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

Composition:

Active substance: zoledronic acid;

100 ml of solution contains 5 mg of zoledronic acid (as monohydrate);

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Agents affecting bone structure and mineralization. Bisphosphonates. ATC code M05B A08.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

Pharmacodynamic effects.

The selective action of bisphosphonates on bone is due to their high affinity for mineralized bone tissue. The primary molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long-lasting effect of zoledronic acid is attributed to its high binding affinity to the active site of farnesyl pyrophosphate synthase and its strong affinity for binding to bone minerals.

Treatment with zoledronic acid rapidly reduces the rate of bone metabolism: from elevated postmenopausal levels to the lowest point for resorption markers at day 7 and formation markers at week 12. After this, bone turnover markers stabilized within the range observed before menopause. There was no progressive decline in bone metabolism markers with repeated annual doses.

Clinical efficacy in the treatment of postmenopausal osteoporosis.

The efficacy and safety of zoledronic acid at a dose of 5 mg once yearly for 3 consecutive years were demonstrated in postmenopausal women (7736 women aged 65–89 years) with the following characteristics: a T-score of bone mineral density (BMD) at the femoral neck ≤ –1.5 and at least one moderate vertebral fracture or two mild vertebral fractures;

or a T-score of BMD at the femoral neck ≤ –2.5 with or without evidence of vertebral fracture. 85% of patients had never previously received bisphosphonate therapy. Women assessed for vertebral fracture frequency did not receive concomitant osteoporosis therapy, whereas women included in the assessment of hip fractures and all clinically evident fractures were permitted to receive such therapy. Concomitant osteoporosis therapy included calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; other bisphosphonates were excluded. All women additionally received 1000 to 1500 mg of elemental calcium and 400 to 1200 IU of vitamin D daily.

Effect on morphometric vertebral fractures.

Treatment with zoledronic acid significantly reduced the incidence of one or more new vertebral fractures over three years, with a significant effect already evident at one year (see Table 1).

Summary of efficacy data on vertebral fractures at 12, 24, and 36 months

Table 1

** p <0.0001

In patients over 75 years of age receiving zoledronic acid treatment, the risk of vertebral fractures decreased by 60% compared to placebo group patients (p<0.0001).

Effect on hip fractures.

A sustained effect of zoledronic acid over 3 years has been demonstrated, resulting in a 41% reduction in the risk of hip fractures (95% CI, 17% to 58%). The incidence of hip fractures was 1.44% in patients receiving zoledronic acid compared to 2.49% in patients receiving placebo. Risk reduction was 51% in patients who had never previously taken bisphosphonates and 42% in patients allowed to receive concomitant osteoporosis therapy.

Effect on clinical fractures.

All clinical fractures were diagnosed based on radiography and/or clinical findings. Summary results are presented in Table 2.

Incidence of key clinical fracture endpoints over 3 years

Table 2

*p <0.001, **p <0.0001

(1) Except for the thumb, the great toe, and facial bone fractures.

(2) Including clinically evident fractures of the ribs and lumbar vertebrae.

Effect on Bone Mineral Density (BMD).

Treatment with zoledronic acid resulted in a statistically significant increase in BMD of the lumbar spine, femoral neck, and distal radius compared to placebo at all time points (6, 12, 24, and 36 months). Treatment with zoledronic acid led to an increase of 6.7% in lumbar spine BMD, 6.0% in total hip BMD, 5.1% in femoral neck BMD, and 3.2% in distal radius BMD compared to placebo over 3 years.

Bone Histology.

Bone biopsies were obtained from the iliac crest one year after the third annual dose in 152 postmenopausal women with osteoporosis treated with zoledronic acid (N=82) or placebo (N=70). Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with zoledronic acid, no cases of osteomalacia, bone marrow fibrosis, or immature bone formation were observed. Tetracycline labeling was detected in 81 out of 82 biopsies from the zoledronic acid group. Micro-computed tomography (μCT) analysis showed increased trabecular bone volume and preserved trabecular architecture in the zoledronic acid group compared to the placebo group.

Bone Turnover Markers.

Bone-specific alkaline phosphatase (BSAP), plasma procollagen type I N-terminal propeptide (P1NP), and plasma beta-C-telopeptides (b-CTx) were measured in subgroups of 517 to 1246 patients at periodic intervals throughout the study. With annual 5 mg zoledronic acid treatment, a statistically significant 30% reduction in bone-specific alkaline phosphatase from baseline was observed at 12 months, which was maintained at 28% below baseline at 36 months. P1NP levels were statistically significantly reduced by 61% from baseline at 12 months and remained 52% below baseline at 36 months. Beta-C-telopeptide levels were statistically significantly reduced by 61% from baseline at 12 months and remained 55% below baseline at 36 months. Throughout the treatment period, bone turnover markers remained within the premenopausal reference range at the end of each year. Re-administration of zoledronic acid did not result in additional reductions in bone turnover markers.

Effect on Height.

In the three-year osteoporosis study, standing height was measured annually using a stadiometer. The zoledronic acid group showed significantly less height loss (approximately 2.5 mm less) compared to the placebo group (95% CI: 1.6 mm, 3.5 mm) [p <0.0001].

Days of Disability.

Treatment with zoledronic acid significantly reduced the mean number of days with limited activity and days spent in bed due to back pain by 17.9 and 11.3 days, respectively, compared to placebo. It also significantly reduced the mean number of days with limited activity and days spent in bed due to fractures by 2.9 and 0.5 days, respectively, compared to placebo (p <0.01 for all endpoints).

Clinical Efficacy in Treating Osteoporosis in Patients at High Risk of Fractures Following a Recent Hip Fracture (RHF).

The incidence of clinical fractures, including vertebral fractures, non-vertebral fractures, and hip fractures, was evaluated in 2127 men and women aged 50–95 years (mean age 74.5 years) who had recently (within 90 days) sustained a low-trauma hip fracture, with a mean follow-up of 2 years of study drug administration. Approximately 42% of patients had a femoral neck BMD T-score below –2.5, and approximately 45% had a T-score above –2.5. Zoledronic acid was administered once yearly until clinically evident fractures were confirmed in at least 211 patients in the study population. Vitamin D levels were generally not assessed, but most patients received a loading dose of vitamin D (50,000 to 125,000 IU orally or intramuscularly) within 2 weeks prior to infusion. All participants additionally received 1000 to 1500 mg of elemental calcium and 800 to 1200 IU of vitamin D daily. 95% of patients received their infusion 2 or more weeks after hip fracture healing, with infusions administered on average approximately 6 weeks after fracture healing. The primary efficacy endpoint was the incidence of clinical fractures over the entire study period.

Effect on All Clinical Fractures.

The incidence of key endpoints for clinical fractures is presented in Table 3.

Incidence of Key Endpoints for Clinical Fractures

Table 3

*p <0.05, **p <0.01

(1) Except for the thumb, the great toe, and facial bone fractures.

(2) Including clinically evident fractures of the thoracic spine and lumbar vertebrae.

The study was not designed to determine statistically significant differences in the number of hip fractures, but a trend toward reduction in the incidence of new hip fractures was observed.

All-cause mortality was 10% (101 patients) in the zoledronic acid treatment group compared to 13% (141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of death from any cause (p=0.01).

The incidence of delayed healing of hip fractures was comparable between the zoledronic acid group (34 [3.2%]) and the placebo group (29 [2.7%]).

Effect on bone mineral density (BMD).

In the HORIZON-RFT study, statistically significant increases in BMD at the total hip and femoral neck were observed with zoledronic acid treatment compared to placebo at all time points. Treatment with zoledronic acid resulted in a 5.4% increase in total hip BMD and a 4.3% increase in femoral neck BMD over 24 months compared to placebo.

Clinical efficacy in men.

In the HORIZON-RFT study, 508 men were randomized into the study, and 185 patients had BMD assessments at 24 months. After 24 months, a similar statistically significant increase of 3.6% in total hip BMD was observed in patients receiving zoledronic acid treatment compared to the effect observed in postmenopausal women in the HORIZON-PFT study. This study was not sufficiently powered to demonstrate a reduction in the number of clinically evident fractures in men; the incidence of clinically evident fractures was 7.5% in men receiving zoledronic acid compared to 8.7% in those receiving placebo.

In another study involving men (study CZOL446M2308), annual infusion of zoledronic acid provided non-inferior efficacy compared to weekly alendronate with respect to changes in lumbar spine BMD after 24 months of treatment compared to baseline.

Clinical efficacy in glucocorticoid-induced osteoporosis.

The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated with long-term systemic glucocorticoid therapy were evaluated in a randomized, multicenter, double-blind, stratified, active-controlled study involving 833 men and women aged 18 to 85 years (mean age 56.4 years for men and 53.5 years for women) who were receiving prednisone at a dose >7.5 mg/day (or equivalent). Patients were stratified according to duration of glucocorticoid use prior to randomization (≤3 months vs >3 months). The study duration was one year. Patients were randomized to receive either a single 5 mg infusion of zoledronic acid or daily oral risedronate 5 mg for one year. All participants also received 1000 mg of elemental calcium and 400 to 1000 IU of vitamin D daily. Efficacy was considered demonstrated if non-inferiority of risedronate was shown with respect to the percentage change in lumbar spine BMD at 12 months compared to baseline in the treatment and prevention subpopulations, respectively. Most patients continued glucocorticoid therapy throughout the one-year study period.

Effect on bone mineral density (BMD).

Increases in lumbar spine and femoral neck BMD were statistically significantly greater in the zoledronic acid group compared to the risedronate group (for all endpoints p<0.03). In the subpopulation of patients who had been taking glucocorticoids for more than 3 months prior to randomization, zoledronic acid increased lumbar spine BMD by 4.06% compared to 2.71% with risedronate (mean difference 1.36%; p<0.001). In the subpopulation of patients who had taken glucocorticoids for 3 months or less prior to randomization, zoledronic acid increased lumbar spine BMD by 2.60% compared to 0.64% with risedronate (mean difference 1.96%; p<0.001). This study was not sufficiently powered to demonstrate a reduction in the number of clinically evident fractures compared to risedronate treatment. The number of fracture events was 8 in patients receiving zoledronic acid compared to 7 in patients receiving risedronate (p=0.8055).

Clinical efficacy in the treatment of Paget's disease of bone.

The efficacy of zoledronic acid was studied in male and female patients over 30 years of age with primary mild to moderate Paget's disease of bone (median serum alkaline phosphatase levels 2.6–3 times above the upper limit of the age-specific normal range at study entry), confirmed radiologically.

The efficacy of a single 5 mg infusion of zoledronic acid compared to daily 30 mg risedronate for 2 months was demonstrated in two 6-month comparative studies. At 6 months, response and normalization of plasma alkaline phosphatase (PALP) levels were observed in 96% (169/176) and 89% (156/176) of patients in the zoledronic acid group compared to 74% (127/171) and 58% (99/171) of patients receiving risedronate (all endpoints p<0.001).

According to pooled results, a similar reduction in pain severity was observed over 6 months with zoledronic acid and risedronate treatment.

Patients classified as responders at the end of the 6-month core study were considered eligible for entry into the extended observation period. Of 153 patients treated with zoledronic acid and 115 patients treated with risedronate who entered the extended observation study, after a mean observation period of 3.8 years from treatment, the proportion of patients who discontinued the study due to the need for retreatment (based on clinical assessment) was higher in the risedronate group (48 patients, or 41.7%) compared to the zoledronic acid group (11 patients, or 7.2%). The mean time to study discontinuation due to the need for retreatment for Paget's disease from initial treatment was longer for patients receiving zoledronic acid (7.7 years) than for those receiving risedronate (5.1 years).

Six patients who achieved a therapeutic response 6 months after treatment with zoledronic acid and who later experienced disease relapse during the extended observation period received retreatment with zoledronic acid on average 6.5 years after initial treatment. Five out of six patients had plasma alkaline phosphatase levels within the normal range at 6 months.

Bone histology was evaluated in 7 patients with Paget's disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed normal bone quality without signs of impaired bone remodeling and without evidence of mineralization defects. These findings are consistent with the biochemical marker of normalization of bone remodeling.

The European Medicines Agency has waived the requirement for zoledronic acid study results in all subgroups of the pediatric population for Paget's disease of bone, as well as for postmenopausal osteoporosis in women at increased risk of fracture, osteoporosis in men at increased risk of fracture, and for the prevention of clinical fractures after hip fracture in men and women.

Pharmacokinetics.

Following single and multiple 5- and 15-minute infusions of 2, 4, 8, and 16 mg zoledronic acid administered to 64 patients, the following dose-independent pharmacokinetic data were obtained.

Distribution.

After the start of zoledronic acid infusion, plasma concentrations of the active substance rapidly increased, reaching a peak at the end of the infusion, then rapidly declined to <10% of peak within 4 hours and to <1% of peak within 24 hours, followed by a prolonged period of very low concentrations not exceeding 0.1% of peak levels.

Elimination.

Intravenously administered zoledronic acid is eliminated by the kidneys in three phases: rapid biphasic elimination from systemic circulation with half-lives t1/2 of 0.24 (alpha phase) and t1/2 of 1.87 (beta phase) hours, followed by a prolonged elimination phase with a terminal half-life t1/2γ of 146 hours. No accumulation of the active substance in plasma was observed after multiple doses administered every 28 days. Rapid distribution to bone and renal elimination may occur during the early disposition phases (alpha and beta). Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. Within the first 24 hours, 39 ± 16% of the administered dose is excreted in urine, while the remainder is primarily bound to bone tissue. This uptake by bone tissue is characteristic of all bisphosphonates and is believed to occur due to structural similarity to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bone tissue is very long.

Subsequently, there is a slow release of zoledronic acid from bone tissue back into systemic circulation and its renal elimination. Total clearance is 5.04 ± 2.5 L/h. It is independent of dose, gender, age, race, and body weight. Intra- and inter-individual variations in plasma clearance of zoledronic acid have been shown to be 36% and 34%, respectively. Increasing infusion duration from 5 to 15 minutes results in a 30% reduction in zoledronic acid concentration at the end of infusion, but does not affect the area under the plasma concentration-time curve.

Pharmacokinetic/pharmacodynamic interactions.

No interaction studies between zoledronic acid and other medicinal products have been conducted. Since zoledronic acid is not metabolized in the human body and the identified substance has little or no activity as a direct or irreversible inhibitor of cytochrome P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances metabolized via the cytochrome P450 enzyme system. Zoledronic acid has a low degree of plasma protein binding (approximately 43–55%), and this binding is concentration-independent. Therefore, the likelihood of interaction due to displacement by highly protein-bound drugs is low.

Special patient populations.

Patients with renal impairment.

Renal clearance of zoledronic acid correlated with creatinine clearance, with renal clearance accounting for 75±33% of creatinine clearance, which showed a mean value of 84 ± 29 mL/min (range 22 to 143 mL/min) in 64 studied patients. A slight increase in AUC(0-24h) of approximately 30–40% in mild to moderate renal impairment compared to patients with normal renal function, and the absence of zoledronic acid accumulation after multiple administrations regardless of renal function, indicate that dose adjustment is not required in patients with mild (CrCl = 50–80 mL/min) and moderate (up to CrCl 35 mL/min) renal impairment. Since only limited data are available for severe renal impairment (creatinine clearance <35 mL/min), no dosing recommendations can be made for this population.

Clinical characteristics.

Indications.

• Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures, including those with a recent low-trauma hip fracture.
• Treatment of glucocorticoid-induced osteoporosis in postmenopausal women and in men at increased risk of fractures.
• Treatment of Paget's disease of bone in adults.

Contraindications.

• Hypersensitivity to the active substance, bisphosphonates, and/or any of the excipients of the medicinal product.
• Hypocalcemia.
• Severe renal impairment with creatinine clearance < 35 mL/min.
• Pregnancy.
• Breastfeeding.

Interaction with other medicinal products and other forms of interaction.

No specific drug interaction studies with zoledronic acid have been conducted.

Zoledronic acid is not systemically metabolized and does not affect human cytochrome P450 enzymes in vitro. It is only slightly bound to plasma proteins (binding is approximately 43–55%), therefore interactions due to displacement of highly protein-bound drugs are unlikely.

Zoledronic acid is eliminated via renal excretion. Caution should be exercised when administering the medicinal product in combination with agents that may significantly affect renal function (e.g., aminoglycosides or diuretics that may cause dehydration).

In patients with impaired renal function, systemic exposure to concurrently administered medicinal products that are primarily eliminated via the kidneys may be increased.

Special precautions.

General.

The frequency of symptoms occurring during the first 3 days after administration of the medicinal product can be reduced by taking paracetamol or ibuprofen immediately after infusion.

For oncological indications, other medicinal products containing zoledronic acid as the active substance are available. Patients receiving this medicinal product should not take such products or any other bisphosphonates concomitantly, as the cumulative effect of these substances is unknown.

Renal function impairment risk.

The use of the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 35 ml/min) due to the risk of renal failure in this patient group.

Renal function impairment has been observed during zoledronic acid administration, particularly in patients with pre-existing renal dysfunction or other risk factors, including advanced age, concomitant use of nephrotoxic medicinal products, diuretics, or dehydration following zoledronic acid infusion. Renal impairment has been reported even after a single administration. Renal failure requiring dialysis or resulting in fatal outcome has been rarely observed in patients with pre-existing renal impairment or any of the aforementioned risk factors.

To minimize the risk of renal adverse reactions, the following precautions should be considered:

• prior to each administration of the medicinal product, creatinine clearance should be determined based on body weight using the Cockcroft–Gault formula;
• transient increases in plasma creatinine levels may be greater in patients with pre-existing renal impairment;
• monitoring of plasma creatinine levels should be performed in patients at risk;
• the medicinal product should be used with caution when administered concomitantly with other medicinal products that may affect renal function;
• patients, especially elderly patients and those receiving diuretics, require adequate hydration prior to administration of the medicinal product;
• the single dose of the medicinal product should not exceed 5 mg, and the infusion duration should be no less than 15 minutes.

Hypocalcemia risk.

Pre-existing hypocalcemia should be adequately corrected with calcium and vitamin D supplementation prior to initiating treatment with the medicinal product.

Enhanced bone remodeling is characteristic of Paget's disease with bone involvement. Due to the rapid onset of zoledronic acid's effect on bone remodeling, transient hypocalcemia, sometimes with clinical manifestations, may occur, typically peaking within the first 10 days after infusion.

During treatment with the medicinal product, adequate intake of calcium and vitamin D is recommended. In addition, patients with Paget's disease should receive sufficient supplemental calcium intake equivalent to at least 500 mg of elemental calcium twice daily for 10 days following infusion.

Patients should be informed about the symptoms of hypocalcemia and adequate monitoring should be ensured throughout the risk period. In patients with Paget's disease, plasma calcium levels should be measured before infusion of the medicinal product.

Rarely, severe and sometimes incapacitating bone, joint, and/or muscle pain has been reported in patients receiving bisphosphonates, including zoledronic acid.

Patients with other mineral metabolism disorders.

Other disorders of mineral metabolism, such as hypoparathyroidism or impaired intestinal calcium absorption, also require effective treatment. Physicians should carefully monitor these patients.

Osteonecrosis of the jaw risk.

Post-marketing reports have described osteonecrosis of the jaw in patients receiving zoledronic acid for osteoporosis.

Initiation of treatment or a new treatment course should be postponed in patients with unhealed open soft tissue lesions in the oral cavity. Prior to starting treatment in patients with concomitant risk factors, a dental examination with appropriate preventive dental treatment and individual benefit-risk assessment is recommended.

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

• the antiresorptive potency of the medicinal product (higher potency compounds carry a higher risk), route of administration (parenteral administration carries a higher risk), and cumulative antiresorptive therapy dose;
• cancer, concomitant diseases (such as anemia, coagulopathy, infection), smoking;
• concomitant treatments: corticosteroids, chemotherapy, angiogenesis inhibitors, head and neck radiotherapy;
• poor oral hygiene; periodontal disease; ill-fitting dentures; history of dental disease; invasive dental procedures, such as tooth extraction.

During treatment with the medicinal product, all patients are recommended to maintain proper oral and dental hygiene, undergo regular dental check-ups, and promptly report any oral symptoms, such as tooth mobility, pain or swelling, non-healing ulcers, or discharge. Invasive dental procedures should be performed with caution during treatment, avoiding direct proximity to the site of zoledronic acid administration.

Treatment plans for patients who develop osteonecrosis of the jaw should be developed in close collaboration between the physician and a dentist or oral surgeon experienced in managing patients with osteonecrosis of the jaw. Temporary discontinuation of the medicinal product 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 reported during bisphosphonate use, mainly during long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid and chemotherapy use 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.

Atypical femoral fracture risk.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate use, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur, from below the lesser trochanter to above the supracondylar flare. These fractures occur after minimal or no trauma, and in some patients, pain in the thigh or groin, often accompanied by radiographic signs of stress fracture, may appear weeks or months before a complete femoral fracture is detected. Fractures are often bilateral; therefore, the contralateral femur should also be examined in patients receiving the medicinal product who have confirmed diaphyseal femoral fracture. Delayed healing of such fractures has been observed. Discontinuation of the medicinal product in patients suspected of having an atypical femoral fracture should be considered after careful patient evaluation, taking into account individual benefit-risk assessment.

During treatment with the medicinal product, patients should be advised to report any pain in the thigh, hip, or groin area, and all patients experiencing such symptoms should be evaluated for incomplete femoral fracture.

Acute-phase reaction risk.

Acute-phase reactions or post-dose symptoms, including fever, myalgia, flu-like symptoms, arthralgia, and headache, have been reported, most occurring within three days after zoledronic acid infusion. Acute-phase reactions may sometimes be severe or prolonged. The incidence of post-dose symptoms can be reduced by administering paracetamol or ibuprofen shortly after zoledronic acid infusion. It may also be appropriate to delay treatment if the patient is clinically unstable due to an acute medical condition and problematic acute-phase reactions (see section "Adverse reactions").

Precautions related to excipients.

The medicinal product contains less than 1 mmol sodium (23 mg) per vial (100 ml), i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product is contraindicated during pregnancy. Data on the use of zoledronic acid for treating pregnant women are lacking. Animal studies have demonstrated toxic effects on reproductive function, including developmental abnormalities. The potential risk to humans is unknown.

Breastfeeding period.

It is unknown whether zoledronic acid is excreted in human breast milk. The medicinal product is contraindicated during breastfeeding.

Use in women of reproductive potential.

The medicinal product is not recommended for use in women of reproductive potential.

Effect on fertility.

The potential adverse effect of zoledronic acid on fertility was studied in rats of parental and F1 generations. The results revealed an exaggerated pharmacological effect considered to be related to the inhibition of skeletal calcium mobilization, leading to perinatal hypocalcemia—an effect characteristic of the bisphosphonate class—dystocia, and premature termination of the study. Therefore, the results do not allow definitive conclusions regarding the effect of zoledronic acid on human fertility.

Ability to influence reaction speed when driving or operating machinery.

Adverse reactions such as dizziness may affect the ability to drive or operate machinery.

Administration and Dosage.

The medicinal product is intended for intravenous use.

Infusion should be administered under conditions of adequate patient hydration. This is particularly important for elderly patients (≥ 65 years of age) and patients receiving diuretics.

Adequate intake of calcium and vitamin D is recommended during treatment with this medicinal product.

Dosage.

Osteoporosis.

The recommended dose of the medicinal product is one 5 mg intravenous infusion per year: for the treatment of postmenopausal osteoporosis, osteoporosis in men, and glucocorticoid-induced osteoporosis.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be periodically re-evaluated by assessing the benefit-risk ratio for each individual patient, especially after 5 or more years of treatment.

For patients with recent low-trauma femoral fracture, administration of the medicinal product is recommended 2 or more weeks after surgery for femoral fracture.

For patients with recent low-trauma femoral fracture, a loading dose of vitamin D (50,000–125,000 IU) is recommended orally or intramuscularly prior to the first administration of the medicinal product.

Paget's Disease.

The recommended dose of the medicinal product is one 5 mg intravenous infusion.

The medicinal product should only be prescribed by a physician experienced in the management of Paget’s disease with bone involvement.

Additionally, patients with Paget’s disease require supplementation with calcium, at least 500 mg of elemental calcium twice daily for at least 10 days following infusion.

Re-treatment in Paget's Disease.

After initiation of treatment with zoledronic acid for Paget’s disease, a prolonged remission period is observed in patients who respond to therapy. Re-treatment consists of an additional 5 mg intravenous infusion of the medicinal product administered to patients who have relapsed, with an interval of 1 year or longer since initial treatment. Data on re-treatment of Paget’s disease are limited.

Special Patient Populations.

Patients with Renal Impairment.

The use of the medicinal product is not recommended in patients with renal impairment and a creatinine clearance < 35 mL/min.

Dosage adjustment is not required for patients with renal impairment and a creatinine clearance > 35 mL/min.

Patients with Hepatic Impairment.

Dosage adjustment is not required for these patients.

Elderly Patients (aged 65 years and older).

Dosage adjustment is not required, as the bioavailability, distribution, and elimination of zoledronic acid in elderly patients are similar to those in younger patients.

Administration Method.

The medicinal product should be administered slowly through a dedicated infusion set equipped with an air vent and at a constant infusion rate.

The infusion time should be no less than 15 minutes.

Any unused portion or waste should be disposed of in accordance with local requirements.

Only a clear, particle-free solution without discoloration should be used.

If the solution has been refrigerated, allow it to reach room temperature before administration. Aseptic techniques should be followed during preparation of the intravenous infusion solution.

The medicinal product is for single use only.

From a microbiological standpoint, the product should be used immediately. Otherwise, the user is responsible for the storage duration and conditions. The solution is recommended to be stored for no more than 24 hours at 2–8 °C.

Children.

The medicinal product should not be used in children and adolescents (under 18 years of age).

Overdose.

Clinical experience with acute overdose is limited. Patients who have received doses exceeding the recommended dose require careful monitoring.

In the event of overdose leading to clinically significant hypocalcemia, correction of the condition may be achieved by additional oral administration of calcium and/or intravenous infusion of calcium gluconate.

Adverse Reactions

The overall percentage of patients who experienced adverse reactions was 44.7%, 16.7%, and 10.2% after the first, second, and third administration of zoledronic acid, respectively.

The incidence of individual adverse reactions after the first dose was: fever – 17.1%, myalgia – 7.8%, influenza-like symptoms – 6.7%, arthralgia – 4.8%, and headache – 5.1%. The frequency of these reactions notably decreased with subsequent annual doses of zoledronic acid.

Most of these reactions occurred within the first 3 days after administration, were mild or moderate in intensity, and resolved within 3 days. In a small study where prophylaxis against adverse reactions was implemented as described below, the percentage of patients experiencing adverse reactions was lower (19.5%, 10.4%, 10.7% after the first, second, and third administration, respectively).

The adverse reactions listed below are systematically categorized by MedDRA organ system classes and 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 not known (frequency cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations:

uncommon – influenza, nasopharyngitis.

Blood and lymphatic system disorders:

uncommon – anaemia.

Immune system disorders:

not known** – hypersensitivity reactions, including rare cases of bronchospasm, urticaria, and angioedema, and very rare cases of anaphylactic reactions/shock.

Metabolism and nutrition disorders:

common – hypocalcaemia*; uncommon – decreased appetite; rare – hypophosphataemia.

Psychiatric disorders:

uncommon – insomnia.

Nervous system disorders:

common – headache, dizziness; uncommon – lethargy, paraesthesia, somnolence, tremor, syncope, taste disturbance.

Eye disorders:

common – eye hyperaemia; uncommon – conjunctivitis, eye pain; rare – uveitis, episcleritis, iriditis; not known** – scleritis, eye inflammation.

Ear and labyrinth disorders:

uncommon – vertigo.

Cardiac disorders:

common – atrial fibrillation; uncommon – palpitations.

Vascular disorders:

uncommon – hypertension, hot flushes; not known** – hypotension (in some patients with risk factors).

Respiratory, thoracic and mediastinal disorders:

uncommon – cough, dyspnoea.

Gastrointestinal disorders:

common – nausea, vomiting, diarrhoea; uncommon – dyspepsia, epigastric pain, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis#.

Skin and subcutaneous tissue disorders:

uncommon – rash, hyperhidrosis, pruritus, erythema.

Musculoskeletal and connective tissue disorders:

common – myalgia, arthralgia, bone pain, back pain, limb pain; uncommon – neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscle weakness; rare – atypical subtrochanteric and diaphyseal femoral fractures† (a class adverse reaction of bisphosphonates); very rare – osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates); not known** – osteonecrosis of the jaw.

Renal and urinary disorders:

uncommon – increased plasma creatinine, polyuria, proteinuria; not known** – renal function impairment.

Rare cases of renal failure requiring haemodialysis and rare fatal cases have been observed in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant use of nephrotoxic drugs, concomitant diuretic therapy, or post-infusion dehydration.

Investigations:

common – increased C-reactive protein levels; uncommon – decreased plasma calcium levels.

General disorders and administration site conditions:

very common – fever; common – influenza-like symptoms, chills, fatigue, asthenia, pain, malaise, infusion site reaction;

uncommon – peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain; not known** – secondary dehydration associated with symptoms such as fever, vomiting, and diarrhoea occurring after administration.

Observed in patients receiving concomitant glucocorticoids.

* Occurs only in Paget’s disease.

** Based on post-marketing reports. Frequency cannot be estimated from available data.

† Identified during post-marketing surveillance.

Atrial fibrillation

During the HORIZON – Pivotal Fracture Trial (PFT), the overall incidence of atrial fibrillation as an adverse reaction was 2.5% (96 out of 3,862 patients) in the zoledronic acid group compared to 1.9% (75 out of 3,852 patients) in the placebo group. The incidence of serious atrial fibrillation was 1.3% (51 out of 3,862) in patients receiving zoledronic acid compared to 0.6% (22 out of 3,852) in the placebo group. The mechanism underlying the increased incidence of atrial fibrillation is unknown. In osteoporosis trials (PFT, HORIZON – Recurrent Fracture Trial [RFT]), the overall incidence of atrial fibrillation was comparable in the zoledronic acid group (2.6%) and the placebo group (2.1%). The overall incidence of serious atrial fibrillation was 1.3% in patients receiving zoledronic acid compared to 0.8% in the placebo group.

Class effects

Renal function disorders

Adverse reactions manifesting as worsening renal function (including increased plasma creatinine levels) and rarely acute renal failure have been observed with zoledronic acid administration. Renal function impairment occurred during treatment with zoledronic acid, particularly in patients with a history of kidney disease or additional risk factors (such as advanced age, concomitant chemotherapy, concomitant use of nephrotoxic drugs, concomitant diuretic therapy, or severe dehydration); most of these patients received zoledronic acid at a dose of 4 mg every 3–4 weeks, but renal function impairment was occasionally observed after a single dose.

In clinical osteoporosis trials, changes in creatinine clearance (measured annually before administration of zoledronic acid), frequency of renal failure, and renal function impairment were comparable over three years between the zoledronic acid and placebo groups. Transient increases in plasma creatinine levels within 10 days were observed in 1.8% of patients receiving zoledronic acid compared to 0.8% of patients receiving placebo.

Hypocalcaemia

Based on clinical osteoporosis trials, approximately 0.2% of patients experienced a notable decrease in plasma calcium levels (below 1.87 mmol/L) after zoledronic acid administration. No cases of symptomatic hypocalcaemia were observed. In Paget’s disease trials, symptomatic hypocalcaemia occurred in approximately 1% of patients; all cases were transient.

Transient asymptomatic decreases in calcium levels below the normal range (below 2.10 mmol/L) occurred in 2.3% of patients receiving zoledronic acid in a large clinical trial, compared to 21% of patients in Paget’s disease trials. The incidence of hypocalcaemia was significantly lower with subsequent doses.

In postmenopausal osteoporosis trials for prevention of clinical fractures, including hip fracture and Paget’s disease studies, all patients received appropriate vitamin D and calcium supplements. In the clinical fracture prevention trial following recent hip fracture, vitamin D levels were generally not measured, but most patients received a loading dose of vitamin D prior to zoledronic acid administration.

Local reactions

In a large clinical trial, local infusion site reactions (0.7%) were reported: redness, swelling, and/or pain after zoledronic acid administration.

Osteonecrosis of the jaw

Cases of jaw necrosis have been observed primarily in cancer patients receiving bone resorption inhibitors, including zoledronic acid. In a large clinical trial involving 7,736 patients, only one case of osteonecrosis of the jaw was observed in a patient receiving zoledronic acid and one case in a patient receiving placebo. Cases of osteonecrosis of the jaw have been reported during post-marketing use of zoledronic acid.

Acute phase reactions

The overall percentage of patients reporting acute phase reactions or post-dose symptoms (including serious reactions) after zoledronic acid administration is as follows (frequencies from osteoporosis treatment trials in postmenopausal women): fever (18.1%), myalgia (9.4%), influenza-like symptoms (7.8%), arthralgia (6.8%), and headache (6.5%). Most of these symptoms occurred within the first 3 days after administration. The majority of these symptoms were mild or moderate in severity and resolved within 3 days. The frequency of these symptoms decreased with subsequent annual doses of zoledronic acid. The percentage of patients experiencing adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second, and third infusions, respectively), where prophylaxis against adverse reactions was applied (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25°C, out of reach of children.

After opening, the vial should be stored at 2–8°C and used within 24 hours.

Incompatibilities

The solution must not be mixed with calcium-containing solutions.

The solution must not be mixed or administered intravenously with other medicinal products.

Packaging

100 ml solution in a vial, 1 vial in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mefar Ilac San. A.S., Turkey.

Manufacturer’s address and location of operations

Ramazanoglu Mah. Ensar Cad. No. 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing authorization holder

WORLD MEDICINE, LLC, Ukraine.