Zoledronic acid-vista

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

Composition:

Active substance: zoledronic acid;

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

1 ml of concentrate contains 0.8 mg of zoledronic acid, equivalent to 0.8528 mg of zoledronic acid monohydrate;

Excipients: mannitol, sodium citrate dihydrate, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution.

Pharmacotherapeutic group. Agents 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 known inhibitors of osteoclast-mediated bone resorption available today.

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 adversely affecting bone formation, mineralization, or mechanical bone properties.

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

In vivo — inhibition of osteoclast-mediated bone resorption acting on the microcrystalline matrix structure of bone, resulting in reduced tumor growth; antiangiogenic effects (acting on blood vessels, leading to reduced tumor blood supply) and analgesic effects.

In vitro — inhibition of osteoblast proliferation, cytostatic effects, pro-apoptotic effects on tumor cells, synergistic cytostatic effects 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 zoledronic acid administered to 64 patients. Pharmacokinetic parameters were independent of dose. After the start of infusion, plasma concentrations of zoledronic acid rapidly increased, reaching peak levels at the end of the infusion. This was followed by a rapid decline in concentration to less than 10% of peak levels within 4 hours and less than 1% within 24 hours, with a subsequent prolonged phase of low concentrations not exceeding 0.1% of peak levels until the second 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 dosing 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 back into systemic circulation from bone and eliminated via the kidneys. 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 the infusion duration from 5 to 15 minutes reduces the 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, as with other bisphosphonates, was high.

Pharmacokinetic data 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. Animal experimental 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 is 75±33% of creatinine clearance, averaging 84±29 mL/min (range 22–143 mL/min) in 64 oncology patients included in the study. 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 (creatinine clearance < 30 mL/min) are limited.

Zoledronic acid has been shown to have 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 are similar to those in adults when equivalent doses (mg/kg) are administered. Age, body weight, gender, and creatinine clearance have been shown not to affect systemic exposure to zoledronic acid.

Clinical characteristics

Indications

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

During clinical studies, other medicinal products were frequently administered concomitantly with zoledronic acid, 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 systems. However, specific clinical studies on 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 advised when using bisphosphonates concomitantly with loop diuretics, as they may have an additive effect, increasing the risk of hypocalcemia. Zoledronic acid should be administered cautiously 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 were observed when bisphosphonates were administered intravenously in combination with thalidomide.

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

Special precautions for use

General

Before administration of zoledronic acid, adequate hydration should be ensured in all patients, particularly in patients with mild to moderate renal impairment. Overhydration should be avoided in patients at risk of developing heart failure. Standard metabolic parameters associated with hypercalcaemia, such as calcium, phosphate and magnesium levels, should be closely monitored after initiation of therapy. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occurs, short-term corrective therapy may be required. Patients with untreated hypercalcaemia usually have some degree of renal impairment, therefore careful monitoring of renal function parameters is necessary.

Patients receiving this medicinal product should not simultaneously take other medicinal products containing zoledronic acid. Also, patients should not use any other bisphosphonates.

Renal impairment

When considering the use of zoledronic acid in patients with hypercalcaemia due to malignancy and underlying 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 making a decision about treating patients with bone metastases for the prevention of skeletal-related events, it should be considered that the effect of the medicinal product becomes apparent after 2–3 months. Renal dysfunction has been reported in association with the use of bisphosphonates. Factors that may increase the risk of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of treatment with zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion 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 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 the initial or a single 4 mg dose of zoledronic acid.

Elevated serum creatinine levels have also been observed in some patients receiving the medicinal product at the recommended doses for the prevention of skeletal-related events, although this occurs infrequently. Serum creatinine levels should be assessed in patients before each dose of zoledronic acid. For patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors for the prevention of bone loss and fractures, lower doses of zoledronic acid are recommended in cases of mild to moderate renal impairment (see table in section "Dosage and administration"). In patients who experience worsening renal function during treatment, the medicinal product may be resumed only when serum creatinine returns to baseline ±10%. When resuming therapy, the same dose as before the temporary interruption should be used. Due to the potential impact 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, in patients with tumour-induced hypercalcaemia, and 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 for the 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, as only limited clinical data are available.

Osteonecrosis

Osteonecrosis of the jaw. Osteonecrosis of the jaw has been reported primarily in oncology patients receiving treatment regimens that included 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 course of treatment 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 are recommended to undergo a dental examination with appropriate preventive dental treatment and individual benefit-risk assessment.

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

• Bisphosphonate potency (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose.
• Cancer, concomitant diseases (e.g., anaemia, coagulopathies, infection), smoking.
• Concomitant therapy: chemotherapy, angiogenesis inhibitors (see section "Interaction with other medicinal products and other forms of interaction"), radiotherapy to the head and neck, corticosteroids.
• Dental history, inadequate oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

Prior to starting bisphosphonate therapy, an oral cavity examination should be performed with appropriate dental prophylaxis. Patients should immediately report any symptoms arising in the oral cavity, such as loose teeth, pain, swelling, non-healing ulcers or discharge, during treatment with zoledronic acid.

During therapy, invasive dental procedures should be avoided if possible. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data in patients requiring dental procedures to determine whether discontinuation of bisphosphonate therapy reduces the risk of developing osteonecrosis of the jaw. Treatment regimens 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 as much as possible. Osteonecrosis at other anatomical sites. Osteonecrosis of the external auditory canal has been observed with bisphosphonate use, mainly during long-term therapy. Risk factors for osteonecrosis of the external auditory canal include steroid and chemotherapy use, as well as local risk factors such as infections or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who report symptoms related to the auditory organs, particularly chronic ear infections. In addition, sporadic reports of osteonecrosis at other sites, including the hip and femur, have been received, primarily in adult cancer patients receiving zoledronic acid.

Musculoskeletal pain

During post-marketing surveillance, severe, sometimes incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including zoledronic acid. However, such reports were isolated. The time to onset of symptoms varied from one day to several months after initiation of treatment. In most patients, symptoms improved after discontinuation of therapy. Recurrence of symptoms was observed in this patient group when treatment was resumed with the same medicinal product 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 condyles. They occur with minimal or no trauma, and some patients experience thigh or groin pain, often accompanied by 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 evaluated in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Poor healing of such fractures has also been reported. Discontinuation of bisphosphonate therapy should be considered in patients suspected of having atypical femoral fractures based on individual benefit-risk assessment. During bisphosphonate therapy, patients should inform their physician of any pain in the hip, thigh or groin. Each patient with such symptoms should be evaluated for the presence of an incomplete femoral fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients receiving zoledronic acid. Cardiac arrhythmias and neurological reactions (including seizures, numbness and tetany) secondary to severe hypocalcaemia have been observed. Cases of severe hypocalcaemia requiring hospitalization have been reported. Hypocalcaemia may sometimes be life-threatening (see section "Adverse reactions").

Zoledronic acid should be used with caution in combination with medicinal products that cause hypocalcaemia, as they may have a synergistic effect leading to severe hypocalcaemia (see section "Interaction with other medicinal products and other forms of interaction"). Serum calcium levels should be measured and hypocalcaemia corrected before initiating therapy. Patients should receive adequate calcium and vitamin D.

Sodium content

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e., essentially "sodium-free".

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. Reproductive toxicity has been observed in animal studies. The potential risk to humans is unknown. Women of childbearing potential should be advised to avoid pregnancy.

Breastfeeding. It is unknown whether zoledronic acid is excreted in human milk. The medicinal product is contraindicated in women who are breastfeeding (see section "Special precautions for use").

Fertility. A potential negative effect of zoledronic acid on fertility was evaluated in rat studies. The drug caused pronounced pharmacological effects believed to be related to inhibition of skeletal calcium metabolism. This led to postpartum hypocalcaemia (a class effect of bisphosphonates), dystocia, and premature termination of these studies. The results obtained do not allow a full assessment of the ultimate effect of zoledronic acid on fertility in humans.

Ability to affect the speed of reactions while driving or operating machinery

Adverse reactions to the medicinal product, such as dizziness and somnolence, may affect the ability to drive or operate machinery. Therefore, caution is required during the use of zoledronic acid when driving or operating complex machinery.

Administration and Dosage

The medicinal product must be administered only by physicians experienced in intravenous administration of bisphosphonates.

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

The medicinal product 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 line.

Prevention of skeletal-related events in patients with advanced malignancies

Adults and 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) per day.

When making treatment decisions for patients with bone metastases for the 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 and elderly patients

For the treatment of hypercalcemia (serum calcium level corrected for albumin ≥ 12 mg/dL or ≥ 3 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 after careful assessment of the risk of using the medicinal product and the anticipated benefit. 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 for patients with hypercalcemia of malignancy who have serum creatinine levels < 400 μmol/L or < 4.5 mg/dL.

Prevention of skeletal-related events in patients with advanced malignancies

Prior to initiating treatment in patients with multiple myeloma or solid tumor bone metastases, serum creatinine and creatinine clearance should be determined. Creatinine clearance should be calculated using the Cockcroft-Gault formula. 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 (ml/min)	Recommended dose *
> 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 were calculated assuming an AUC value of 0.66 mg·h/L (creatinine clearance of 75 mL/min). For patients with impaired renal function, a dose reduction is recommended to achieve an AUC equivalent 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 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.

During clinical studies, zoledronic acid therapy was resumed after serum creatinine returned to baseline value ±10%. 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 use in children.

Preparation of zoledronic acid doses

For intravenous administration.

5 mL of the 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 the drug.

Preparation of reduced drug doses:

Withdraw the appropriate volume of concentrate:

• 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 pediatric patients have not been established.

Overdose

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

Treatment. Patients who have received a dose exceeding the recommended amount should be placed 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 case of hypocalcemia, calcium gluconate infusion should be administered as clinically indicated. Treatment is symptomatic.

Adverse Reactions

Summary of safety profile

Acute-phase reactions typically occurred within 3 days after administration of zoledronic acid, with symptoms including bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritic joint swelling. These symptoms usually resolve within a few days. Serious adverse reactions identified during treatment with zoledronic acid include 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 during treatment with zoledronic acid 4 mg is primarily based on data obtained from 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.

List of adverse reactions

The following adverse reactions were observed during clinical trials, primarily after prolonged treatment with zoledronic acid.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: common — anaemia; uncommon — thrombocytopenia, leucopenia; rare — pancytopenia.

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

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

Nervous system disorders: common — headache; uncommon — paraesthesia, dizziness, taste disturbances, hypoaesthesia, hyperaesthesia, tremor, somnolence; very rare — epileptic seizures, convulsions, tetany and paralysis (secondary to hypocalcemia).

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

Cardiac 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).

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

Respiratory, thoracic and mediastinal disorders: uncommon — dyspnoea, 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 anatomical sites, including the femur and thigh.

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

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

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

Description of selected adverse reactions

Renal function disorders

Deterioration of renal function has been reported during treatment with zoledronic acid. Based on safety data analysis from registration trials of zoledronic acid for prevention of skeletal events in patients with advanced malignancies, the incidence of renal function disorders considered related to zoledronic acid was as follows: 3.2% in multiple myeloma, 3.1% in prostate cancer, 4.3% in breast cancer, and 3.2% in lung cancer and other solid tumours. Risk factors for renal dysfunction include dehydration, pre-existing renal impairment, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of other nephrotoxic agents, or shortening of the recommended infusion time. Cases of worsening renal function, progression of renal failure, and need for haemodialysis have been reported after the first or single infusion of zoledronic acid 4 mg (see section "Special precautions for use").

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been observed predominantly in oncology patients receiving zoledronic acid (see section "Special precautions for use"). Many of these patients had signs of local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction.

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% (96 of 3,862) in the group receiving zoledronic acid 5 mg and 1.9% (75 of 3,852) in the placebo group. The incidence of atrial fibrillation with serious clinical outcomes was 1.3% (51 of 3,862) and 0.6% (22 of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The imbalance in atrial fibrillation incidence observed in this trial was not seen in other studies involving oncology patients treated with zoledronic acid. The reason for the increased incidence of atrial fibrillation is unknown.

Acute-phase reactions

Acute-phase adverse reactions, which may occur within the first 3 days after zoledronic acid infusion, include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhoea, arthralgia, and arthritis associated with joint swelling. These reactions are referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

Rarely, during post-marketing use, atypical subtrochanteric and diaphyseal femoral fractures have been reported (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

Hypocalcemia is an important identified risk with zoledronic acid use under 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 a link between hypocalcemia and secondary neurological reactions, including epileptic seizures, tetany, and paralysis (see section "Special precautions for use").

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

After dilution in sterile 0.9% sodium chloride solution or 5% glucose solution, the medicinal product is stable for 24 hours at a storage temperature of 2–8 °C. After aseptic dilution, the prepared solution should be used immediately.

Storage conditions

No special storage conditions required.

Keep out of the reach and sight of children.

Incompatibilities

Zoledronic acid concentrate 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 set. 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 of concentrate in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Pliva Croatia Ltd.

Manufacturer's name and address of place of business

Prilaz Baruna Filipovića 25, Zagreb, Grad Zagreb, 10000, Croatia.