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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Zoledronic acid Zentiva 5 mg / 100 ml solution for infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each bag with 100 ml of solution contains 5 mg zoledronic acid anhydrous (as monohydrate).

Each ml of the solution contains 0.05 mg zoledronic acid anhydrous, (as monohydrate).

Excipient with known effect: This medicinal product contains less than 1 mmol sodium (23 mg) per bag (100 ml), i.e. essentially “sodium-free”.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM Solution for infusion.

Clear and colourless solution.

The pH of the solution is 6.2 - 6.8.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of osteoporosis

•    in post-menopausal women,

•    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,

• in adult men, at increased risk of fracture.

4.2 Posology and method of administration

Posology

Patients must be appropriately hydrated prior to administration of zoledronic acid. This is especially important for the elderly and for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with zoledronic acid 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 zoledronic acid 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 zoledronic acid 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 the zoledronic acid 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 zoledronic acid infusion.

Paget’s Disease

For the treatment of Paget’s disease, zoledronic acid 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 zoledronic acid. 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 zoledronic acid administration (see section 4.4).

Re-treatment of Paget’s disease: After initial treatment with zoledronic acid in Paget’s disease an extended remission period is observed in responding patients. Retreatment consists of an additional intravenous infusion of 5mg zoledronic acid 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 (see section 5.1).

Special populations

Patients with renal impairment

Zoledronic acid is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).

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

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Older people ^ 65 years)

No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Paediatric population

The safety and efficacy of zoledronic acid in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration Intravenous use.

Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and given at a constant infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of zoledronic acid see section 6.6.

.3    Contraindications

Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients (listed in section 6.1).

-    Patients with hypocalcaemia (see section 4.4).

-    Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).

-    Pregnancy and breast-feeding (see section 4.6).

4.4    Special warnings and precautions for use

Renal function

The use of zoledronic acid 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 (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), 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 zoledronic acid 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.

•    Zoledronic acid should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).

•    Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of zoledronic acid.

•    A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).

Hypocalcaemia

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with zoledronic acid (see section 4.3). 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 the 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 zoledronic acid (see section 4.8).

Adequate calcium and vitamin D intake are recommended in association with zoledronic acid 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 zoledronic acid administration (see section 4.2). 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 zoledronic acid 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 zoledronic acid (see section 4.8).

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw has been reported in patients treated with zoledronic acid. Many of the reported cases have been associated with dental procedures such as tooth extraction. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, anti-angiogenic medicinal products, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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.

General

The incidence of post-dose symptoms occurring within the first three days after administration of zoledronic acid can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid administration.

Zoledronic acid 5 mg/100 ml solution for infusion contains the same active substance found in Zoledronic acid 4 mg/5 ml concentrate for solution for infusion (zoledronic acid), used for oncology indications, and a patient being treated with Zoledronic acid 4 mg/5 ml concentrate for solution for infusion should not be treated with Zoledronic acid 5 mg/100 ml solution for infusion

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per bag (100 ml), i.e. essentially “sodium-free”.

4.5 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 (see section 5.2). Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound drugs are therefore unlikely.

Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4).

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Zoledronic acid is contraindicated during pregnancy (see section 4.3).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 (see section 5.3). The potential risk for humans is unknown.

Breast-feeding

Zoledronic acid is contraindicted during breast -feeding (see section 4.3). It is unknown whether zoledronic acid is excreted into human milk.

Women of childbearing potential

Zoledronic acid is not recommended in women of childbearing potential.

Fertility

Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered related to the compound’s inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of zoledronic acid on fertility in humans.

4.7 Effects on ability to drive and use machines

Zoledronic acid has no or negligible influence on the ability to drive and use machines. Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no studies on this effect with zoledronic acid have been performed.

4.8 Undesirable effects

Summary of the safety profile

The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: fever (17.1%), myalgia

(7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of zoledronic acid. The majority of these reactions occur within the first three days following zoledronic acid administration. The majority of these reactions were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used.

In the HORIZON - Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving zoledronic acid (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for zoledronic acid and 0.8% for placebo.

Tabulated list of adverse reactions

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention: 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.

Table 1

Infections and infestations
Uncommon	Influenza, nasopharyngitis
Blood and lymphatic system disorders
Uncommon	Anaemia
Immune system disorders
Not known**	Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock
Metabolism and nutrition disorders
Common	Hypocalcaemia*
Uncommon	Anorexia, decreased appetite
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 orbital inflammation
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, oesophagitis, toothache, gastritis#
Skin and subcutaneous tissue disorders
Uncommon	Rash, hyperhydrosis, 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 fracturesf (bisphosphonate class adverse reaction)
Not known**	Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects)
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 (see sections 4.4 and 4.8 Class effects)
General disorders and administration site conditions
Very common	Fever
Common	Flu-like symptoms, 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 fever, vomiting and diarrhoea
Investigations
Common	C-reactive protein increased
Uncommon	Blood calcium decreased

#    Observed in patients taking concomitant glucocorticosteroids.

*    Common in Paget’s disease only.

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

f Identified in post-marketing experience.

Description of selected adverse reactions

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.

In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the zoledronic acid and placebo treatment groups over three years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of zoledronic acid-treated patients versus 0.8% of placebo-treated patients.

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 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-treated patients in a large clinical trial compared to 21% of zoledronic acid-treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.

All patients received adequate supplementation with vitamin D and calcium in the post-menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials (see also section 4.2). 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 (see section 4.2).

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

Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, preexisting dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with zoledronic acid and one patient treated with placebo. Both cases resolved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08.

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 based on their high affinity for mineralised bone.

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.

Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.

Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)

The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years were demonstrated in post-menopausal women (7,736 women aged 65-89 years) with either: a femoral neck bone mineral density (BMD) with a T-score < -1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score < -2.5 with or without evidence of existing vertebral fracture(s). 85% of patients were bisphosphonate-naive. Women who were evaluated for the incidence of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy included: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded other bisphosphonates. All women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU of vitamin D supplements daily.

Effect on morphometric vertebral fractures

Zoledronic acid significantly decreased the incidence of one or more new vertebral fractures over three years and as early as the one year timepoint (see Table 2).

Table 2 Summary of vertebral fracture efficacy at 12, 24 and 36 months

Outcome	Zoledronic acid (%)	Placebo (%)	Absolute reduction in fracture incidence % (CI)	Relative reduction in fracture incidence % (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 year)	2.2	7.7	5.5 (4.4, 6.6)	71 (62, 78)**
At least one new vertebral fracture (0-3 year)	3.3	10.9	7.6 (6.3, 9.0)	70 (62, 76)**
** p <0.0001

Zoledronic acid-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral fractures compared to placebo patients

(p<0.0001).

Effect on hip fractures

Zoledronic acid demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for zoledronic acid-treated patients compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-naive patients and 42% in patients allowed to take concomitant osteoporosis therapy.

Effect on all clinical fractures

All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 3.

Table 3 Between treatment comparisons of the incidence of key clinical _fracture variables over 3 years __

Outcome	Zoledronic acid (N=3,875) event rate (%)	Placebo (N=3,861) event rate (%)	Absolute reduction in fracture event rate % (CI)	Relative risk reduction in fracture incidence % (CI)
Any clinical fracture (1)	8.4	12.8	4.4 (3.0, 5.8)	33 (23, 42)**
Clinical vertebral fracture (2)	0.5	2.6	2.1 (1.5, 2.7)	77 (63, 86)**
Non-vertebral fracture (1)	8.0	10.7	2.7 (1.4, 4.0)	25 (13, 36)*

Effect on bone mineral density (BMD)

Zoledronic acid significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment with placebo at all timepoints (6, 12, 24 and 36 months). Treatment with zoledronic acid resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal radius over 3 years as compared to placebo.

Bone histology

Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post-menopausal patients 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 osteomalacia, marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 82 biopsies obtained from patients on zoledronic acid. Microcomputed tomography (^CT) analysis demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients treated with zoledronic acid compared to placebo.

Bone turnover markers

Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic intervals throughout the study. Treatment with a 5 mg annual dose of zoledronic acid significantly reduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 52% below baseline levels at 36 months. B-CTx was significantly reduced by 61% below baseline levels at 12 months and was sustained at 55% below baseline levels at 36 months. During this entire time period bone turnover markers were within the pre-menopausal range at the end of each year. Repeat dosing did not lead to further reduction of bone turnover markers.

Effect on height

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

Days of disability

Zoledronic acid significantly reduced the mean days of limited activity and the days of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo (all p<0.01).

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

The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low-trauma hip fracture who were

followed for an average of 2 years on study medication. Approximately 42% of patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral neck BMD T-score above -2.5. Zoledronic acid was administered once a year, until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.

Effect on all clinical fractures

The incidence rates of key clinical fracture variables are presented in Table 4.

Table 4 Between treatment comparisons of the incidence of key clinical fracture variables

Outcome	Zoledronic acid (N=1,065) event rate (%)	Placebo (N=1,062) event rate (%)	Absolute reduction in fracture event rate % (CI)	Relative risk reduction in fracture incidence % (CI)
Any clinical fracture (1)	8.6	13.9	5.3 (2.3, 8.3)	35 (16, 50)**
Clinical 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-value <0.05, **p-value <0.01 (1)    Excluding finger, toe and facial fractures (2)    Including clinical thoracic and clinical lumbar vertebral fractures

The study was not designed to measure significant differences in hip fracture, but a trend was seen towards reduction in new hip fractures.

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

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

Effect on bone mineral density (BMD)

In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip and femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to placebo.

Clinical efficacy in men

In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients treated with Zoledronic acid as compared to the effects observed in post-menopausal women in the HORIZON-PFT study. The study was not powered to show a reduction in clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus 8.7% for placebo.

In another study in men (study CZOL446M2308) an annual infusion of zoledronic acid was non-inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline.

Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated with long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women aged 18-85 years (mean age for men 56.4 years; for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified with respect to duration of glucocorticoid use prior to randomisation (< 3 months versus > 3 months). The duration of the trial was one year. Patients were randomised to either zoledronic acid 5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mg elemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if noninferiority to risedronate was shown sequentially with respect to the percentage change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention subpopulations, respectively. The majority of patients continued to receive glucocorticoids for the one year duration of the trial.

Effect on bone mineral density (BMD)

The increases in BMD were significantly greater in the zoledronic acid-treated group at the lumbar spine and femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving glucocorticoids for more than 3 months prior to randomisation, zoledronic acid increased lumbar spine BMD by 4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the subpopulation of patients that had received glucocorticoids for 3 months or less prior to randomisation, zoledronic acid increased lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96% ; p<0.001). The study was not powered to show a reduction in clinical fractures compared to risedronate. The incidence of fractures was 8 for Zoledronic acid-treated patients versus 7 for risedronate-treated patients (p=0.8055).

Clinical efficacy in the treatment of Paget’s disease of the bone

Zoledronic acid was studied in male and female patients aged above 30 years with

primarily mild to moderate

Paget’s disease of the bone (median serum alkaline phosphatase level 2.6.-.3.0 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month comparative trials. After 6 months, zoledronic acid showed 96% (169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/171) and 58% (99/171) for risedronate (all p.<.0.001).

In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for zoledronic acid and risedronate.

Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 153 zoledronic acid-treated patients and 115 risedronate-treated patients who entered an extended observation study, after a mean duration of follow-up of 3.8 years from time of dosing, the proportion of patients ending the Extended Observation Period due to the need for retreatment (Clinical judgment) was higher for risedronate (48 patients. or 41.7%) compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period due to the need for Paget’s re-treatment from the initial dose was longer for zoledronic acid (7.7 years) than for risedronate(5.1 years).

Six patients who achieved therapeutic response 6 months after treatment with zoledronic acid and later experienced disease relapse during the extended follow-up period were re-treated with zoledronic acid after a mean time of 6.5 years from initial treatment to re-treatment. 5 of the 6 patients had SAP within the normal range at month 6 (Last Observation Carried Forward, LOCF).

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralisation defects. These results were consistent with biochemical marker evidence of normalisation of bone turnover.

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product in all subsets of the paediatric population in Paget’s disease of the bone, osteoporosis in post-menopausal women at an increased risk of fracture, osteoporosis in men at increased risk of fracture and prevention of clinical fractures after a hip fracture in men and women (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.

Distribution

After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, 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 levels.

Elimination

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of ti/₂₍₁ 0.24 and t^ 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t/ 146 hours. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (a and P, with t_/ 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. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones 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 or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes caused a 30% 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.

Pharmacokinetic/phamacodynamic relati onships

No interaction studies with other medicinal products have been performed with zoledronic acid. 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. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.

Special populations (see section 4.2)

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 (Cl_cr = 50-80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of zolendronic acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population

5.3 Preclinical safety data

Acute toxicity

The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.

Subchronic and chronic toxicity

In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to 7 times the human therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were well-tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when given for 52 weeks.

Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, and at the site of intravenous administration. The clinical relevance of these findings is unknown. The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological antiresorptive activity.

Reproduction toxicity

Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was observed in rats at doses > 0.2 mg/kg and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to decreased serum calcium levels.

Mutagenicity and carcinogenic potential

Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Mannitol (E421)

Sodium citrate dihydrate (E331)

Sodium hydroxide (E524) for pH-adjustment Hydrochloric acid (E507) for pH-adjustment Water for injections

Incompatibilities

This medicinal product must not be allowed to come into contact with any calcium-containing solutions. Zoledronic acid must not be mixed or given intravenously with any other medicinal products.

6.3    Shelf-life

Unopened infusion bag: 2 years.

After opening: 24 hours at 2°C - 8 °C

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. and would normally not be longer than 24 hours at 2°C -8°C.

6.4    Special precautions for storage

Store below 25 °C

For storage condition of the medicinal product after opening, please see section 6.3.

6.5    Nature and contents of container

100 ml solution in a transparent plastic (polyolefin film) bag with one port and one connector with a grey rubber membrane.

Zoledronic acid is supplied in packs containing one bag.

6.6    Special precautions for disposal and other handling

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Only clear solution free from particles and discoloration should be used.

If refrigerated, allow the refrigerated solution to reach room temperature before administration. Aseptic techniques must be followed during the preparation of the infusion.

MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited, One Onslow Street,

Guildford,

GU1 4YS

Trading as: Zentiva,

One Onslow Street,

Guildford,

GU1 4YS

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0650

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/07/2012

10 DATE OF REVISION OF THE TEXT

01/04/2015