Zoledronic acid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLEDRONIC ACID (ZOLEDRONIC ACID)

Composition:

Active substance: zoledronic acid monohydrate (zoledronic acid);

One ampoule (5 ml) contains zoledronic acid monohydrate, calculated as 100% anhydrous substance – 4.0 mg; 1 ml of concentrate contains 0.8 mg of anhydrous zoledronic acid;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: colorless clear liquid.

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 osteoclastic 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 osteoclastic activity has not yet been fully elucidated. Animal studies have demonstrated that zoledronic acid inhibits bone resorption without negatively affecting bone formation, mineralization, or mechanical bone properties.

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.

In vivo – inhibition of osteoblastic bone resorption acting on the microcrystalline matrix structure of bone, resulting in reduced tumor growth, antiangiogenic effect (action on blood vessels leading to decreased tumor blood supply), and 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 mg, 4 mg, 8 mg, and 16 mg of zoledronic acid administered to 64 patients. Pharmacokinetic parameters were independent of the dose administered.

After the start of zoledronic acid infusion, plasma concentration of the drug rapidly increases, reaching peak levels at the end of the infusion. This is followed by a rapid decline to 10% of peak concentration within 4 hours and to less than 1% of peak concentration within 24 hours, with a prolonged period of low concentrations thereafter, not exceeding 0.1% of peak levels, until the next infusion on day 28. Intravenously administered zoledronic acid is eliminated via 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 is primarily bound to bone tissue. Subsequently, zoledronic acid is slowly released from bone back into systemic circulation and eliminated renally. Total systemic clearance of the drug is 5.04±2.5 L/h and is independent of dose, gender, age, race, and body weight. Increasing infusion duration from 5 to 15 minutes reduces zoledronic acid concentration at the end of infusion by 30%, but does not affect the plasma concentration-time curve (AUC).

Inter-patient variability in the pharmacokinetic parameters of zoledronic acid was high, consistent with observations for 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 the human CYP450 enzyme 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, with the renal clearance of zoledronic acid averaging 75±33% of creatinine clearance. In 64 oncology patients included in the study, creatinine clearance averaged 84±29 mL/min (range 22–143 mL/min). Analysis of patient subgroups showed that in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 50 mL/min (moderate renal impairment), relative zoledronic acid clearance was 37% and 72%, respectively. However, pharmacokinetic data in patients with severe renal impairment (<30 mL/min) are limited.

Zoledronic acid shows low affinity for blood cellular components. Plasma protein binding is low, with the 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, gender, and creatinine clearance do not appear to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

• Prevention of symptoms related to bone involvement (pathological fractures, spinal cord compression, complications following surgical procedures or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced malignant diseases.
• Treatment of hypercalcemia due to malignancy.

Contraindications.

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

Pregnancy or breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

During clinical studies, other medicinal products were frequently administered concomitantly, including anticancer agents, diuretics, antibiotics, and analgesics. No clinically significant interactions were observed.

According to in vitro study data, zoledronic acid does not significantly bind to plasma proteins and does not inhibit cytochrome P450 enzyme system. However, specific clinical studies on drug interactions have not been conducted.

Caution is recommended when bisphosphonates are used concomitantly with aminoglycosides, as they may have an additive effect, potentially leading to prolonged reduction in serum calcium levels. Caution is also recommended when bisphosphonates are used concomitantly with loop diuretics, as they may have an additive effect, potentially resulting in hypocalcemia. Care should be taken when administering zoledronic acid together with other potentially nephrotoxic medicinal products. The possibility of developing hypomagnesemia during treatment should also be considered.

In patients with multiple myeloma, no clinically significant interactions have been observed with intravenous administration of bisphosphonates in combination with thalidomide.

Osteonecrosis of the jaw has been reported in patients receiving zoledronic acid concomitantly with antiangiogenic medicinal products (agents that reduce tumor blood supply).

Special precautions for use.

General

Before administration of the medicinal product Zoledronic Acid, ensure adequate hydration in all patients, including patients with mild to moderate renal impairment.

Avoid overhydration in patients at risk of developing heart failure.

Standard metabolic parameters associated with hypercalcaemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored at the beginning of treatment with Zoledronic Acid. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term corrective therapy may be necessary.

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

Patients receiving Zoledronic Acid should not be treated concurrently with other medicinal products containing zoledronic acid, nor should any other bisphosphonates be administered.

Renal impairment

When considering the use of Zoledronic Acid in patients with hypercalcaemia due to malignancy and concomitant renal impairment, the patient's condition should be evaluated and a decision made as to whether the potential benefit of treatment outweighs the possible risk.

When deciding on treatment of patients with bone metastases for the prevention of skeletal-related events, it should be noted that the effect of the drug becomes apparent after 2–3 months.

Renal dysfunction associated with bisphosphonate use has been reported. Factors increasing the risk of renal impairment include dehydration; pre-existing renal impairment; multiple cycles of zoledronic acid or other bisphosphonates; use of nephrotoxic agents; and infusion administered over a shorter duration than recommended. Although the risk is reduced when Zoledronic Acid is administered at a dose of 4 mg over no less than 15 minutes, deterioration in renal function may still occur. Cases of renal impairment progressing to renal failure and requiring dialysis have been observed in patients after administration of an initial or single 4 mg dose of zoledronic acid.

Elevations in serum creatinine have also been observed in some patients receiving the drug at recommended doses for prevention of skeletal-related events, although this occurs infrequently.

Serum creatinine levels should be assessed in patients before each dose of Zoledronic Acid. In patients with bone metastases, including postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, lower doses of Zoledronic Acid are recommended in cases of mild or moderate renal impairment (see table in the section "Dosage and administration"). If renal impairment occurs during treatment, administration of the drug may be resumed only when serum creatinine returns to within 10% of baseline values.

Due to the potential effect of bisphosphonates, including Zoledronic Acid, on renal function, and in the absence of comprehensive clinical safety data in patients with severe renal impairment (serum creatinine >400 μmol/L or >4.5 mg/dL for patients with tumour-induced hypercalcaemia, and serum creatinine >265 μmol/L or >3 mg/dL for patients with bone metastases, including 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 is not recommended in patients with severe renal impairment.

Hepatic impairment

There are no specific recommendations for patients with severe hepatic impairment.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported primarily in oncology patients receiving treatment regimens that include bisphosphonates, including Zoledronic Acid. 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 of treatment or a new treatment course should be delayed if patients have unhealed open soft tissue lesions in the oral cavity, except in medical emergencies. Prior to starting bisphosphonate therapy, patients with concomitant risk factors should undergo a dental examination with appropriate preventive dental treatment and individual assessment of benefit and risk.

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

• bisphosphonate potency (higher risk with more potent compounds), route of administration (higher risk with parenteral administration), and cumulative dose;
• cancer, chemotherapy, radiotherapy, corticosteroid therapy, concomitant diseases (e.g., anaemia, coagulopathy, infection), smoking;
• history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

A dental examination with appropriate preventive dental care should be performed before starting bisphosphonate therapy.

During therapy, invasive dental procedures should be avoided whenever possible in these patients. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data available on patients requiring dental procedures to suggest whether discontinuation of bisphosphonate therapy reduces the risk of developing osteonecrosis of the jaw. The treatment regimen for patients who develop osteonecrosis of the jaw should be developed in close collaboration between the treating physician and a dentist or oral surgeon experienced in managing patients with osteonecrosis of the jaw. Temporary discontinuation of zoledronic acid should be considered until the condition normalizes and risk factors are minimized.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been observed during bisphosphonate therapy, primarily during long-term treatment. Possible 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 report symptoms related to the auditory organs, including chronic ear infections.

Musculoskeletal pain

Severe, sometimes incapacitating, bone, joint, and/or muscle pain has been reported in patients receiving bisphosphonates. However, such reports have been infrequent. This class of drugs includes Zoledronic Acid. The time to onset of symptoms varied from one day to several months after starting treatment. In most patients, symptoms improved after discontinuation of therapy. In this patient group, recurrence of symptoms was observed upon reinitiation of therapy with the same or another bisphosphonate.

Atypical femoral fracture

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 supracondylar region. These fractures occur with minimal or no trauma, and some patients experience pain in the groin or thigh, often associated with radiological signs of stress fracture, several weeks or months before a complete femoral fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be examined in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Poor healing of such fractures has also been reported. Based on individual assessment of risk versus benefit, a decision should be made regarding discontinuation of bisphosphonate therapy in patients suspected of having atypical femoral fractures.

During bisphosphonate treatment, patients should be instructed to inform their physician of any pain in the pelvis, thigh, or groin. Any patient presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients receiving Zoledronic Acid. Cases of cardiac arrhythmia and neurological reactions (including seizures, numbness, and tetany) secondary to severe hypocalcaemia have been documented. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some cases, hypocalcaemia may be life-threatening.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Pregnancy

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

Period of breastfeeding

It is unknown whether zoledronic acid passes into breast milk.

Ability to influence reaction rate when driving or operating machinery.

Adverse reactions of the drug, such as dizziness and somnolence, may affect the ability to drive or operate machinery; therefore, caution is advised when driving or operating complex machinery during treatment with Zoledronic Acid.

Administration and Dosage

Zoledronic acid must be administered only by a physician experienced in intravenous administration of bisphosphonates.

Prior to administration, 5 mL of zoledronic acid concentrate containing 4 mg of zoledronic acid should be diluted in 100 mL of 0.9% sodium chloride solution or 5% glucose solution. The prepared zoledronic acid solution for infusion must be administered as a single intravenous infusion over no less than 15 minutes.

Zoledronic acid concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution. It must be administered as a single intravenous infusion using a separate infusion line.

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).

When deciding to use zoledronic acid in patients with bone metastases 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

For the treatment of hypercalcemia (serum calcium corrected for albumin ≥12.0 mg/dL or ≥3.0 mmol/L), a single 4 mg dose of 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 drug. There is no clinical experience with the use of the drug in patients with serum creatinine levels >400 µmol/L or >4.5 mg/dL. Dose adjustment is not required for 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

Prior to initiating therapy in patients with multiple myeloma or bone metastases from solid tumors, serum creatinine levels and creatinine clearance should be determined. Creatinine clearance should be calculated using the Cockcroft-Gault formula based on serum creatinine levels. Zoledronic acid is not recommended for patients with severe renal impairment prior to starting therapy (creatinine clearance <30 mL/min). Clinical studies on the use of zoledronic acid in patients with serum creatinine levels ≥265 µmol/L or ≥3 mg/dL have not been conducted.

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

INITIAL CREATININE CLEARANCE LEVEL (ML/MIN)	RECOMMENDED DOSE OF ZOLEDRONIC ACID (MG)*
>60	4 mg
50-60	3.5 mg*
40-49	3.3 mg*
30-39	3 mg*

* Doses were calculated assuming a target AUC = 0.66 mg•h/L (creatinine clearance of 75 mL/min). For patients with impaired renal function, the dose should be reduced to achieve an AUC similar to that observed in patients with a creatinine clearance of 75 mL/min.

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

In clinical studies, renal function impairment was defined by the following criteria:

• For patients with normal baseline serum creatinine (<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 (>1.4 mg/dL, or >124 µmol/L) – an increase of 1 mg/dL, or 88 µmol/L.

During clinical trials, treatment was resumed once serum creatinine returned to within 10% of the baseline value. Zoledronic acid therapy should be resumed at the same dose used 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 use of this medicinal product in pediatric patients.

Instructions for preparation of zoledronic acid doses

For intravenous infusion.

5 mL of zoledronic acid 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.

Reduced doses of zoledronic acid are recommended for patients with mild to moderate renal impairment.

Instructions for preparation of reduced doses of zoledronic acid

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.

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

Children

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

Overdose.

Clinical experience with acute overdose of zoledronic acid is limited. Cases of accidental administration of up to 48 mg of zoledronic acid have been reported. Patients who receive doses exceeding the recommended amount should be kept under close 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 should be administered based on clinical indications. Treatment is symptomatic.

Side effects.

For three days following administration of zoledronic acid, acute-phase reactions have been commonly reported, with symptoms including bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms usually resolve within a few days.

The following serious adverse reactions have been identified with the use of zoledronic acid:

renal impairment, osteonecrosis of the jaw, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, and interstitial lung disease.

Information on the frequency of adverse reactions with zoledronic acid 4 mg is primarily based 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.

The following adverse reactions were collected from clinical studies, predominantly during prolonged treatment with zoledronic acid.

Adverse reactions are classified by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and 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, hyposthesia, hyperesthesia, tremor, somnolence;

very rare – epileptic seizures, tetany and numbness (secondary to hypocalcemia).

Psychiatric disorders:

uncommon – anxiety, 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, 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).

Cardiovascular disorders:

uncommon – arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension leading to syncope and circulatory collapse;

rare – bradycardia;

very rare – 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 – angioneurotic edema.

General disorders and administration site conditions:

common – fever, influenza-like illness (including fatigue, chills, malaise, and flushing); uncommon – injection site reactions (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, weight increase, anaphylactic reactions/shock, urticaria;

rare – arthritis and joint swelling as symptoms of acute-phase reaction.

Investigations:

very common – hypophosphatemia;

common – increased blood creatinine and urea, hypocalcemia;

uncommon – hypomagnesemia, hypokalemia;

rare – hyperkalemia, hypernatremia.

Renal function impairment

Renal function impairment has been reported with the use of zoledronic acid.

Based on safety data analysis regarding prevention of adverse reactions related to bone tissue damage in patients with advanced malignancies, the incidence of renal function disorders considered 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%. Risk factors that may increase the risk of renal impairment include dehydration, pre-existing renal dysfunction, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of other nephrotoxic agents, or shortened infusion duration. Cases of renal impairment, progression of renal failure, and the need for hemodialysis have been reported after the first or single administration of 4 mg zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been reported primarily in patients with malignancies treated with zoledronic acid. 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 cancer diagnosis, concomitant therapies (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathy, infections, pre-existing oral diseases).

Although a causal relationship has not been established, these 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 associated with joint swelling, which may begin within the first 3 days after zoledronic acid infusion. These reactions are referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

Acute subtrochanteric and diaphyseal fractures of the femur (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

Hypocalcemia is an important identified risk with the use of zoledronic acid for approved indications. Clinical and post-marketing data indicate an association between zoledronic acid therapy, reports of hypocalcemia, and the development of secondary cardiac arrhythmias. Additionally, data suggest an association between hypocalcemia and secondary neurological reactions, including epileptic seizures, numbness, and tetany.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

After dilution in sterile 0.9% sodium chloride solution or 5% glucose solution, the preparation is stable for 24 hours when stored at 2–8 °C.

After aseptic dilution, the ready-to-use solution should be administered immediately.

Incompatibilities.

The concentrate of zoledronic acid must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate of zoledronic acid must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution. It must be administered as a single infusion using a separate infusion system.

Studies with glass vials and various types of infusion bags and infusion sets 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 of concentrate for infusion solution in a vial. 1, 5, or 10 vials per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and place of business.

36 Severina Pototskogo Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.