ACLASTA 5mg / 100ml infusion solution medication leaflet

Aclasta 5 mg solution for infusion

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

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

For the full list of excipients, see section 6.1.

Solution for infusion

Clear and colourless solution.

Treatment of osteoporosis

* in post-menopausal women

* in adult menat 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 menat increased risk of fracture.

Treatment of Paget’s disease of the bone in adults.

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

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

Osteoporosis

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

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The needfor continued treatment should be re-evaluated periodically based on the benefits and potential risks of

Aclasta 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 Aclasta infusion atleast two weeks after hip fracture repair (see section 5.1). In patients with a recent low-trauma hipfracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscularroute is recommended prior to the first Aclasta infusion.

Paget’s disease

For the treatment of Paget’s disease, Aclasta should be prescribed only by physicians with experiencein the treatment of Paget’s disease of the bone. The recommended dose is a single intravenous infusionof 5 mg Aclasta. In patients with Paget’s disease, it is strongly advised that adequate supplementalcalcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 daysfollowing Aclasta administration (see section 4.4).

Re-treatment of Paget’s disease: After initial treatment with Aclasta in Paget’s disease, an extendedremission period is observed in responding patients. Re-treatment consists of an additional intravenousinfusion of 5 mg Aclasta after an interval of one year or longer from initial treatment in patients whohave relapsed. Limited data on re-treatment of Paget’s disease are available (see section 5.1).

Aclasta 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.

No dose adjustment is required (see section 5.2).

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

Aclasta should not be used in children and adolescents below 18 years of age. There are no dataavailable for children under 5 years of age. Currently available data for children aged 5 to 17 years aredescribed in section 5.1.

Aclasta is administered via a vented infusion line and given slowly at a constant infusion rate. Theinfusion time must not be less than 15 minutes. For information on the infusion of Aclasta, seesection 6.6.

Patients treated with Aclasta should be given the package leaflet and the patient reminder card.

- Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipientslisted 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).

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

Renal impairment has been observed following the administration of Aclasta (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), ordehydration occurring after Aclasta administration. Renal impairment has been observed in patientsafter a single administration. Renal failure requiring dialysis or with a fatal outcome has rarelyoccurred 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 adversereactions:

* Creatinine clearance should be calculated based on actual body weight using the

Cockcroft-Gault formula before each Aclasta dose.

* Transient increase in serum creatinine may be greater in patients with underlying impaired renalfunction.

* Monitoring of serum creatinine should be considered in at-risk patients.

* Aclasta should be used with caution when concomitantly used with other medicinal productsthat could impact renal function (see section 4.5).

* Patients, especially elderly patients and those receiving diuretic therapy, should be appropriatelyhydrated prior to administration of Aclasta.

* A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least15 minutes (see section 4.2).

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D beforeinitiating therapy with Aclasta (see section 4.3). Other disturbances of mineral metabolism must alsobe 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 ofeffect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, maydevelop and is usually maximal within the first 10 days after infusion of Aclasta (see section 4.8).

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

In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calciumcorresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 daysfollowing Aclasta administration (see section 4.2).

Patients should be informed about symptoms of hypocalcaemia and receive adequate clinicalmonitoring during the period of risk. Measurement of serum calcium before infusion of Aclasta isrecommended for patients with Paget´s disease.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reportedin patients taking bisphosphonates, including zoledronic acid (see section 4.8).

ONJ has been reported in the post-marketing setting in patients receiving Aclasta (zoledronic acid) forosteoporosis (see section 4.8).

The start of treatment or of a new course of treatment should be delayed in patients with unhealedopen soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individualbenefit-risk assessment is recommended prior to treatment with Aclasta in patients with concomitantrisk 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 potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy.

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

- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy tohead 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 check-ups,and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing ofsores or discharge during treatment with zoledronic acid. While on treatment, invasive dentalprocedures should be performed with caution and avoided in close proximity to zoledronic acidtreatment.

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

Osteonecrosis of the external auditory canal

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

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique fractures can occur anywhere along the femur from just below the lesser trochanter to justabove the supracondylar flare. These fractures occur after minimal or no trauma and some patientsexperience thigh or groin pain, often associated with imaging features of stress fractures, weeks tomonths before presenting with a completed femoral fracture. Fractures are often bilateral; therefore thecontralateral femur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation ofbisphosphonate therapy in patients suspected to have an atypical femur fracture should be consideredpending 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Acute phase reactions

Acute phase reactions (APRs) or post-dose symptoms such as fever, myalgia, flu-like symptoms,arthralgia and headache have been observed, the majority of which occurred within three daysfollowing Aclasta administration.

APRs may sometimes be serious or prolonged in duration. The incidence of post-dose symptoms canbe reduced with the administration of paracetamol or ibuprofen shortly following Aclastaadministration. It is also advisable to postpone treatment if the patient is clinically unstable due to anacute medical condition and an APR could be problematic (see section 4.8).

Other products containing zoledronic acid as an active substance are available for oncologyindications. Patients being treated with Aclasta should not be treated with such products or any otherbisphosphonate concomitantly, since the combined effects of these agents are unknown.

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

No interaction studies with other medicinal products have been performed. Zoledronic acid is notsystemically metabolised and does not affect human cytochrome P450 enzymes in vitro (seesection 5.2). 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 thereforeunlikely.

Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid isadministered 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 areprimarily excreted via the kidney may increase.

Aclasta is not recommended in women of childbearing potential.

Aclasta is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use ofzoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductivetoxicological effects including malformations (see section 5.3). The potential risk for humans isunknown.

Aclasta is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronicacid is excreted into human milk.

Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1generation. This resulted in exaggerated pharmacological effects considered related to the compound’sinhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, abisphosphonate class effect, dystocia and early termination of the study. Thus these results precludeddetermining a definitive effect of Aclasta on fertility in humans.

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

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 reactionsfollowing the first infusion was: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%),arthralgia (4.8%) and headache (5.1%), see “acute phase reactions” below.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequencycategory. 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 frequencygrouping, 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 rarecases of bronchospasm, urticaria andangioedema, and very rare cases ofanaphylactic reaction/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, 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 hadunderlying risk factors)

Respiratory, thoracic and mediastinal Uncommon Cough, dyspnoeadisorders

Gastrointestinal disorders Common Nausea, vomiting, diarrhoea

Uncommon Dyspepsia, abdominal pain upper,abdominal pain, gastro-oesophagealreflux disease, constipation, dry mouth,oesophagitis, toothache, gastritis#

Skin and subcutaneous tissue disorders Uncommon Rash, hyperhidrosis, pruritus, erythema

Musculoskeletal and connective tissue Common Myalgia, arthralgia, bone pain, backdisorders pain, pain in extremity

Uncommon Neck pain, musculoskeletal stiffness,joint swelling, muscle spasms,musculoskeletal chest pain,musculoskeletal pain, joint stiffness,arthritis, muscular weakness

Rare Atypical subtrochanteric and diaphysealfemoral fractures† (bisphosphonate classadverse reaction)

Very rare Osteonecrosis of the external auditorycanal (bisphosphonate class adversereaction)

Not known** Osteonecrosis of the jaw (seesections 4.4 and 4.8 Class effects)

Renal and urinary disorders Uncommon Blood creatinine increased, pollakiuria,proteinuria

Not known** Renal impairment. Rare cases of renalfailure requiring dialysis and rare caseswith a fatal outcome have been reportedin patients with pre-existing renaldysfunction or other risk factors such asadvanced age, concomitant nephrotoxicmedicinal products, concomitant diuretictherapy, or dehydration in the postinfusion period (see sections 4.4 and 4.8

Class effects)

General disorders and administration Very common Pyrexiasite conditions Common Influenza-like illness, chills, fatigue,asthenia, pain, malaise, infusion sitereaction

Uncommon Peripheral oedema, thirst, acute phasereaction, non-cardiac chest pain

Not known** Dehydration secondary to acute phasereactions (post-dose symptoms such aspyrexia, 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.† Identified in post-marketing experience.

Atrial fibrillation

In the HORIZON - Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrialfibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving Aclasta andplacebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patientsreceiving Aclasta (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In theosteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillationincidences were comparable between Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation seriousadverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.

Zoledronic acid has been associated with renal impairment manifested as deterioration in renalfunction (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment hasbeen observed following the administration of zoledronic acid, especially in patients with pre-existingrenal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy,concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), withthe majority of them receiving a 4 mg dose every 3-4 weeks, but it has been observed in patients aftera 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 Aclasta and placebotreatment groups over three years. There was a transient increase in serum creatinine observed within10 days in 1.8% of Aclasta-treated patients versus 0.8% of placebo-treated patients.

In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calciumlevels (less than 1.87 mmol/l) following Aclasta administration. No symptomatic cases ofhypocalcaemia were observed.

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

Based on laboratory assessment, transient asymptomatic calcium levels below the normal referencerange (less than 2.10 mmol/l) occurred in 2.3% of Aclasta-treated patients in a large clinical trialcompared to 21% of Aclasta-treated patients in the Paget’s disease trials. The frequency ofhypocalcaemia was much lower following subsequent infusions.

All patients received adequate supplementation with vitamin D and calcium in the post-menopausalosteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s diseasetrials (see also section 4.2). In the trial for the prevention of clinical fractures following a recent hipfracture, vitamin D levels were not routinely measured but the majority of patients received a loadingdose of vitamin D prior to Aclasta 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, werereported (0.7%) following the administration of zoledronic acid.

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated withmedicinal products that inhibit bone resorption, including zoledronic acid (see section 4.4). In a largeclinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with

Aclasta and one patient treated with placebo. Cases of ONJ have been reported in the post-marketingsetting for Aclasta.

Acute phase reactions

The overall percentage of patients who reported acute phase reactions or post-dose symptoms(including serious cases) after Aclasta administration is as follows (frequencies derived from the studyin treatment of post-menopausal osteoporosis): fever (18.1%), myalgia (9.4%), flu-like symptoms(7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occurred within the first 3 daysfollowing Aclasta administration. The majority of these symptoms were mild to moderate in natureand resolved within 3 days of the event onset. The incidence of these symptoms decreased withsubsequent annual doses of Aclasta. The percentage of patients who experienced adverse reactionswas 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 (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Clinical experience with acute overdose is limited. Patients who have received doses higher than thoserecommended should be carefully monitored. In the event of overdose leading to clinically significanthypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an intravenousinfusion of calcium gluconate.

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

M05BA08

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

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 pyrophosphatesynthase. The long duration of action of zoledronic acid is attributable to its high binding affinity forthe active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bonemineral.

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

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

The efficacy and safety of Aclasta 5 mg once a year for 3 consecutive years were demonstrated inpost-menopausal women (7,736 women aged 65-89 years) with either: a femoral neck bone mineraldensity (BMD) with a T-score ≤ -1.5 and at least two mild or one moderate existing vertebralfracture(s); or a femoral neck BMD T-score ≤ -2.5 with or without evidence of existing vertebralfracture(s). 85% of patients were bisphosphonate-naïve. Women who were evaluated for the incidenceof vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for womencontributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapyincluded: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded otherbisphosphonates. All women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU ofvitamin D supplements daily.

Effect on morphometric vertebral fractures

Aclasta significantly decreased the incidence of one or more new vertebral fractures over three yearsand as early as the one year timepoint (see Table 2).

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

Outcome Aclasta Placebo Absolute reduction in Relative reduction in(%) (%) fracture incidence % fracture incidence %(CI) (CI)

At least one new vertebral 1.5 3.7 2.2 (1.4, 3.1) 60 (43, 72)**fracture (0-1 year)

At least one new vertebral 2.2 7.7 5.5 (4.4, 6.6) 71 (62, 78)**fracture (0-2 year)

At least one new vertebral 3.3 10.9 7.6 (6.3, 9.0) 70 (62, 76)**fracture (0-3 year)

** p <0.0001

Aclasta-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebralfractures compared to placebo patients (p<0.0001).

Effect on hip fractures

Aclasta demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hipfractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for Aclasta-treated patientscompared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-naïvepatients 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 ofresults is presented in Table 3.

Table 3 Between treatment comparisons of the incidence of key clinical fracture variablesover 3 years

Outcome Aclasta Placebo Absolute Relative risk(N=3,875) (N=3,861) reduction in reduction inevent rate event rate fracture event rate fracture(%) (%) % incidence %(CI) (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)*

*p-value <0.001, **p-value <0.0001(1) Excluding finger, toe and facial fractures(2) Including clinical thoracic and clinical lumbar vertebral fractures

Effect on bone mineral density (BMD)

Aclasta significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatmentwith placebo at all timepoints (6, 12, 24 and 36 months). Treatment with Aclasta 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 thedistal 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 in152 post-menopausal patients with osteoporosis treated with Aclasta (N=82) or placebo (N=70).

Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with

Aclasta, no osteomalacia, marrow fibrosis or woven bone formation was detected. Tetracycline labelwas detectable in all but one of 82 biopsies obtained from patients on Aclasta. Microcomputedtomography (μCT) analysis demonstrated increased trabecular bone volume and preservation oftrabecular bone architecture in patients treated with Aclasta 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 patientsat periodic intervals throughout the study. Treatment with a 5 mg annual dose of Aclasta significantlyreduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baselinelevels at 36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months andwas 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 endof 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

Aclasta 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

Aclasta significantly reduced the mean days of limited activity and the days of bed rest due to backpain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the meandays of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectivelycompared to placebo (all p<0.01).

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

The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluatedin 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 treatment (Aclasta).

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. Aclasta was administered once a year,until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levelswere not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or byintramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participantsreceived 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementationper day. Ninety-five percent of the patients received their infusion two or more weeks after the hipfracture repair and the median timing of infusion was approximately six weeks after the hip fracturerepair. The primary efficacy variable was the incidence of clinical fractures over the duration of thestudy.

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 Aclasta Placebo Absolute Relative risk(N=1,065) (N=1,062) reduction in reduction inevent rate event rate fracture event fracture incidence(%) (%) rate % % (CI)(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 seentowards reduction in new hip fractures.

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

The incidence of delayed hip fracture healing was comparable between Aclasta (34 [3.2%]) andplacebo (29 [2.7%]).

Effect on bone mineral density (BMD)

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

Clinical efficacy in men

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

In another study in men (study CZOL446M2308) an annual infusion of Aclasta was non-inferior toweekly 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 Aclasta in the treatment and prevention of osteoporosis associated withlong-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 men56.4 years; for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patientswere stratified with respect to duration of glucocorticoid use prior to randomisation (≤ 3 monthsversus > 3 months). The duration of the trial was one year. Patients were randomised to either Aclasta5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mgelemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy wasdemonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentagechange in lumbar spine BMD at 12 months relative to baseline in the treatment and preventionsubpopulations, respectively. The majority of patients continued to receive glucocorticoids for the oneyear duration of the trial.

Effect on bone mineral density (BMD)

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

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

Aclasta 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 ofthe age-specific normal reference range at the time of study entry) confirmed by radiographicevidence.

The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for2 months was demonstrated in two 6-month comparative trials. After 6 months, Aclasta showed 96%(169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation ratescompared 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 tobaseline were observed over 6 months for Aclasta and risedronate.

Patients who were classified as responders at the end of the 6 month core study were eligible to enteran extended follow-up period. Of the 153 Aclasta-treated patients and 115 risedronate-treated patientswho entered an extended observation study, after a mean duration of follow-up of 3.8 years from timeof dosing, the proportion of patients ending the Extended Observation Period due to the need forre-treatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%) compared withzoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period dueto 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 Aclasta and laterexperienced disease relapse during the extended follow-up period were re-treated with Aclasta after amean time of 6.5 years from initial treatment to re-treatment. Five of the 6 patients had SAP within thenormal 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 mgzoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impairedbone remodelling and no evidence of mineralisation defects. These results were consistent withbiochemical marker evidence of normalisation of bone turnover.

A randomised, double-blind, placebo-controlled study was conducted in paediatric patients aged 5 to17 years treated with glucocorticoids who had decreased bone mineral density (lumbar spine BMD Z-score of -0.5 or less) and a low impact/fragility fracture. The patient population randomised in thisstudy (ITT population) included patients with several sub-types of rheumatic conditions, inflammatorybowel disease, or Duchenne muscular dystrophy. The study was planned to include 92 patients,however only 34 patients were enrolled and randomised to receive either a twice-yearly 0.05 mg/kg(max. 5 mg) intravenous zoledronic acid infusion or placebo for one year. All patients were required toreceive background therapy of vitamin D and calcium.

Zoledronic acid infusion resulted in an increase in the lumbar spine BMD Z-score least square (LS)mean difference of 0.41 at month 12 relative to baseline compared to placebo (95% CI: 0.02, 0.81;18 and 16 patients, respectively). No effect on lumbar spine BMD Z-score was evident after 6 monthsof treatment. At month 12, a statistically significant (p<0.05) reduction in three bone turnover markers(P1NP, BSAP, NTX) was observed in the zoledronic acid group as compared to the placebo group. Nostatistically significant differences in total body bone mineral content were observed between patientstreated with zoledronic acid versus placebo at 6 or 12 months. There is no clear evidence establishinga link between BMD changes and fracture prevention in children with growing skeletons.

No new vertebral fractures were observed in the zoledronic acid group as compared to two newfractures in the placebo group.

The most commonly reported adverse reactions after infusion of zoledronic acid were arthralgia(28%), pyrexia (22%), vomiting (22%), headache (22%), nausea (17%), myalgia (17%), pain (17%),diarrhoea (11%) and hypocalcaemia (11%).

More patients reported serious adverse events in the zoledronic acid group than in the placebo group(5 [27.8%] patients versus 1 [6.3%] patient).

In the 12-month open-label extension of the above-mentioned core study, no new clinical fractureswere observed. However 2 patients, one in each of the core study treatment groups (zoledronic acidgroup: 1/9, 11.1% and placebo group: 1/14, 7.1%), had new morphometric vertebral fractures. Therewere no new safety findings.

Long-term safety data in this population cannot be established from these studies.

The European Medicines Agency has waived the obligation to submit the results of studies with

Aclasta in all subsets of the paediatric population in Paget’s disease of the bone, osteoporosis inpost-menopausal women at an increased risk of fracture, osteoporosis in men at increased risk offracture and prevention of clinical fractures after a hip fracture in men and women (see section 4.2 forinformation on paediatric use).

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

After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increasedrapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% ofpeak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very lowconcentrations not exceeding 0.1% of peak levels.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasicdisappearance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hours, followed bya long elimination phase with a terminal elimination half-life of t½γ 146 hours. There was noaccumulation of the active substance in plasma after multiple doses given every 28 days. The earlydisposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone andexcretion 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 boundto bone tissue. This uptake into bone is common for all bisphosphonates and is presumably aconsequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retentiontime of zoledronic acid in bones is very long. From the bone tissue it is released very slowly back intothe 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-subjectvariation 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 acidconcentration at the end of the infusion, but had no effect on the area under the plasma concentrationversus time curve.

No interaction studies with other medicinal products have been performed with zoledronic acid. Sincezoledronic acid is not metabolised in humans and the substance was found to have little or no capacityas a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronicacid is unlikely to reduce the metabolic clearance of substances which are metabolised via thecytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins(approximately 43-55% bound) and binding is concentration independent. Therefore, interactionsresulting from displacement of highly protein-bound medicinal products are unlikely.

Special populations (see section 4.2)

The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearancerepresenting 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22to 143 ml/min) in the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30% to40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lackof accumulation of drug with multiple doses irrespective of renal function, suggest that doseadjustments of zoledronic acid in mild (Clcr = 50-80 ml/min) and moderate renal impairment down toa creatinine clearance of 35 ml/min are not necessary. The use of Aclasta in patients with severe renalimpairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renalfailure in this population.

Acute toxicity

The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg inrats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeuticexposure 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 whengiven 0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose thatcorresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minuteinfusions of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to7 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 dailywas well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg inrats and dogs, respectively, when given for 52 weeks.

Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximumintended human exposure produced toxicological effects in other organs, including the gastrointestinaltract and liver, and at the site of intravenous administration. The clinical relevance of these findings isunknown. The most frequent finding in the repeat-dose studies consisted of increased primaryspongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding thatreflected 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 andskeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested inrats. No teratological or embryo/foetal effects were observed in rabbits, although maternal toxicity wasmarked 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 didnot provide any evidence of carcinogenic potential.

Mannitol

Sodium citrate

Water for injections

This medicinal product must not be allowed to come into contact with any calcium-containingsolutions. Aclasta must not be mixed or given intravenously with any other medicinal products.

Unopened bottle: 3 years

After opening: 24 hours at 2°C - 8°C

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

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

100 ml solution in a transparent plastic (cycloolefinic polymer) bottle closed with a fluoro-polymercoated bromobutyl rubber stopper and an aluminium/polypropylene cap with a flip component.

Aclasta is supplied in packs containing one bottle as unit pack, or in multipacks comprising five packs,each containing one bottle.

Not all pack sizes may be marketed.

For single use only.

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.

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

Sandoz Pharmaceuticals d.d.

Verovškova ulica 571000 Ljubljana

Slovenia

EU/1/05/308/001

EU/1/05/308/002

Date of first authorisation: 15 April 2005

Date of latest renewal: 19 January 2015

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu