INSTRUCTION

for medical use of the medicinal product

ZOLEUM

 

Composition:

active substance: zoledronic acid;

100 ml of solution contains zoledronic acid monohydrate equivalent to zoledronic acid 5 mg;

excipients: mannitol (E421), sodium citrate, water for injection.

 

Pharmaceutical form. Solution for infusion.

Basic physical and chemical properties: a clear colourless solution.

 

Pharmacotherapeutic group. Drugs affecting bone structure and mineralization. Bisphosphonates. ATC code: М05ВА08.

 

Pharmacological properties.

Pharmacodynamics.

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

Pharmacodynamic properties.

The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone tissue. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.

Treatment with zoledronic acid rapidly decreased the intensity of bone metabolism: from elevated levels in the postmenopausal period with the lowest point for resorption markers on Day 7 to formation markers on Week 12. Thereafter, the levels of bone metabolism markers stabilize within the premenopausal range. No progressive reduction in bone metabolism marker levels was observed with repeated annual dosing.

Clinical efficacy in the treatment of postmenopausal osteoporosis

The efficacy and safety of zoledronic acid at a dose of 5 mg once yearly for three consecutive years were demonstrated in postmenopausal women (7,736 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 ones; a femoral neck BMD T-score ≤ –2.5 with or without evidence of vertebral fracture. 85% of patients had never previously received bisphosphonates. Women who were assessed for vertebral fracture incidence did not receive concomitant osteoporosis therapy, which was permitted in women evaluated for hip and all clinically apparent fractures. 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 statistically significant effect observed as early as one year (see Table 1).

 

 

 

 

 

 

Table 1

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

Outcome	Zoledronic acid (%)	Placebo (%)	Absolute fracture risk reduction % (confidence interval – CI)	Relative fracture risk reduction % (CI)
At least one new vertebral fracture (0–1 year)	1.5	3.7	2.2 (1.4, 3.1)	60 (43, 72)*
At least one new vertebral fracture (0–2 years)	2.2	7.7	5.5 (4.4, 6.6)	71 (62, 78)*
At least one new vertebral fracture (0–3 years)	3.3	10.9	7.6 (6.3, 9.0)	70 (62, 76)*

* p < 0.0001

 

In patients aged 75 years and older who received treatment with zoledronic acid, the risk of vertebral fractures was reduced by 60% compared to the placebo group (p < 0.0001).

Effect on hip fractures

A sustained effect of zoledronic acid over 3 years was 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 those receiving placebo. The risk reduction was 51% in patients who had never previously received bisphosphonates and 42% in those allowed concomitant osteoporosis therapy.

Effect on clinically apparent fractures

All clinically apparent fractures were diagnosed based on radiographic evidence and/or clinical findings. The results are presented in Table 2.

Table 2

Incidence of key clinically apparent fracture outcomes over 3 years

Outcome	Zoledronic acid (N = 3875), incidence (%)	Placebo (N = 3861), incidence (%)	Absolute fracture risk reduction % (CI)	Relative fracture risk reduction % (CI)
Any clinically apparent fracture (1)	8.4	12.8	4.4 (3.0, 5.8)	33 (23, 42)**
Clinically apparent vertebral fracture (2)	0.5	2.6	2.1 (1.5, 2.7)	77 (63, 86)**
Fracture at other sites (1)	8.0	10.7	2.7 (1.4, 4.0)	25 (13, 36)*

*p < 0,001.

**p < 0,0001.

(1) Excluding fractures of the thumb, big toe, and facial bones.

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

 

Effect on bone mineral density (BMD)

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

Bone histology

Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 postmenopausal women with osteoporosis treated with either zoledronic acid (N = 82) or placebo (N = 70). Histomorphometric analysis showed a 63% reduction in bone remodeling. In patients receiving zoledronic acid, there was no evidence of osteomalacia, bone marrow fibrosis, or formation of immature bone tissue. Tetracycline labeling was present in 81 out of 82 biopsies from the zoledronic acid group. Micro-computed tomography (micro-CT) analysis demonstrated an increase in trabecular bone volume and preservation of trabecular bone architecture in the zoledronic acid group compared to placebo.

Markers of bone remodeling

Bone-specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP), and serum beta-C-terminal telopeptides (b-CTx) were measured in subgroups ranging from 517 to 1246 patients at periodic intervals throughout the study. Treatment with zoledronic acid at an annual dose of 5 mg resulted in a statistically significant 30% reduction in BSAP from baseline at 12 months, which remained 28% below baseline at 36 months. The level of N-terminal propeptide was significantly reduced by 61% at 12 months and remained 52% below baseline at 36 months. The level of beta-C-telopeptides was significantly reduced by 61% at 12 months and remained 55% below baseline at 36 months. Throughout the treatment period, bone remodeling markers remained within the premenopausal range at the end of each year. Repeat dosing did not lead to further reductions in bone remodeling markers.

Effect on height

In the three-year osteoporosis study, standing height was measured annually using a stadiometer. The zoledronic acid group showed less height loss (approximately 2.5 mm) compared to placebo (95% CI: 1.6 mm to 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 days 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 days and 0.5 days, respectively, compared to placebo (for all comparisons, p < 0.01).

Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fractures following a recent hip fracture (RFT)

The incidence of clinically apparent fractures, including vertebral fractures, non-vertebral fractures, and hip fractures, was assessed in 2,127 men and women aged 50 to 95 years (mean age 74.5 years) who had recently (within 90 days) sustained a low-trauma hip fracture. These patients were followed for an average of 2 years while receiving the investigational treatment. Approximately 42% of patients had a femoral neck BMD T-score below –2.5, while approximately 45% had a T-score above –2.5. Zoledronic acid was administered once yearly until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were generally not assessed, but most patients received a loading dose of vitamin D (ranging from 50,000 to 125,000 IU orally or intramuscularly) within 2 weeks prior to infusion. All participants additionally received 1,000 to 1,500 mg of elemental calcium and 800 to 1,200 IU of vitamin D daily. 95% of patients received their infusion two or more weeks after hip fracture healing, with the infusion administered on average approximately 6 weeks post-fracture healing. The primary efficacy endpoint was the incidence of clinically apparent fractures throughout the study period.

Effect on all clinically apparent fractures

The incidence of key clinically apparent fracture outcomes is presented in Table 3.

 

 

 

 

 

Table 3

Incidence of key clinically apparent fracture outcomes

Outcome	Zoledronic Acid (N = 1065) Incidence (%)	Placebo (N = 1062) Incidence (%)	Absolute reduction in fracture incidence % (CI)	Relative risk reduction in fracture incidence % (CI)
Any clinically apparent fracture (1)	8.6	13.9	5.3 (2.3, 8.3)	35 (16, 50)**
Clinically apparent vertebral fracture (2)	1.7	3.8	2.1 (0.5, 3.7)	46 (8, 68)*
Non-vertebral fracture (1)	7.6	10.7	3.1 (0.3, 5.9)	27 (2, 45)*

*p < 0.05.

**p < 0.01.

(1) Excluding fractures of the thumb, big toe, and facial bones.

(2) Including clinically apparent thoracic and lumbar vertebral fractures.

 

The study was not powered to detect statistically significant differences in the incidence of hip fractures, but a trend toward reduced incidence of new hip fractures was observed.

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

The incidence of delayed healing of hip fractures was similar 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, treatment with zoledronic acid resulted in a statistically significant increase in BMD at all hip sites and the femoral neck compared to placebo at all-time points. Treatment with zoledronic acid led to a 5.4% increase in BMD of total hip and a 4.3% increase in BMD of the femoral neck over 24 months compared to placebo.

Clinical efficacy in men

In the HORIZON-RFT study, 508 men were randomized to participate, and 185 patients underwent BMD assessment at 24 months. After 24 months, a comparable and statistically significant 3.6% increase in total hip BMD was observed in men treated with zoledronic acid, similar to the effect seen in postmenopausal women in the HORIZON-PFT study. This study was not powered to demonstrate a reduction in the incidence of clinically apparent fractures in men; the incidence of clinically apparent fractures was 7.5% in men treated with zoledronic acid compared to 8.7% in those receiving placebo.

In a separate study involving men (CZOL446M2308 study), an annual infusion of zoledronic acid was non-inferior to weekly alendronate in terms of 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 for the treatment and prevention of glucocorticoid-induced osteoporosis 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; 53.5 years for women), who were receiving prednisone >7.5 mg/day (or equivalent). Patients were stratified based on the duration of glucocorticoid use prior to randomization (≤3 months vs. >3 months). The study duration was 1 year. Participants were randomized to receive either a single 5 mg infusion of zoledronic acid or oral risedronate 5 mg once daily for one year. All subjects also received 1000 mg of elemental calcium and 400 to 1000 IU of vitamin D per day. Efficacy was considered demonstrated if non-inferiority of risedronate compared with the percentage change in lumbar spine BMD at 12 months from baseline was shown in the treatment and prevention subpopulations, respectively. Most patients continued glucocorticoid therapy during the one-year study period.

Effect on bone mineral density (BMD)

The increases in BMD at the lumbar spine and femoral neck were statistically significantly greater in the zoledronic acid group compared to the risedronate group (for all comparisons, 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% for risedronate (mean difference 1.36%; p < 0.001). In the subpopulation of patients who had been on glucocorticoids for 3 months or less, zoledronic acid increased lumbar spine BMD by 2.60% compared to 0.64% for risedronate (mean difference 1.96%; p < 0.001). This study was not powered to show a difference in the incidence of clinically apparent fractures compared to risedronate. The number of fracture events was 8 in the zoledronic acid group versus 7 in the risedronate group (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 the age of 30 with primary mild to moderate Paget’s disease of bone (median serum alkaline phosphatase levels 2.6–3.0 times above the age-specific upper limit of normal at study entry), confirmed radiographically.

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, therapeutic response and normalization of serum alkaline phosphatase levels (ALP) were achieved 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 (for all comparisons, p < 0.001), respectively.

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

Patients classified as responders at the end of the 6-month core study were eligible for enrollment in the extended observation period. Of the 153 patients treated with zoledronic acid and 115 patients treated with risedronate who entered the extended follow-up study, after a mean follow-up of 3.8 years from the initial treatment, the proportion of patients who discontinued due to the need for retreatment (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 median time to study withdrawal due to the need for retreatment for Paget’s disease was longer in patients who received zoledronic acid (7.7 years) than in those who received risedronate (5.1 years).

6 patients who initially achieved a therapeutic response at 6 months after treatment with zoledronic acid and subsequently experienced disease relapse during the extended follow-up received retreatment with zoledronic acid at a mean of 6.5 years after the first treatment. 5 out of 6 of these patients had serum alkaline phosphatase levels within the normal range at 6 months.

Bone histology was assessed in 7 patients with Paget’s disease 6 months after receiving a 5 mg dose of zoledronic acid. Bone biopsy results demonstrated normal bone quality with no evidence of impaired bone remodeling or mineralization defects. These findings are consistent with biochemical markers indicating normalization of bone remodeling.

The European Medicines Agency has waived the obligation to submit the results of studies with zoledronic acid in all subsets of the pediatric population for Paget’s disease of bone, as well as for osteoporosis in postmenopausal women at increased risk of fractures, osteoporosis in men at increased risk of fractures, and for the prevention of clinical fractures following hip fracture in men and women.

 

Pharmacokinetics

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

After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½α 0.24 and t_½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t_½γ 146 hours. There was no accumulation of zoledronic acid in plasma after multiple doses given every 28 days. The early disposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone and excretion via the kidneys. Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. Such bone uptake is characteristic of all bisphosphonates and is believed to occur due to their structural similarity to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bone tissue is very long. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 l/h, independent of dose, and unaffected by gender, age, race, and body weight. It has been demonstrated that the intra-subject and inter-subject variability in the plasma clearance of zoledronic acid are 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes caused a decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration independent. Thus, the likelihood of interaction as a result of substitution of drugs that are highly protein-bound is negligible.

Special populations

Renal impairment

The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 patients studied. Small observed increases in AUC (0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50–80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. Since only limited data are available for severe renal impairment (creatinine clearance <35 ml/min), no dosage recommendations for this population are possible.

 

Clinical particulars.

Therapeutic indications.

Treatment of osteoporosis in post-menopausal women and in adult men at increased risk of fracture, including those with a recent low-trauma hip fracture.

Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women and in adult men at increased risk of fracture.

Treatment of Paget's disease of bone in adults.

 

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product, or hypersensitivity to bisphosphonates. Hypocalcaemia. Severe renal impairment with creatinine clearance < 35 ml/min. Pregnancy or breastfeeding period.

 

Interaction with other medicinal products and other forms of interaction.

No interaction studies with other medicinal products have been performed. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound medicinal products are therefore unlikely. 

Zoledronic acid is eliminated by renal excretion. Caution is indicated when Zoleum is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration).

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

 

Precautions for use.

The use of Zoleum in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.

Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration occurring after zoledronic acid administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal adverse reactions:

• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula before each Zoleum dose.
• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.
• Monitoring of serum creatinine should be considered in at-risk patients.
• Zoleum should be used with caution when concomitantly used with other medicinal products that could impact renal function.
• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Zoleum.
• A single dose of Zoleum should not exceed 5 mg and the duration of infusion should be at least 15 minutes.

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Zoleum. Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.

Elevated bone turnover is a characteristic of Paget's disease of bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Zoleum.

Adequate calcium and vitamin D intake are recommended in association with Zoleum administration. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Zoleum administration. Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of Zoleum is recommended for patients with Paget´s disease.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Zoleum.

Osteonecrosis of the jaw (ONJ)

ONJ has been reported in the post-marketing setting in patients receiving zoledronic acid for osteoporosis.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Zoleum in patients with concomitant risk factors.

The following should be considered when evaluating a patient's risk of developing ONJ:

- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures, e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental checkups, and immediately report any oral symptoms such as dental mobility, pain or swelling, nonhealing of sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment.

The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Other features

The frequency of symptoms occurring within the first three days after administration of the preparation can be reduced by taking paracetamol or ibuprofen immediately after administration of Zoleum.

For oncology appointments, other preparations containing zoledronic acid as active substance are available. Patients receiving Zoleum should not be given these drugs or any other bisphosphonates at the same time, since the combined effect of these substances is unknown.

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. it is practically free of sodium.

 

Pregnancy and lactation.

Pregnancy

Zoleum is contraindicated during pregnancy. There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations. The potential risk for humans is unknown.

Breastfeeding

Zoleum is contraindicated during breastfeeding. It is unknown whether zoledronic acid is excreted into human milk.

Women of reproductive age

Zoleum is not recommended for use in women of reproductive age

Fertility

The potential adverse effect of zoledronic acid on fertility was studied in parental and F1 generation rats. As a result, an excessively enhanced pharmacological effect was observed, likely due to the drug’s inhibition of skeletal calcium mobilization. This led to the development of perinatal hypocalcemia (an effect typical of bisphosphonates) along with dystocia and early termination of the study. Therefore, these study results do not allow definitive conclusions about the impact of zoledronic acid on human fertility.

 

Effects on ability to drive and use machines.

Adverse reactions, such as dizziness, may affect the ability to drive or use machines.

 

Method of administration and dosage.

Dosage

Patients must be appropriately hydrated prior to administration of Zoleum. This is especially important for the elderly (≥65 years) and for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with Zoleum administration.

Osteoporosis

For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous infusion of 5 mg Zoleum administered once a year.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Zoleum on an individual patient basis, particularly after 5 or more years of use.

In patients with a recent low-trauma hip fracture, it is recommended to give Zoleum infusion at least two weeks after hip fracture repair (see section 5.1). In patients with a recent low-trauma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first Zoleum infusion.

Paget's disease

For the treatment of Paget's disease, Zoleum should be prescribed only by physicians with experience in the treatment of Paget's disease of the bone. The recommended dose is a single intravenous infusion of 5 mg Zoleum. In patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Zoleum administration.

Re-treatment of Paget's disease: After initial treatment with Zoleum in Paget's disease, an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous infusion of 5 mg Zoleum after an interval of one year or longer from initial treatment in patients who have relapsed. Limited data on re-treatment of Paget's disease are available.

Special populations

Patients with renal impairment. Zoleum is contraindicated in patients with creatinine clearance < 35 ml/min.

No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min.

Patients with hepatic impairment. No dose adjustment is required

Elderly (≥ 65 years). No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Method of administration. Zoleum is administered via a vented infusion line and given slowly at a constant infusion rate. The infusion time must not be less than 15 minutes. Discard any unused portion or waste in accordance with local requirements. Only clear solution without visible particles and discoloration must be applied.

If the solution is cool, it should be allowed to reach room temperature before use. Follow the rules of aseptic technique when preparing the solution for intravenous infusion.

For single use only.

From a microbiological point of view, the preparation should be used immediately. Otherwise, the customer is responsible for time and storage conditions of the preparation. It is recommended to store the preparation for a maximum of 24 hours at 2-8 ° C.

 

Children.

Zoleum is not recommended for use in children and adolescents (under 18 years of age) due to insufficient evidence on the safety and efficacy of this product in this age group.

 

Overdose.

Clinical experience with acute overdose is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an 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 infusions of zoledronic acid, respectively. The incidence of specific adverse reactions after the first infusion was as follows: fever – 17.1%, myalgia – 7.8%, flu-like symptoms – 6.7%, arthralgia – 4.8%, and headache – 5.1%. The frequency of these reactions significantly decreased with subsequent annual infusions of zoledronic acid. Most of these reactions occurred within the first three days after administration, were mild to moderate in severity, and resolved within three days. In a small study where preventive measures were taken to reduce adverse reactions (as described below), the incidence of such reactions was lower: 19.5%, 10.4%, and 10.7% after the first, second, and third infusions, respectively.

Adverse reactions are listed according to MedDRA system organ class and frequency category: 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); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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 reaction/shock.

Metabolism and nutrition disorders:

common – hypocalcaemia*

uncommon – decreased appetite

rare – hypophosphatemia

Psychiatric disorders:

uncommon – insomnia

Nervous system disorders:

common – headache, dizziness

uncommon – lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia

Eye disorders:

common – ocular hyperaemia

uncommon – conjunctivitis, eye pain

rare – uveitis, episcleritis, iritis

not known** – scleritis and parophthalmia

Ear and labyrinth disorders:

uncommon – vertigo

Cardiac disorders:

common – atrial fibrillation

uncommon – palpitations

Vascular disorders:

uncommon – hypertension, flushing

not known** – hypotension (some of the patients had underlying risk factors)

Respiratory, thoracic and mediastinal disorders:

uncommon – cough, dyspnoea

Gastrointestinal disorders:

common – nausea, vomiting, diarrhoea

uncommon – dyspepsia, abdominal pain upper, abdominal pain, gastroesophageal reflux disease,

constipation, dry mouth, esophagitis, toothache, gastritis^#

Skin and subcutaneous tissue disorders:

uncommon – rash, hyperhidrosis, pruritus, erythema

Musculoskeletal and connective tissue disorders:

common – myalgia, arthralgia, bone pain, back pain, pain in extremity

uncommon – neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness

rare – atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)

very rare – osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)

not known** – osteonecrosis of the jaw

Renal and urinary disorders:

uncommon – blood creatinine increased, pollakiuria, proteinuria

not known** – renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period

Investigations

common – C-reactive protein increased

uncommon – blood calcium decreased

General disorders and administration site conditions:

very common – pyrexia

common – influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction

uncommon – peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain

not known** – dehydration secondary to post-dose symptoms such as pyrexia, vomiting and diarrhoea

 

# Observed in patients taking concomitant glucocorticosteroids.

* Common in Paget's disease only.

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

† Identified in post-marketing experience.

 

Atrial fibrillation

In the HORIZON Pivotal Fracture Trial (PFT), the overall incidence of atrial fibrillation 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 atrial fibrillation reported as a serious adverse reaction was increased, reaching 1.3% (51 out of 3,862) in patients receiving zoledronic acid, versus 0.6% (22 out of 3,852) in those receiving placebo. The mechanism behind the increased incidence of atrial fibrillation is unknown. In osteoporosis studies (PFT and HORIZON Recurrent Fracture Trial [RFT]), the overall incidence of atrial fibrillation was comparable between the zoledronic acid group (2.6%) and the placebo group (2.1%). The incidence of atrial fibrillation as a serious adverse reaction was 1.3% in the zoledronic acid group compared to 0.8% in the placebo group.

Class effects:

Renal impairment

Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g. advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration.

According to clinical studies on osteoporosis, changes in creatinine clearance (measured annually before each dose), the incidence of renal failure and impaired renal function, were comparable between the zoledronic acid and placebo groups over a three-year period. A transient increase in serum creatinine levels within 10 days was observed in 1.8% of patients receiving zoledronic acid, compared to 0.8% in the placebo group.

Hypocalcaemia

In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/L) following Zoledronic acid Infusion administration. No symptomatic cases of hypocalcaemia were observed.

In the Paget's disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.

Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/L) occurred in 2.3% of Zoledronic acid Infusion-treated patients in a large clinical trial compared to 21% of Zoledronic acid Infusion-treated patients in the Paget's disease trials. The incidence of hypocalcaemia was much lower following subsequent infusions.

All patients received adequate supplementation with vitamin D and calcium in the postmenopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget's disease trials. In the trial for the prevention of clinical fractures following a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to zoledronic acid administration.

Local reactions

In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, including zoledronic acid.

In a large clinical study involving 7,736 patients, only one case of jaw osteonecrosis was observed in a patient receiving zoledronic acid and one case in a patient receiving placebo. Reports of jaw osteonecrosis have also been received during the post-marketing period of zoledronic acid use.

 

Adverse Reactions Reporting

Adverse reactions reporting after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and cases of lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

 

Shelf life. 2 years.

 

Storage conditions.  

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

 

Incompatibility.

Zoleum solution for infusion must not be mixed with solutions containing calcium.

Zoleum must not be mixed or given intravenously with any other medicinal products.

 

Packaging.

100 ml of the preparation in each container. 1 film-coated container in a box

 

 

Terms of dispensing. On prescription.

 

 

Date of last update. 10.02.2025