Aclasta
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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Aclasta 5 mg solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

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. 

 

 

3. PHARMACEUTICAL FORM 
 

Solution for infusion 

 

Clear and colourless solution. 

 

 

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. 

 

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

 

4.2 Posology and method of administration 
 

Posology 

 

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important 

for the elderly (≥65 years)and for patients receiving diuretic therapy. 

 

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

Aclasta on an individual patient basis, particularly after 5 or more years of use. 

 

  



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In patients with a recent low-trauma hip fracture, it is recommended to give the Aclasta 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 Aclasta infusion. 

 

Paget’s disease 

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

 

Re-treatment of Paget’s disease: After initial treatment with Aclasta in Paget’s disease, an extended 

remission period is observed in responding patients. Re-treatment consists of an additional intravenous 

infusion of 5 mg Aclasta 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 

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. 

 

Patients with hepatic impairment 

No dose adjustment is required (see section 5.2). 

 

Elderly (≥ 65 years) 

No dose adjustment is necessary since bioavailability, distribution and elimination were similar in 

elderly patients and younger subjects. 

 

Paediatric population 

Aclasta should not be used in children and adolescents below 18 years of age. There are no data 

available for children under 5 years of age. Currently available data for children aged 5 to 17 years are 

described in section 5.1. 

 

Method of administration 

 

Intravenous use. 

Aclasta is administered via a vented infusion line and given slowly at a constant infusion rate. The 

infusion time must not be less than 15 minutes. For information on the infusion of Aclasta, see 

section 6.6. 

 

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

 

4.3 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). 
 



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4.4 Special warnings and precautions for use 
 

Renal function 

 

The use of Aclasta 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 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), or 

dehydration occurring after Aclasta 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 Aclasta 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. 

 Aclasta 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 Aclasta. 

 A single dose of Aclasta 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 Aclasta (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 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 calcium 

corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days 

following Aclasta 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 Aclasta 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) 

 

ONJ has been reported in the post-marketing setting in patients receiving Aclasta (zoledronic acid) for 

osteoporosis (see section 4.8). 

 

  



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The start of treatment or of a new course of treatment should be delayed in patients with unhealed 

open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual 

benefit-risk assessment is recommended prior to treatment with Aclasta in patients with concomitant 

risk factors. 

 

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

- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent 

compounds), route of administration (higher risk for parenteral administration) and cumulative 

dose of bone resorption therapy. 

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

- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to 

head and neck. 

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, 

invasive dental procedures, e.g. tooth extractions. 

 

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, 

and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of 

sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental 

procedures should be performed with caution and avoided in close proximity to zoledronic acid 

treatment. 

 

The management plan for patients who develop ONJ should be set up in close collaboration between 

the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of 

zoledronic acid treatment should be considered until the condition resolves and contributing risk 

factors are mitigated where possible. 

 

Osteonecrosis of the external auditory canal 

 

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in 

association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory 

canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The 

possibility of osteonecrosis of the external auditory canal should be considered in patients receiving 

bisphosphonates who present with ear symptoms including chronic ear infections. 

 

Atypical fractures of the femur 

 

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate 

therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short 

oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just 

above the supracondylar flare. These fractures occur after minimal or no trauma and some patients 

experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to 

months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the 

contralateral femur should be examined in bisphosphonate-treated patients who have sustained a 

femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of 

bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered 

pending evaluation of the patient, based on an individual benefit risk assessment. 

 

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and 

any patient presenting with such symptoms should be evaluated for an incomplete femur fracture. 

 

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 days 

following Aclasta administration. 

  



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APRs may sometimes be serious or prolonged in duration. The incidence of post-dose symptoms can 

be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta 

administration. It is also advisable to postpone treatment if the patient is clinically unstable due to an 

acute medical condition and an APR could be problematic (see section 4.8). 

 

General 

 

Other products containing zoledronic acid as an active substance are available for oncology 

indications. Patients being treated with Aclasta should not be treated with such products or any other 

bisphosphonate 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”. 

 

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 medicinal products 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 
 

Women of childbearing potential 

 

Aclasta is not recommended in women of childbearing potential. 

 

Pregnancy 

 

Aclasta 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 

 

Aclasta is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic 

acid is excreted into human milk. 

 

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 Aclasta on fertility in humans. 

 



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4.7 Effects on ability to drive and use machines 
 

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

 

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: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), 

arthralgia (4.8%) and headache (5.1%), see “acute phase reactions” below. 

 

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 bronchospasm, urticaria and 

angioedema, and very rare cases of 

anaphylactic 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 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, gastro-oesophageal 

reflux disease, constipation, dry mouth, 

oesophagitis, toothache, gastritis# 

  



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

Musculoskeletal and connective tissue 

disorders 

Common Myalgia, arthralgia, bone pain, back 

pain, pain in extremity 

 Uncommon Neck pain, musculoskeletal stiffness, 

joint swelling, muscle spasms, 

musculoskeletal chest pain, 

musculoskeletal pain, joint stiffness, 

arthritis, muscular weakness 

 Rare Atypical subtrochanteric and diaphyseal 

femoral fractures† (bisphosphonate class 

adverse reaction) 

 Very rare Osteonecrosis of the external auditory 

canal (bisphosphonate class adverse 

reaction) 

 Not known** Osteonecrosis of the jaw (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 Pyrexia 

Common Influenza-like illness, chills, fatigue, 

asthenia, pain, malaise, infusion site 

reaction 

 Uncommon Peripheral oedema, thirst, acute phase 

reaction, non-cardiac chest pain 

 Not known** Dehydration secondary to acute phase 

reactions (post-dose symptoms such as 
pyrexia, 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. 

 

Description of selected adverse reactions 

 

Atrial fibrillation 

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 Aclasta and 

placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients 

receiving Aclasta (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 Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation serious 

adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo. 

 



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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 Aclasta and placebo 

treatment groups over three years. There was a transient increase in serum creatinine observed within 

10 days in 1.8% of Aclasta-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 Aclasta 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 Aclasta-treated patients in a large clinical trial 

compared to 21% of Aclasta-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 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, were 

reported (0.7%) following the administration of zoledronic acid. 

 

Osteonecrosis of the jaw 

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with 

medicinal products that inhibit bone resorption, including zoledronic acid (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 

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

setting 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 study 

in 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 days 

following Aclasta administration. The majority of these symptoms were mild to moderate in nature 

and resolved within 3 days of the event onset. The incidence of these symptoms decreased with 

subsequent annual doses of Aclasta. 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 (see section 4.4). 

 



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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 national reporting system 

listed in Appendix V. 

 

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. PHARMACOLOGICAL PROPERTIES 
 

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. 

 

Aclasta 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 Aclasta 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-naïve. 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 

Aclasta 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). 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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

 

Outcome Aclasta 

(%) 

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 

 

Aclasta-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 

Aclasta 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 Aclasta-treated patients 

compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-naïve 

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 Aclasta 

(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)* 

*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 treatment 

with 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 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 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 label 

was detectable in all but one of 82 biopsies obtained from patients on Aclasta. Microcomputed 

tomography (μCT) analysis demonstrated increased trabecular bone volume and preservation of 

trabecular bone architecture in patients treated with Aclasta compared to placebo. 

 



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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 Aclasta 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 

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 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 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 levels 

were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or by 

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 Aclasta 

(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 

 

  



13 

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 Aclasta-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 Aclasta (34 [3.2%]) and 

placebo (29 [2.7%]). 

 

Effect on bone mineral density (BMD) 

In the HORIZON-RFT study Aclasta treatment significantly increased BMD at the total hip and 

femoral neck relative to treatment with placebo at all timepoints. Treatment with Aclasta 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 Aclasta 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 Aclasta versus 8.7% 

for placebo. 

 

In another study in men (study CZOL446M2308) an annual infusion of Aclasta 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 Aclasta 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 Aclasta 

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 non-inferiority 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 Aclasta-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, Aclasta 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, Aclasta 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 Aclasta-treated patients versus 7 for 

risedronate-treated patients (p=0.8055). 

 

  



14 

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 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, Aclasta 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 Aclasta 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 Aclasta-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 

re-treatment (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 Aclasta and later 

experienced disease relapse during the extended follow-up period were re-treated with Aclasta after a 

mean time of 6.5 years from initial treatment to re-treatment. Five 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. 

 

Paediatric population 

 

A randomised, double-blind, placebo-controlled study was conducted in paediatric patients aged 5 to 

17 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 this 

study (ITT population) included patients with several sub-types of rheumatic conditions, inflammatory 

bowel 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 to 

receive 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 months 

of 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. No 

statistically significant differences in total body bone mineral content were observed between patients 

treated with zoledronic acid versus placebo at 6 or 12 months. There is no clear evidence establishing 

a 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 new 

fractures in the placebo group. 

 



15 

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 fractures 

were observed. However 2 patients, one in each of the core study treatment groups (zoledronic acid 

group: 1/9, 11.1% and placebo group: 1/14, 7.1%), had new morphometric vertebral fractures. There 

were 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 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 t½ 0.24 and t½ 1.87 hours, followed by 

a long elimination phase with a terminal elimination half-life of t½ 146 hours. There was no 

accumulation of the active substance in plasma after multiple doses given every 28 days. The early 

disposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone and 

excretion via the kidneys. 

 

Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 

39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound 

to bone tissue. 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. 

 

  



16 

Pharmacokinetic/pharmacodynamic relationships 

 

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 medicinal products 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 (Clcr = 50–80 ml/min) and moderate renal impairment down to 

a creatinine clearance of 35 ml/min are not necessary. The use of Aclasta 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. 

 



17 

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 

Sodium citrate 

Water for injections 

 

6.2 Incompatibilities 
 

This medicinal product must not be allowed to come into contact with any calcium-containing 

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

 

6.3 Shelf life 
 

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 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 
 

This medicinal product does not require any special storage conditions. 

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

 

6.5 Nature and contents of container 
 

100 ml solution in a transparent plastic (cycloolefinic polymer) bottle closed with a fluoro-polymer 

coated 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. 

 

6.6 Special precautions for disposal and other handling 

 

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 local 

requirements. 

 

 



18 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/308/001 

EU/1/05/308/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 15 April 2005 

Date of latest renewal: 19 January 2015 

 

 

10. DATE OF REVISION OF THE TEXT 
 

 

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

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

 

  

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


19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 



20 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 Additional risk minimisation measures 
 

The MAH shall ensure that the educational programme implemented for the authorised indications of 

treatment of osteoporosis in post-menopausal women and in men at increased risk of fracture, 

including those with a recent low-trauma hip fracture, and treatment of osteoporosis associated with 

long-term systemic glucocorticoid therapy in post-menopausal women and in men at increased risk of 

fracture is updated. The educational programme contains the following: 

 Physician educational material 

 Patient information pack 
 

  



21 

The physician educational material should contain the following key elements: 

 The Summary of Product Characteristics 

 Reminder card with the following key messages: 
o Need to calculate creatinine clearance based on actual body weight using the 

Cockcroft-Gault formula before each treatment with Aclasta 

o Contraindication in patients with creatinine clearance < 35 ml/min 
o Contraindication in pregnancy and in breast-feeding women due to potential 

teratogenicity 

o Need to ensure appropriate hydration of the patient especially those at an advanced 
age and those receiving diuretic therapy 

o Need to infuse Aclasta slowly over a period of no less than 15 minutes 
o Once-yearly dosing regime 
o Adequate calcium and vitamin D intake are recommended in association with Aclasta 

administration 

o Need for appropriate physical activity, non-smoking and healthy diet 

 Patient information pack 
 

The patient information pack should be provided and contain the following key messages: 

 Contraindication in patients with severe kidney problems 

 Contraindication in pregnancy and in breast-feeding women 

 Need for adequate calcium and vitamin D supplementation, appropriate physical activity, 
non-smoking and healthy diet 

 Key signs and symptoms of serious adverse reactions 

 When to seek attention from the health care provider 
 

In addition, the following documents should be included in the patient information pack: 

 Package leaflet 

 Patient reminder card on osteonecrosis of the jaw 
 

  



22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 
  



23 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



24 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON (WITH BLUE BOX) FOR UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aclasta 5 mg solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

Mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

1 bottle of 100 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

After opening: 24 hours at 2°C - 8°C. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



25 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/308/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



26 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aclasta 5 mg solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

1 bottle contains 5 mg zoledronic acid (as monohydrate). 

 

 

3. LIST OF EXCIPIENTS 

 

Mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

100 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

After opening: 24 hours at 2°C - 8°C. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



27 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/308/001 Unit pack 

EU/1/05/308/002 Multipack 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including braille accepted. 

 

  



28 

 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 

CARTON FOR INTERMEDIATE PACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aclasta 5 mg solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

Mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

1 bottle of 100 ml 

Component of a multipack. Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

After opening: 24 hours at 2°C - 8°C. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



29 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/308/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 

  



30 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

PARTICULARS TO APPEAR ON THE OUTER CARTON OF MULTIPACK (INCLUDING 

BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aclasta 5 mg solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

Mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

Multipack: 5 bottles, each bottle of 100 ml. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

After opening: 24 hours at 2°C - 8°C. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



31 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/308/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



32 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



33 

Package leaflet: Information for the user 

 

Aclasta 5 mg solution for infusion 

zoledronic acid 

 

Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Aclasta is and what it is used for 

2. What you need to know before you are given Aclasta 

3. How Aclasta is given 

4. Possible side effects 

5. How to store Aclasta 

6. Contents of the pack and other information 

 

 

1. What Aclasta is and what it is used for 

 

Aclasta contains the active substance zoledronic acid. It belongs to a group of medicines called 

bisphosphonates and is used to treat post-menopausal women and adult men with osteoporosis or 

osteoporosis caused by treatment with corticosteroids used to treat inflammation, and Paget’s disease 

of the bone in adults. 

 

Osteoporosis 

Osteoporosis is a disease that involves the thinning and weakening of the bones and is common in 

women after the menopause, but can also occur in men. At the menopause, a woman’s ovaries stop 

producing the female hormone oestrogen, which helps keep bones healthy. Following the menopause 

bone loss occurs, bones become weaker and break more easily. Osteoporosis could also occur in men 

and women because of the long term use of steroids, which can affect the strength of bones. Many 

patients with osteoporosis have no symptoms but they are still at risk of breaking bones because 

osteoporosis has made their bones weaker. Decreased circulating levels of sex hormones, mainly 

oestrogens converted from androgens, also play a role in the more gradual bone loss observed in men. 

In both women and men, Aclasta strengthens the bone and therefore makes it less likely to break. 

Aclasta is also used in patients who have recently broken their hip in a minor trauma such as a fall and 

therefore are at risk of subsequent bone breaks. 

 

Paget’s disease of the bone 

It is normal that old bone is removed and is replaced with new bone material. This process is called 

remodelling. In Paget’s disease, bone remodelling is too rapid and new bone is formed in a disordered 

fashion, which makes it weaker than normal. If the disease is not treated, bones may become deformed 

and painful, and may break. Aclasta works by returning the bone remodelling process to normal, 

securing formation of normal bone, thus restoring strength to the bone. 

 

 

2. What you need to know before you are given Aclasta 

 

Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given 

Aclasta. 

 

  



34 

You must not be given Aclasta: 

- if you are allergic to zoledronic acid, other bisphosphonates or any of the other ingredients of 
this medicine (listed in section 6). 

- if you have hypocalcaemia (this means that the levels of calcium in your blood are too low). 
- if you have severe kidney problems. 
- if you are pregnant. 
- if you are breast-feeding. 
 

Warnings and precautions 

Talk to your doctor before you are given Aclasta: 

- if you are being treated with any medicine containing zoledronic acid, which is also the active 

substance of Aclasta (zoledronic acid is used in adult patients with certain types of cancer to 

prevent bone complications or to reduce the amount of calcium). 

- if you have a kidney problem, or used to have one. 
- if you are unable to take daily calcium supplements. 
- if you have had some or all of the parathyroid glands in your neck surgically removed. 
- if you have had sections of your intestine removed. 
 

A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported in the 

post-marketing setting in patients receiving Aclasta (zoledronic acid) for osteoporosis. ONJ can also 

occur after stopping treatment. 

 

It is important to try and prevent ONJ developing as it is a painful condition that can be difficult to 

treat. In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions 

you should take. 

 

Before receiving Aclasta treatment, tell your doctor, pharmacist or nurse if 

- you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 
planned tooth extraction; 

- you do not receive routine dental care or have not had a dental check-up for a long time; 
- you are a smoker (as this may increase the risk of dental problems); 
- you have previously been treated with a bisphosphonate (used to treat or prevent bone 

disorders); 

- you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
- you have cancer. 
 

Your doctor may ask you to undergo a dental examination before you start treatment with Aclasta. 

 

While being treated with Aclasta, you should maintain good oral hygiene (including regular teeth 

brushing) and receive routine dental check-ups. If you wear dentures you should make sure these fit 

properly. If you are under dental treatment or are due to undergo dental surgery (e.g. tooth 

extractions), inform your doctor about your dental treatment and tell your dentist that you are being 

treated with Aclasta. Contact your doctor and dentist immediately if you experience any problems 

with your mouth or teeth such as loose teeth, pain or swelling, or non-healing of sores or discharge, as 

these could be signs of osteonecrosis of the jaw. 

 

Monitoring test 

Your doctor should do a blood test to check your kidney function (levels of creatinine) before each 

dose of Aclasta. It is important for you to drink at least 2 glasses of fluid (such as water), within a few 

hours before receiving Aclasta, as directed by your healthcare provider. 

 

Children and adolescents 

Aclasta is not recommended for anyone under 18 years of age. 

 

  



35 

Other medicines and Aclasta 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 

It is important for your doctor to know all the medicines you are taking, especially if you are taking 

any medicines known to be harmful to your kidneys (e.g. aminoglycosides) or diuretics (“waterpills”) 

that may cause dehydration. 

 

Pregnancy and breast-feeding 

You must not be given Aclasta if you are pregnant or breast-feeding, think you may be pregnant or are 

planning to have a baby. 

 

Ask your doctor, pharmacist or nurse for advice before taking this medicine. 

 

Driving and using machines 

If you feel dizzy while taking Aclasta, do not drive or use machines until you feel better. 

 

Aclasta contains sodium 

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

essentially “sodium free”. 

 

 

3. How Aclasta is given 
 

Follow carefully all instructions given to you by your doctor or nurse. Check with your doctor or nurse 

if you are not sure. 

 

Osteoporosis 
The usual dose is 5 mg given as one infusion per year into a vein by your doctor or nurse. The infusion 

will take at least 15 minutes. 

 

In case you recently broke your hip, it is recommended that Aclasta is administered two or more 

weeks after your hip repair surgery. 

 

It is important to take calcium and vitamin D supplements (for example tablets) as directed by your 

doctor. 

 

For osteoporosis, Aclasta works for one year. Your doctor will let you know when to return for your 

next dose. 

 

Paget’s disease 

For the treatment of Paget’s disease, Aclasta should be prescribed only by physicians with experience 

in the treatment of Paget’s disease of the bone. 

 

The usual dose is 5 mg, given to you as one initial infusion into a vein by your doctor or nurse. The 

infusion will take at least 15 minutes. Aclasta may work for longer than one year, and your doctor will 

let you know if you need to be treated again. 

 

Your doctor may advise you to take calcium and vitamin D supplements (e.g. tablets) for at least the 

first ten days after being given Aclasta. It is important that you follow this advice carefully so that the 

level of calcium in your blood does not become too low in the period after the infusion. Your doctor 

will inform you regarding the symptoms associated with hypocalcaemia. 

 

  



36 

Aclasta with food and drink 

Make sure you drink enough fluids (at least one or two glasses) before and after the treatment with 

Aclasta, as directed by your doctor. This will help to prevent dehydration. You may eat normally on 

the day you are treated with Aclasta. This is especially important in patients who take diuretics (“water 

pills”) and in elderly patients (age 65 years or over). 

 

If you missed a dose of Aclasta 

Contact your doctor or hospital as soon as possible to re-schedule your appointment. 

 

Before stopping Aclasta therapy 

If you are considering stopping Aclasta treatment, please go to your next appointment and discuss this 

with your doctor. Your doctor will advise you and decide how long you should be treated with 

Aclasta. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Side effects related to the first infusion are very common (occurring in more than 30% of patients) but 

are less common following subsequent infusions. The majority of the side effects, such as fever and 

chills, pain in the muscles or joints, and headache, occur within the first three days following the dose 

of Aclasta. The symptoms are usually mild to moderate and go away within three days. Your doctor 

can recommend a mild pain reliever such as ibuprofen or paracetamol to reduce these side effects. The 

chance of experiencing these side effects decreases with subsequent doses of Aclasta. 

 

Some side effects could be serious 

Common (may affect up to 1 in 10 people) 

Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving Aclasta for the treatment 

of postmenopausal osteoporosis. It is currently unclear whether Aclasta causes this irregular heart 

rhythm but you should report it to your doctor if you experience such symptoms after you have 

received Aclasta. 

 

Uncommon (may affect up to 1 in 100 people) 

Swelling, redness, pain and itching to the eyes or eye sensitivity to light. 

 

Very rare (may affect up to 1 in 10,000 people) 

Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These could 

be signs of bone damage in the ear. 

 

Not known (frequency cannot be estimated from the available data) 

Pain in the mouth and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness 

or a feeling of heaviness in the jaw, or loosening of a tooth; these could be signs of bone damage in the 

jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms while 

being treated with Aclasta or after stopping treatment. 

 

Kidney disorders (e.g. decreased urine output) may occur. Your doctor should do a blood test to check 

your kidney function before each dose of Aclasta. It is important for you to drink at least 2 glasses of 

fluid (such as water), within a few hours before receiving Aclasta, as directed by your healthcare 

provider. 

 

If you experience any of the above side effects, you should contact your doctor immediately. 

 



37 

Aclasta may also cause other side effects 

Very common (may affect more than 1 in 10 people) 

Fever 

 

Common (may affect up to 1 in 10 people) 

Headache, dizziness, sickness, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or 

joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain), 

chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, swelling and/or pain at 

the infusion site. 

 

In patients with Paget’s disease, symptoms due to low blood calcium, such as muscle spasms, or 

numbness, or a tingling sensation especially in the area around the mouth have been reported. 

 

Uncommon (may affect up to 1 in 100 people) 

Flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness, 

sleepiness which may include reduced alertness and awareness, tingling sensation or numbness, 

extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or 

inflammation with pain and redness, spinning sensation, increased blood pressure, flushing, cough, 

shortness of breath, upset stomach, abdominal pain, constipation, dry mouth, heartburn, skin rash, 

excessive sweating, itching, skin reddening, neck pain, stiffness in muscles, bones and/or joints, joint 

swelling, muscle spasms, shoulder pain, pain in your chest muscles and rib cage, joint inflammation, 

muscular weakness, abnormal kidney test results, abnormal frequent urination, swelling of hands, 

ankles or feet, thirst, toothache, taste disturbances. 

 

Rare (may affect up to 1 in 1,000 people) 

Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may 

occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or 

groin as this may be an early indication of a possible fracture of the thigh bone. Low levels of 

phosphate in the blood. 

 

Not known (frequency cannot be estimated from the available data) 

Severe allergic reactions including dizziness and difficulty breathing, swelling mainly of the face and 

throat, decreased blood pressure, dehydration secondary to acute phase reactions (post-dose symptoms 

such as fever, vomiting and diarrhoea). 

 

Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Aclasta 
 

Your doctor, pharmacist or nurse knows how to store Aclasta properly. 

 

- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP. 
- The unopened bottle does not require any special storage conditions. 
- After opening the bottle, the product should be used immediately in order to avoid microbial 

contamination. 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. Allow 

the refrigerated solution to reach room temperature before administration. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38 

6. Contents of the pack and other information 

 

What Aclasta contains 

- The active substance is zoledronic acid. Each bottle with 100 ml of solution contains 5 mg 
zoledronic acid (as monohydrate). 

One ml solution contains 0.05 mg zoledronic acid (as monohydrate). 

- The other ingredients are mannitol, sodium citrate and water for injections. 
 

What Aclasta looks like and contents of the pack 

Aclasta is a clear and colourless solution. It comes in 100 ml plastic bottles as a ready-to-use solution 

for infusion. It 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. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Sandoz A/S 

Tlf: +45 63 95 10 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 111 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Sandoz A/S 

Tlf: +45 63 95 10 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 



39 

España 

BEXAL FARMACÉUTICA, S.A. 

Tel: +34 900 456 856 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Sandoz 

Tél: +33 800 45 57 99 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Sandoz S.R.L. 

Tel: +40 21 40751 60 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Sandoz A/S 

Tel: +45 63 95 10 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 



40 

INFORMATION FOR THE HEALTHCARE PROFESSIONAL 

 

The following information is intended for healthcare professionals only (see section 3): 

 

How to prepare and administer Aclasta 

 

- Aclasta 5 mg solution for infusion is ready for use. 
 

For single use only. Any unused solution should be discarded. Only clear solution free from particles 

and discoloration should be used. Aclasta must not be mixed or given intravenously with any other 

medicinal product and must be given through a separate vented infusion line at a constant infusion 

rate. The infusion time must not be less than 15 minutes. Aclasta must not be allowed to come into 

contact with any calcium-containing solutions. If refrigerated, allow the refrigerated solution to reach 

room temperature before administration. Aseptic techniques must be followed during preparation of 

the infusion. The infusion must be conducted according to standard medical practice. 

 

How to store Aclasta 

 

- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP. 
- The unopened bottle does not require any special storage conditions. 
- After opening the bottle, the product should be used immediately in order to avoid microbial 

contamination. 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. Allow 

the refrigerated solution to reach room temperature before administration. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you are given aclasta', 'Section_Content': 'follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given aclasta. you must not be given aclasta: - if you are allergic to zoledronic acid, other bisphosphonates or any of the other ingredients of this medicine (listed in section 6). - if you have hypocalcaemia (this means that the levels of calcium in your blood are too low). - if you have severe kidney problems. - if you are pregnant. - if you are breast-feeding. warnings and precautions talk to your doctor before you are given aclasta: - if you are being treated with any medicine containing zoledronic acid, which is also the active substance of aclasta (zoledronic acid is used in adult patients with certain types of cancer to prevent bone complications or to reduce the amount of calcium). - if you have a kidney problem, or used to have one. - if you are unable to take daily calcium supplements. - if you have had some or all of the parathyroid glands in your neck surgically removed. - if you have had sections of your intestine removed. a side effect called osteonecrosis of the jaw (onj) (bone damage in the jaw) has been reported in the post-marketing setting in patients receiving aclasta (zoledronic acid) for osteoporosis. onj can also occur after stopping treatment. it is important to try and prevent onj developing as it is a painful condition that can be difficult to treat. in order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions you should take. before receiving aclasta treatment, tell your doctor, pharmacist or nurse if - you have any problems with your mouth or teeth such as poor dental health, gum disease, or a planned tooth extraction; - you do not receive routine dental care or have not had a dental check-up for a long time; - you are a smoker (as this may increase the risk of dental problems); - you have previously been treated with a bisphosphonate (used to treat or prevent bone disorders); - you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) - you have cancer. your doctor may ask you to undergo a dental examination before you start treatment with aclasta. while being treated with aclasta, you should maintain good oral hygiene (including regular teeth brushing) and receive routine dental check-ups. if you wear dentures you should make sure these fit properly. if you are under dental treatment or are due to undergo dental surgery (e.g. tooth extractions), inform your doctor about your dental treatment and tell your dentist that you are being treated with aclasta. contact your doctor and dentist immediately if you experience any problems with your mouth or teeth such as loose teeth, pain or swelling, or non-healing of sores or discharge, as these could be signs of osteonecrosis of the jaw. monitoring test your doctor should do a blood test to check your kidney function (levels of creatinine) before each dose of aclasta. it is important for you to drink at least 2 glasses of fluid (such as water), within a few hours before receiving aclasta, as directed by your healthcare provider. children and adolescents aclasta is not recommended for anyone under 18 years of age. other medicines and aclasta tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. it is important for your doctor to know all the medicines you are taking, especially if you are taking any medicines known to be harmful to your kidneys (e.g. aminoglycosides) or diuretics ("waterpills") that may cause dehydration. pregnancy and breast-feeding you must not be given aclasta if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. ask your doctor, pharmacist or nurse for advice before taking this medicine. driving and using machines if you feel dizzy while taking aclasta, do not drive or use machines until you feel better. aclasta contains sodium this medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial of aclasta, i.e., essentially "sodium free".', 'Entity_Recognition': [{'Text': 'aclasta', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 14, 'BeginOffset': 104, 'EndOffset': 111, 'Score': 0.6708016395568848, 'Text': 'aclasta', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 135, 'EndOffset': 142, 'Score': 0.6518496870994568, 'Text': 'aclasta', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 157, 'EndOffset': 165}, {'Id': 16, 'BeginOffset': 169, 'EndOffset': 184, 'Score': 0.9973451495170593, 'Text': 'zoledronic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'other bisphosphonates', 'Type': 'TREATMENT', 'BeginOffset': 186, 'EndOffset': 207}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 243, 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{'Title': '3. how aclasta is given', 'Section_Content': 'follow carefully all instructions given to you by your doctor or nurse. check with your doctor or nurse if you are not sure. osteoporosis the usual dose is 5 mg given as one infusion per year into a vein by your doctor or nurse. the infusion will take at least 15 minutes. in case you recently broke your hip, it is recommended that aclasta is administered two or more weeks after your hip repair surgery. it is important to take calcium and vitamin d supplements (for example tablets) as directed by your doctor. for osteoporosis, aclasta works for one year. your doctor will let you know when to return for your next dose. paget\'s disease for the treatment of paget\'s disease, aclasta should be prescribed only by physicians with experience in the treatment of paget\'s disease of the bone. the usual dose is 5 mg, given to you as one initial infusion into a vein by your doctor or nurse. the infusion will take at least 15 minutes. aclasta may work for longer than one year, and your doctor will let you know if you need to be treated again. your doctor may advise you to take calcium and vitamin d supplements (e.g. tablets) for at least the first ten days after being given aclasta. it is important that you follow this advice carefully so that the level of calcium in your blood does not become too low in the period after the infusion. your doctor will inform you regarding the symptoms associated with hypocalcaemia. aclasta with food and drink make sure you drink enough fluids (at least one or two glasses) before and after the treatment with aclasta, as directed by your doctor. this will help to prevent dehydration. you may eat normally on the day you are treated with aclasta. this is especially important in patients who take diuretics ("water pills") and in elderly patients (age 65 years or over). if you missed a dose of aclasta contact your doctor or hospital as soon as possible to re-schedule your appointment. before stopping aclasta therapy if you are considering stopping aclasta treatment, please go to your next appointment and discuss this with your doctor. your doctor will advise you and decide how long you should be treated with aclasta. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'aclasta', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 22, 'BeginOffset': 125, 'EndOffset': 137, 'Score': 0.9558750987052917, 'Text': 'osteoporosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9184126257896423}]}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 156, 'EndOffset': 157}, {'Id': 0, 'BeginOffset': 199, 'EndOffset': 203, 'Score': 0.7091251611709595, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the infusion', 'Type': 'TREATMENT', 'BeginOffset': 229, 'EndOffset': 241}, {'Text': '15', 'Type': 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. side effects related to the first infusion are very common (occurring in more than 30% of patients) but are less common following subsequent infusions. the majority of the side effects, such as fever and chills, pain in the muscles or joints, and headache, occur within the first three days following the dose of aclasta. the symptoms are usually mild to moderate and go away within three days. your doctor can recommend a mild pain reliever such as ibuprofen or paracetamol to reduce these side effects. the chance of experiencing these side effects decreases with subsequent doses of aclasta. some side effects could be serious common (may affect up to 1 in 10 people) irregular heart rhythm (atrial fibrillation) has been seen in patients receiving aclasta for the treatment of postmenopausal osteoporosis. it is currently unclear whether aclasta causes this irregular heart rhythm but you should report it to your doctor if you experience such symptoms after you have received aclasta. uncommon (may affect up to 1 in 100 people) swelling, redness, pain and itching to the eyes or eye sensitivity to light. very rare (may affect up to 1 in 10,000 people) talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. these could be signs of bone damage in the ear. not known (frequency cannot be estimated from the available data) pain in the mouth and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or loosening of a tooth; these could be signs of bone damage in the jaw (osteonecrosis). tell your doctor and dentist immediately if you experience such symptoms while being treated with aclasta or after stopping treatment. kidney disorders (e.g. decreased urine output) may occur. your doctor should do a blood test to check your kidney function before each dose of aclasta. it is important for you to drink at least 2 glasses of fluid (such as water), within a few hours before receiving aclasta, as directed by your healthcare provider. if you experience any of the above side effects, you should contact your doctor immediately. aclasta may also cause other side effects very common (may affect more than 1 in 10 people) fever common (may affect up to 1 in 10 people) headache, dizziness, sickness, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain), chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, swelling and/or pain at the infusion site. in patients with paget's disease, symptoms due to low blood calcium, such as muscle spasms, or numbness, or a tingling sensation especially in the area around the mouth have been reported. uncommon (may affect up to 1 in 100 people) flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness, sleepiness which may include reduced alertness and awareness, tingling sensation or numbness, extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or inflammation with pain and redness, spinning sensation, increased blood pressure, flushing, cough, shortness of breath, upset stomach, abdominal pain, constipation, dry mouth, heartburn, skin rash, excessive sweating, itching, skin reddening, neck pain, stiffness in muscles, bones and/or joints, joint swelling, muscle spasms, shoulder pain, pain in your chest muscles and rib cage, joint inflammation, muscular weakness, abnormal kidney test results, abnormal frequent urination, swelling of hands, ankles or feet, thirst, toothache, taste disturbances. rare (may affect up to 1 in 1,000 people) unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur rarely. contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or groin as this may be an early indication of a possible fracture of the thigh bone. low levels of phosphate in the blood. not known (frequency cannot be estimated from the available data) severe allergic reactions including dizziness and difficulty breathing, swelling mainly of the face and throat, decreased blood pressure, dehydration secondary to acute phase reactions (post-dose symptoms such as fever, vomiting and diarrhoea). reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'aclasta', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all 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{'Title': '5. how to store aclasta', 'Section_Content': 'your doctor, pharmacist or nurse knows how to store aclasta properly. - keep this medicine out of the sight and reach of children. - do not use this medicine after the expiry date which is stated on the carton and bottle after exp. - the unopened bottle does not require any special storage conditions. - after opening the bottle, the product should be used immediately in order to avoid microbial contamination. 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 8. allow the refrigerated solution to reach room temperature before administration.', 'Entity_Recognition': [{'Text': 'aclasta', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 144, 'EndOffset': 157}, {'Text': 'opening the bottle', 'Type': 'TREATMENT', 'BeginOffset': 311, 'EndOffset': 329}, {'Text': 'the product', 'Type': 'TREATMENT', 'BeginOffset': 331, 'EndOffset': 342}, {'Text': 'microbial contamination', 'Type': 'PROBLEM', 'BeginOffset': 388, 'EndOffset': 411}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 560, 'EndOffset': 562}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 572, 'EndOffset': 573}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 574, 'EndOffset': 576}, {'Text': 'the refrigerated solution', 'Type': 'TREATMENT', 'BeginOffset': 583, 'EndOffset': 608}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what aclasta contains - the active substance is zoledronic acid. each bottle with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate). one ml solution contains 0.05 mg zoledronic acid (as monohydrate). - the other ingredients are mannitol, sodium citrate and water for injections. what aclasta looks like and contents of the pack aclasta is a clear and colourless solution. it comes in 100 ml plastic bottles as a ready-to-use solution for infusion. it 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.', 'Entity_Recognition': [{'Text': 'aclasta', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 48, 'EndOffset': 63, 'Score': 0.9983807802200317, 'Text': 'zoledronic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.975894570350647, 'RelationshipScore': 0.9903648495674133, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 82, 'EndOffset': 88, 'Text': '100 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9717098474502563, 'RelationshipScore': 0.994426965713501, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 92, 'EndOffset': 100, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 82, 'EndOffset': 85}, {'Text': '5 mg zoledronic acid (as monohydrate)', 'Type': 'TREATMENT', 'BeginOffset': 110, 'EndOffset': 147}, {'Text': '0.05 mg zoledronic acid (as monohydrate)', 'Type': 'TREATMENT', 'BeginOffset': 174, 'EndOffset': 214}, {'Id': 11, 'BeginOffset': 244, 'EndOffset': 252, 'Score': 0.9023212194442749, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.4399571418762207, 'RelationshipScore': 0.9795292019844055, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 13, 'BeginOffset': 283, 'EndOffset': 293, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 12, 'BeginOffset': 254, 'EndOffset': 268, 'Score': 0.9993306398391724, 'Text': 'sodium citrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.4399571418762207, 'RelationshipScore': 0.9999905824661255, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 13, 'BeginOffset': 283, 'EndOffset': 293, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 283, 'EndOffset': 293}, {'Text': 'the pack aclasta', 'Type': 'TREATMENT', 'BeginOffset': 335, 'EndOffset': 351}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 400, 'EndOffset': 403}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 454, 'EndOffset': 462}]}