Zoledrovista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLENDROVISTA (ZOLENDROVISTA)

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 0.8 mg of anhydrous zoledronic acid (in the form of zoledronic acid monohydrate);

Excipients: mannitol (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 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 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 osteoclastic 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. 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 decreased tumor blood supply), and analgesic effect. In vitro – inhibition of osteoblast proliferation, cytostatic and pro-apoptotic effects 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 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 to 10% of peak concentration within 4 hours and to less than 1% of peak concentration within 24 hours, with subsequent prolonged low-level concentrations not exceeding 0.1% of peak until the next infusion on day 28. Zoledronic acid administered intravenously 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 half-life 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 by 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 was high, as is also 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 does not influence the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with 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 clearance of zoledronic acid was 37% and 72%, 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 are similar to those 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 disease.
• 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, diuretics, antibiotics, and analgesics—were frequently administered concomitantly with zoledronic acid. 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 co-administering bisphosphonates and aminoglycosides, as they may have an additive effect, resulting in serum calcium levels remaining low for a prolonged period. Caution is also recommended when co-administering bisphosphonates and loop diuretics, as their combined effect may lead to hypocalcemia. Care should be taken when administering this medicinal product together with other potentially nephrotoxic medicinal agents. The possibility of developing hypomagnesemia during treatment should be considered. In patients with multiple myeloma, intravenous administration of bisphosphonates in combination with thalidomide increases the risk of renal impairment. Cases of osteonecrosis of the jaw have been reported in patients receiving zoledronic acid concomitantly with antiangiogenic medicinal agents (agents that reduce tumor blood supply).

Special precautions for use.

General

Before administering the medicinal product ZoledroVista, ensure adequate hydration of all patients, including those with mild to moderate renal impairment. Hyperhydration should be avoided in patients at risk of developing heart failure. Standard metabolic parameters associated with hypercalcaemia, such as levels of calcium, phosphates, and magnesium, should be carefully monitored after initiation of treatment. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term corrective therapy may be required.

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

Patients receiving treatment with ZoledroVista must not concurrently use other medicinal products containing zoledronic acid, nor should they use any other bisphosphonates.

Renal impairment

When considering the use of the medicinal product in patients with malignancy-induced hypercalcaemia 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 prevention of skeletal-related events, it should be considered that the therapeutic effect of the medicinal product becomes evident after 2–3 months.

There have been reports of renal dysfunction associated with the use of bisphosphonates. Factors increasing the risk of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of ZoledroVista or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion times shorter than recommended. Although the risk is reduced when ZoledroVista is administered at a dose of 4 mg over no less than 15 minutes, renal impairment remains possible. Cases of renal dysfunction, progression to renal failure, and need for dialysis have been observed in patients after administration of an initial or single dose of 4 mg zoledronic acid.

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

Due to the potential effect of bisphosphonates, including ZoledroVista, 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 and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors [AIs] for prevention of bone mass loss and fractures, respectively) and only limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of the medicinal product in patients with severe renal impairment is not recommended.

Hepatic impairment

Specific recommendations for patients with severe hepatic impairment are not available, as only limited clinical data are accessible.

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 or re-initiation of treatment should be postponed in patients with non-healing open soft tissue lesions in the oral cavity, unless medically necessary. Prior to starting bisphosphonate therapy, patients with concomitant risk factors should undergo a dental examination, receive appropriate preventive dental care, and have an individual benefit-risk assessment.

The following risk factors should be considered when evaluating individual risk of 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, comorbid conditions (e.g., anaemia, coagulopathy, infection), smoking.
• Concomitant treatments: chemotherapy, anti-angiogenic agents, radiotherapy to the head and neck, corticosteroid therapy.
• Dental history, 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.

All patients should be informed of the need to maintain good oral hygiene, undergo regular dental check-ups, and report symptoms such as tooth mobility, pain, swelling, or non-healing wounds 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 available on patients requiring dental procedures to determine whether discontinuation of bisphosphonates reduces the risk of osteonecrosis of the jaw. The treating physician should make decisions based on an individual benefit-risk assessment for each patient. The treatment regimen for patients who develop osteonecrosis of the jaw should be developed jointly by 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 of the external auditory canal

Osteonecrosis of the external auditory canal has been observed with bisphosphonate use, primarily during long-term therapy. Possible risk factors include steroid use, chemotherapy, and/or local risk factors such as infection or trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with otological symptoms, including chronic ear infections. Sporadic reports of osteonecrosis in other bones, including the femur and pelvic bones, have been reported in adult oncology patients receiving bisphosphonate therapy.

Musculoskeletal pain

In post-marketing surveillance, severe and sometimes disabling bone, joint, and/or muscle pain has been reported in patients taking 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 initiation of treatment. In most patients, symptoms decreased after discontinuation of treatment. Recurrence of symptoms was observed in some patients upon re-initiation of therapy with the same or another bisphosphonate.

Atypical femoral fracture

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, particularly 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 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 examined in patients on bisphosphonate therapy who have sustained a femoral fracture. Poor healing of such fractures has also been reported. Based on individual benefit-risk assessment, consideration should be given to discontinuing bisphosphonate therapy in patients suspected of having atypical femoral fractures.

Patients receiving bisphosphonate therapy should be advised to report any pain in the hip, 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 arrhythmias and neurological reactions (including epileptic seizures, hypoaesthesia, numbness, and tetany) secondary to severe hypocalcaemia; and cases of severe hypocalcaemia requiring hospitalization. In some cases, hypocalcaemia may be life-threatening. Caution should be exercised when zoledronic acid is used concomitantly with medicinal products that may 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 checked before starting treatment and corrected if necessary. Patients should receive adequate supplementation with calcium and vitamin D.

Important information about excipients.

Sodium

The medicinal product ZoledroVista contains 24 mg of sodium per dose. Caution should be exercised when administering the medicinal product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

The medicinal product ZoledroVista 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.

Breastfeeding

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

Fertility

Zoledronic acid has been evaluated in rats for potential adverse effects on fertility. Study results did not allow determination of the effect of zoledronic acid on human fertility.

Ability to affect reaction speed 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 should be exercised when driving or operating complex machinery during treatment with the medicinal product.

Administration and Dosage

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

Prior to administration, 5 ml of ZolendroVista 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 not less than 15 minutes.

ZolendroVista 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 intravenous infusion using a separate infusion system.

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 supplementation with 500 mg of calcium and 400 IU of vitamin D.

When considering treatment of patients with bone metastases for prevention of skeletal-related events, it should be noted that the onset of treatment effect occurs after 2–3 months.

Treatment of hypercalcemia of malignancy.

Adults and elderly patients.

For the treatment of hypercalcemia (serum calcium 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 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 zoledronic acid 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. ZolendroVista is not recommended for 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 bone metastases and mild to moderate renal impairment prior to initiation of therapy (creatinine clearance 30–60 mL/min), the following dosage recommendations apply:

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

Serum creatinine levels should be measured before administration of each dose of the medicinal product. If renal function impairment occurs, treatment should be discontinued. In clinical studies, renal function impairment was defined 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 abnormal baseline serum creatine levels (> 1.4 mg/dL or > 124 µmol/L) – an increase of 1 mg/dL or 88 µmol/L.

During clinical studies, treatment with zoledronic acid was resumed once serum creatinine returned to within 10% of the baseline value. Zoledronic acid therapy should be resumed at the same dose as prior to treatment interruption.

Children

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

Instructions for preparation of zoledronic acid doses.

For intravenous use.

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 ZolendroVista.

Instructions for preparation of reduced doses of the medicinal product:

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 ZolendroVista.

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 zoledronic acid in doses 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 case of hypocalcemia, calcium gluconate infusion should be administered as clinically indicated. Treatment is symptomatic.

Adverse Reactions

Acute-phase reactions have been reported within 3 days after administration of zoledronic acid, with symptoms including bone pain, fever, weakness, arthralgia, myalgia, chills, arthritis with joint swelling. These symptoms usually resolve within a few days.

Important adverse reactions identified with the use of 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 with zoledronic acid 4 mg is primarily based on data obtained during long-term treatment. 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 adverse reactions listed below were collected from clinical trials, primarily during long-term 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 (≥ 1/10,000, < 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, hypoesthesia, numbness and tetany (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 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.

Cardiac and vascular 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 system 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, flu-like symptoms (including fatigue, chills, malaise, and hot flushes);
Uncommon – 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 abnormalities:

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 reported with the use of zoledronic acid. Based on safety data analysis from registration trials of zoledronic acid for prevention of skeletal-related events in patients with advanced malignancies, the frequency 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 impairment, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of other nephrotoxic agents, or shortening of the recommended infusion duration. Cases of renal function impairment, progression of renal failure, and need for hemodialysis have been reported following the first or single administration of zoledronic acid 4 mg.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been reported primarily in oncology patients receiving 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 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

The efficacy and safety of zoledronic acid in postmenopausal women with osteoporosis were evaluated, with an overall incidence of atrial fibrillation of 2.5% in the group receiving zoledronic acid 5 mg 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 drug infusion. This reaction is referred to as a "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

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

Adverse reactions due to hypocalcemia

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

After dilution: from a microbiological standpoint, the medicinal product should be used immediately.

If not used immediately, the product must be stored for no more than 24 hours at 2–8 °C 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 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. It must be administered as a single infusion using a separate infusion system.

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

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

Sintrop Spain, S.L.

Manufacturer's location and address of business operations.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.