. The potential risk to humans is unknown.

Breastfeeding.

It is unknown whether zoledronic acid is excreted in human milk.

Fertility.

Zoledronic acid has been administered to rats to evaluate potential adverse effects on fertility. Study results did not allow determination of the effect of zoledronic acid on human fertility.

Ability to influence reaction rate when driving or operating machinery.

Adverse reactions of the medicinal product, such as dizziness and somnolence, may affect the ability to drive or operate machinery; therefore, caution is required when driving or operating complex machinery during treatment with "Zoledronic Acid-Vista AS".

Administration and Dosage

The medicinal product should only be administered by physicians experienced in intravenous bisphosphonate administration.

Before administration, 5 ml of the concentrate of "Zoledronic Acid-Vista AS" containing 4 mg of zoledronic acid must be diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The resulting infusion solution of "Zoledronic Acid-Vista AS" is administered as a single intravenous infusion over no less than 15 minutes.

The concentrate of "Zoledronic Acid-Vista AS" must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution, and should be administered as a single intravenous infusion using a separate infusion system.

Prevention of skeletal-related events in patients with advanced malignancies.

Adults, including elderly patients.

The recommended dose of zoledronic acid is 4 mg administered as an infusion every 3–4 weeks. Patients should also receive daily oral calcium supplementation (500 mg) and vitamin D (400 IU) daily. When considering treatment of patients with metastatic bone disease for prevention of skeletal-related events, it should be noted that the onset of therapeutic effect occurs after 2–3 months.

Treatment of hypercalcemia of malignancy.

Adults, including elderly patients.

When using the medicinal product for hypercalcemia (serum calcium level corrected for albumin ≥ 12.0 mg/dL, or ≥ 3.0 mmol/L), a single dose of 4 mg zoledronic acid is recommended.

Renal Impairment.

Hypercalcemia of malignancy.

Treatment of hypercalcemia of malignancy in patients with severe renal impairment may be considered only after careful assessment of the risks and expected benefits of the medicinal product. There is no clinical experience with the use of the medicinal product in patients with serum creatinine levels > 400 μmol/L, or > 4.5 mg/dL. Dose adjustment is not required in patients with hypercalcemia of malignancy and serum creatinine levels < 400 μmol/L, or < 4.5 mg/dL.

Prevention of skeletal-related events in patients with advanced malignancies.

At the start of treatment in patients with multiple myeloma or metastatic bone disease due to solid tumors, serum creatinine and creatinine clearance should be determined. Creatinine clearance should be calculated using the Cockcroft-Gault formula. "Zoledronic Acid-Vista AS" is not recommended for use in patients with severe renal impairment prior to initiation of therapy (creatinine clearance < 30 mL/min). Clinical studies on the use of the medicinal product in patients with serum creatinine levels > 265 μmol/L, or ≥ 3 mg/dL, have not been conducted.

For patients with metastatic bone disease and mild to moderate renal impairment prior to initiation of therapy (creatinine clearance 30–60 mL/min), the following dosage recommendations apply:

Initial creatinine clearance level (ml/min)	Recommended dose of the medicinal product*
>60	4 mg zoledronic acid
50–60	3.5 mg zoledronic acid*
40–49	3.3 mg zoledronic acid*
30–39	3 mg zoledronic acid*

*Doses calculated assuming a target AUC = 0.66 mg•h/L (creatinine clearance 75 mL/min). For patients with impaired renal function, dose reduction is recommended to achieve the same AUC as in patients with a creatinine clearance of 75 mL/min.

Serum creatinine levels should be measured before administration of each dose of zoledronic acid-Vista AC after initiation of therapy. If renal function impairment occurs, treatment should be discontinued.

Renal function impairment was defined in clinical studies as follows:

• for patients with normal baseline serum creatinine levels (< 1.4 mg/dL, or < 124 µmol/L) — an increase of 0.5 mg/dL, or 44 µmol/L;
• for patients with elevated baseline serum creatinine levels (> 1.4 mg/dL, or > 124 µmol/L) — an increase of 1 mg/dL, or 88 µmol/L.

In clinical studies, treatment with zoledronic acid-Vista AC was resumed after serum creatinine levels returned to within 10% of the baseline value. Zoledronic acid-Vista AC treatment should be resumed at the same dose as prior to treatment interruption.

Pediatric populations.

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations regarding the method of administration of the medicinal product in children.

Instructions for preparation of doses of «Zoledronic Acid-Vista AC».

For intravenous administration.

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

Patients with mild to moderate renal impairment should receive reduced doses of zoledronic acid-Vista AC. Instructions for preparation of reduced doses of «Zoledronic Acid-Vista AC».

Withdraw the appropriate volume of concentrate as indicated below:

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

The required amount of liquid concentrate should be diluted in 100 mL of sterile 0.9% sodium chloride solution or 5% glucose solution for intravenous infusion.

Adequate hydration of the patient should be ensured before and after administration of zoledronic acid-Vista AC.

Children.

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

Overdose.

Symptoms. Clinical experience with acute overdose of zoledronic acid is limited. Cases of accidental administration of zoledronic acid at doses up to 48 mg have been reported.

Treatment. Patients who have received a dose exceeding the recommended dose should be under continuous medical supervision, as renal function impairment (including renal failure) and changes in serum electrolyte levels (including calcium, phosphate, and magnesium concentrations) may occur. In the event of hypocalcemia, calcium gluconate infusion is recommended based on clinical indications. Treatment is symptomatic.

Side effects

Within three days following administration of the medicinal product "Zoledronic Acid-Vista AS", acute-phase reactions have been commonly reported. Symptoms of these reactions include bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritic joint swelling. These symptoms usually resolve within several days.

Significant adverse reactions identified with use of "Zoledronic Acid-Vista AS" include: renal impairment, jaw necrosis, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, and interstitial lung disease. Information on the frequency of adverse reactions with the 4 mg dose is primarily based on data obtained from long-term treatment studies. Adverse reactions associated with "Zoledronic Acid-Vista AS" are similar to those reported with other bisphosphonates and may occur in approximately one-third of all patients.

The following adverse reactions were collected from clinical trials, primarily during long-term treatment with zoledronic acid.

Adverse reactions are classified by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: common — anemia; uncommon — thrombocytopenia, leukopenia; rare — pancytopenia.

Nervous system disorders: common — headache; uncommon — paresthesia, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, somnolence; very rare — epileptic seizures, numbness, and tetany (secondary to hypocalcemia).

Psychiatric disorders: uncommon — restlessness, sleep disorders; rare — confusion.

Eye disorders: common — conjunctivitis; uncommon — blurred vision, scleritis, and orbital inflammation; rare — uveitis; very rare — episcleritis.

Gastrointestinal disorders: common — nausea, vomiting, anorexia; uncommon — diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory system disorders: uncommon — dyspnea, cough, bronchoconstriction; rare — interstitial lung disease.

Skin and subcutaneous tissue disorders: uncommon — pruritus, rash (including erythematous and macular rashes), increased sweating.

Musculoskeletal and connective tissue disorders: common — bone pain, myalgia, arthralgia, generalized pain; uncommon — muscle cramps, osteonecrosis of the jaw; very rare — osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates) and of other bones, including the femur and pelvic bones.

Cardiovascular disorders: uncommon — arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension leading to syncope and circulatory collapse; rare — bradycardia, cardiac arrhythmia (secondary to hypocalcemia).

Renal and urinary disorders: common — renal impairment; uncommon — acute renal failure, hematuria, proteinuria; rare — acquired Fanconi syndrome; frequency not known — tubulointerstitial nephritis.

Immune system disorders: uncommon — hypersensitivity reactions; rare — angioedema.

General disorders and administration site conditions: uncommon — pyrexia, influenza-like illness (including fatigue, chills, malaise, and flushing); rare — injection site reactions (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria; rare — arthritis and joint swelling as symptoms of acute-phase reaction.

Laboratory findings: very common — hypophosphatemia; common — increased blood creatinine and urea levels, hypocalcemia; uncommon — hypomagnesemia, hypokalemia; rare — hyperkalemia, hypernatremia.

Renal function impairment.

Renal function impairment has been observed with use of the medicinal product. According to safety data from registration trials of "Zoledronic Acid-Vista AS" evaluating adverse events related to bone involvement in patients with advanced malignancies, the incidence of renal function impairment considered related to "Zoledronic Acid-Vista AS" was as follows: multiple myeloma — 3.2%, prostate cancer — 3.1%, breast cancer — 4.3%, lung cancer and other solid tumors — 3.2%. Risk factors for renal impairment include dehydration, pre-existing renal dysfunction, multiple courses of treatment with "Zoledronic Acid-Vista AS" or other bisphosphonates, concomitant use of other nephrotoxic agents, and shortened infusion duration. Cases of renal function impairment, progression of renal failure, and need for hemodialysis have been reported following the first or a single dose of 4 mg zoledronic acid.

Osteonecrosis of the jaw.

Cases of osteonecrosis (predominantly of the jaw) have been reported primarily in cancer patients receiving "Zoledronic Acid-Vista AS". Many of these patients had signs of local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction. Osteonecrosis of the jaw has several established risk factors, including malignancy, concomitant therapy (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathy, infections, oral cavity diseases). Although a causal relationship has not been established, patients are advised to avoid invasive dental procedures.

Atrial fibrillation.

In a randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of zoledronic acid in postmenopausal women with osteoporosis, the overall incidence of atrial fibrillation was 2.5% in the group receiving 5 mg zoledronic acid and 1.9% in the placebo group. The reason for the increased incidence of atrial fibrillation is unknown.

Acute-phase reactions.

These adverse reactions include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea, arthralgia, and arthritis with associated joint swelling, which may occur within the first 3 days after infusion of "Zoledronic Acid-Vista AS". This reaction is referred to as flu-like syndrome or post-dose syndrome.

Atypical femoral fractures.

During the post-marketing period, rare reports of subtrochanteric and diaphyseal femoral fractures (an adverse reaction associated with bisphosphonates) have been reported.

Adverse reactions due to hypocalcemia.

Hypocalcemia is an important identified risk with "Zoledronic Acid-Vista AS" when used according to approved indications. Clinical and post-marketing data indicate an association between "Zoledronic Acid-Vista AS" therapy, reported hypocalcemia, and development of secondary cardiac arrhythmias. Additionally, data suggest a link between hypocalcemia and secondary neurological reactions, including epileptic seizures, hypoesthesia, numbness, and tetany.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product registration is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 3 years.

After dilution: from a microbiological standpoint, the product should be used immediately. If not used immediately, it may be stored at 2–8 °C for up to 24 hours after opening.

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

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Incompatibilities.

The concentrate of "Zoledronic Acid-Vista AS" must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution, and must be administered as a single infusion using a separate infusion system. Compatibility studies with glass vials and various 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) have shown no incompatibility with the above-mentioned packaging materials.

Packaging.

5 ml in a vial, 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sintrop Spain, S.L.

Manufacturer's address and place of business.

C/ Castelló, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.