Zoledronic acid Teva Generics

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion in bottles 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each bottle 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 zoledronic acid. This is especially 
important for the elderly and for patients receiving diuretic therapy. 
 
Adequate calcium and vitamin D intake are recommended in association with zoledronic acid administration. 
 
Osteoporosis 
For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis 
associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous 
infusion of 5 mg zoledronic acid administered once a year. 
 
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for 
continued treatment should be re-evaluated periodically based on the benefits and potential risks of 
zoledronic acid on an individual patient basis, particularly after 5 or more years of use. 
 
In patients with a recent low-trauma hip fracture, it is recommended to give the zoledronic acid infusion at 
least two weeks after hip fracture repair (see section 5.1). In patients with a recent low-trauma hip fracture, a 

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loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is 
recommended prior to the first zoledronic acid infusion. 
 
Paget’s disease 
For the treatment of Paget’s disease, zoledronic acid should be prescribed only by physicians with 
experience in the treatment of Paget’s disease of the bone. The recommended dose is a single intravenous 
infusion of 5 mg zoledronic acid. In patients with Paget’s disease, it is strongly advised that adequate 
supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 
10 days following zoledronic acid administration (see section 4.4). 
 
Re-treatment of Paget’s disease: After initial treatment with zoledronic acid in Paget’s disease an extended 
remission period is observed in responding patients. Re-treatment consists of an additional intravenous 
infusion of 5 mg zoledronic acid after an interval of one year or longer from initial treatment in patients who 
have relapsed. Limited data on re-treatment of Paget’s disease are available (see section 5.1). 
 
Special populations 
Patients with renal impairment 
Zoledronic acid is contraindicated in patients with creatinine clearance < 35 ml/min (see 
sections 4.3 and 4.4). 
 
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min. 
 
Patients with hepatic impairment  
No dose adjustment is required (see section 5.2). 
 
Older people (≥ 65 years)  
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly 
patients and younger subjects. 
 
Paediatric population  
The safety and efficacy of zoledronic acid in children and adolescents below 18 years of age have not been 
established. No data are available. 
 
Method of administration  
Intravenous use.  
Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and 
given at a constant infusion rate. The infusion time must not be less than 15 minutes.  For information on the 
infusion of zoledronic acid, see section 6.6. 
 
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). 
 
4.4 Special warnings and precautions for use 
 
Renal function 
The use of zoledronic acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is 
contraindicated due to an increased risk of renal failure in this population. 
 

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Renal impairment has been observed following the administration of zoledronic acid (see section 4.8), 
especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant 
nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring 
after zoledronic acid administration. Renal impairment has been observed in patients after a single 
administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with 
underlying renal impairment or with any of the risk factors described above. 
 
The following precautions should be taken into account to minimise the risk of renal adverse reactions:  
• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault 

formula before each zoledronic acid dose. 
• Transient increase in serum creatinine may be greater in patients with underlying impaired renal 

function. 
• Monitoring of serum creatinine should be considered in at-risk patients. 
• Zoledronic acid should be used with caution when concomitantly used with other medicinal products 

that could impact renal function (see section 4.5). 
• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately 

hydrated prior to administration of zoledronic acid. 
• A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be at least 

15 minutes (see section 4.2).  
 
Hypocalcaemia 
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating 
therapy with zoledronic acid (see section 4.3). Other disturbances of mineral metabolism must also be 
effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should 
consider clinical monitoring for these patients. 
 
Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of 
zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is 
usually maximal within the first 10 days after infusion of zoledronic acid (see section 4.8). 
 
Adequate calcium and vitamin D intake are recommended in association with zoledronic acid administration. 
In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium 
corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following 
zoledronic acid administration (see section 4.2). 
 
Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring 
during the period of risk. Measurement of serum calcium before infusion of zoledronic acid is recommended 
for patients with Paget´s disease. 
 
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in 
patients taking bisphosphonates, including zoledronic acid (see section 4.8). 
 
Osteonecrosis of the jaw (ONJ)  
Osteonecrosis of the jaw has been reported in patients treated with zoledronic acid. Many of the reported 
cases have been associated with dental procedures such as tooth extraction. A dental examination with 
appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients 
with concomitant risk factors (e.g. cancer, chemotherapy, anti-angiogenic medicinal products, 
corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental 
procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, 
dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data 
available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of 
the jaw. The clinical judgement of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. 
 
Atypical fractures of the femur 
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, 
primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique 

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fractures can occur anywhere along the femur from just below the lesser trochanter to just above the 
supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or 
groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with 
a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be 
examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture.  Poor healing of 
these fractures has also been reported.  Discontinuation of bisphosphonate therapy in patients suspected to 
have an atypical femur fracture should be considered pending evaluation of the patient, based on an 
individual benefit risk assessment. 
 
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any 
patient presenting with such symptoms should be evaluated for an incomplete femur fracture. 
 
General 
Other products containing zoledronic acid as active substances are available for oncology indications. 
Patients being treated with Zoledronic acid Teva Generics should not be treated with such products or 
any other bisphosphonate concomitantly, since the combined effects of these agents are unknown. 
 
The incidence of post-dose symptoms occuring within the first three days after administration of 
Zoledronic acid Teva Generics can be reduced with the administration of paracetamol or ibuprofen 
shortly following Zoledronic acid Teva Generics administration 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially “sodium –
free.” 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies with other medicinal products have been performed. Zoledronic acid is not 
systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). 
Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions 
resulting from displacement of highly protein-bound drugs are therefore unlikely. 
 
Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered 
in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or 
diuretics that may cause dehydration) (see section 4.4). 
 
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are 
primarily excreted via the kidney may increase. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy  
Zoledronic acid is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use 
of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive 
toxicological effects including malformations (see section 5.3). The potential risk for humans is unknown. 

 
Breast-feeding 
Zoledronic acid is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic 
acid is excreted into human milk. 
 
Women of childbearing potential  
Zoledronic acid is not recommended in women of childbearing potential. 
 
Fertility  
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 
generation. This resulted in exaggerated pharmacological effects considered related to the compound’s 
inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class 

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effect, dystocia and early termination of the study. Thus these results precluded determining a definitive 
effect of zoledronic acid on fertility in humans. 
 
4.7 Effects on ability to drive and use machines 
 
Zoledronic acid Teva Generics has no or negligible influence on the ability to drive and use machines. 
Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no studies on 
this effect with zoledronic acid have been performed. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after 
the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first 
infusion was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache 
(5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of zoledronic 
acid. The majority of these reactions occur within the first three days following zoledronic acid 
administration. The majority of these reactions were mild to moderate and resolved within three days of the 
event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study 
(19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against 
adverse reactions was used. 
 
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation 
was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid and placebo, 
respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving 
zoledronic acid (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852).  
The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials 
(PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable 
between zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled 
incidences were 1.3% for zoledronic acid and 0.8% for placebo. 
 
Tabulated list of adverse reactions 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category.  
Frequency categories are defined using the following convention: very common (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not 
known (cannot be estimated from the available data).  Within each frequency grouping, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1  
 

Infections and infestations  Uncommon  Influenza, nasopharyngitis  
Blood and lymphatic system disorders  Uncommon  Anaemia  
Immune system disorders  Not known**  Hypersensitivity reactions including rare 

cases of bronchoconstriction, urticaria 
and angioedema, and very rare cases of 
anaphylactic reaction/shock  

Metabolism and nutrition disorders  Common  Hypocalcaemia*  
 Uncommon Anorexia, decreased appetite  
Psychiatric disorders  Uncommon  Insomnia  
Nervous system disorders  Common  Headache, dizziness  
 Uncommon Lethargy, paraesthesia, somnolence, 

tremor, syncope, dysgeusia  
Eye disorders  Common  Ocular hyperaemia  
 Uncommon  Conjunctivitis, eye pain  
 Rare  Uveitis, episcleritis, iritis  

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 Not known**  Scleritis and orbital inflammation  
Ear and labyrinth disorders  Uncommon  Vertigo  
Cardiac disorders  Common  Atrial fibrillation  
 Uncommon  Palpitations  
Vascular disorders  Uncommon  Hypertension, flushing  
 Not known** Hypotension (some of the patients had 

underlying risk factors)  
Respiratory, thoracic and mediastinal 
disorders  

Uncommon  Cough, dyspnoea  

Gastrointestinal disorders  Common  Nausea, vomiting, diarrhoea  
 Uncommon Dyspepsia, abdominal pain upper, 

abdominal pain, gastroesophageal reflux 
disease, constipation, dry mouth, 
oesophagitis, toothache, gastritis#

 

Skin and subcutaneous tissue disorders  Uncommon  Rash, hyperhydrosis, pruritus, erythema  
Musculoskeletal and connective tissue 
disorders 

Common  Myalgia, arthralgia, bone pain, back 
pain, pain in extremity 

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

 Rare Atypical subtrochanteric and diaphyseal 
femoral fractures† (bisphosphonate class 
adverse reaction) 

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

Renal and urinary disorders 
 

Uncommon Blood creatinine increased, pollakiuria, 
proteinuria 

 Not known** Renal impairment. Rare cases of renal 
failure requiring dialysis and rare cases 
with a fatal outcome have been reported 
in patients with pre-existing renal 
dysfunction or other risk factors such as 
advanced age, concomitant nephrotoxic 
medicinal products, concomitant diuretic 
therapy, or dehydration in the post 
infusion period (see sections 4.4 and 4.8 
Class effects) 

General disorders and administration site 
conditions 

Very common Fever 

 Common Flu-like symptoms, chills, fatigue, 
asthenia, pain, malaise, infusion site 
reaction 

 Uncommon Peripheral oedema, thirst, acute phase 
reaction, non-cardiac chest pain 

 Not known** Dehydration secondary to post-dose 
symptoms such as fever, vomiting and 
diarrhoea 

Investigations Common C-reactive protein increased 
 Uncommon Blood calcium decreased 

#  Observed in patients taking concomitant glucocorticosteroids.  
*  Common in Paget’s disease only.  
**  Based on post-marketing reports.  Frequency cannot be estimated from available data. 
†  Identified in post-marketing experience. 

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Description of selected adverse reactions 
Class effects:  
Renal impairment  
Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. 
increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed 
following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or 
additional risk factors (e.g. advanced age, oncology patients with chemotherapy, concomitant nephrotoxic 
medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 
4 mg dose every 3-4 weeks, but it has been observed in patients after a single administration. 
 
In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and 
the incidence of renal failure and impairment was comparable for both the zoledronic acid and placebo 
treatment groups over three years.  There was a transient increase in serum creatinine observed within 
10 days in 1.8% of zoledronic acid-treated patients versus 0.8% of placebo-treated patients. 
 
Hypocalcaemia  
In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels 
(less than 1.87 mmol/l) following zoledronic acid administration. No symptomatic cases of hypocalcaemia 
were observed. 
 
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in 
all of whom it resolved. 
 
Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range 
(less than 2.10 mmol/l) occurred in 2.3% of zoledronic acid-treated patients in a large clinical trial compared 
to 21% of zoledronic acid-treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was 
much lower following subsequent infusions. 
 
All patients received adequate supplementation with vitamin D and calcium in the post-menopausal 
osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials 
(see also section 4.2). In the trial for the prevention of clinical fractures following a recent hip fracture, 
vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin 
D prior to zoledronic acid administration (see section 4.2). 
 
Local reactions  
In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were 
reported (0.7%) following the administration of zoledronic acid.  
 
Osteonecrosis of the jaw  
Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer 
patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local 
infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth 
extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors 
including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, anti-angiogenic medicinal 
products, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, 
pre-existing dental disease). It is prudent to avoid dental surgery as recovery may be prolonged (see 
section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one 
patient treated with zoledronic acid and one patient treated with placebo. Both cases resolved. 
 
Atypical fractures of the femur 
During post-marketing experience the following reactions have been reported (frequency rare): 
Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction). 
 

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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. 
 
Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels 
with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter 
bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone 
turnover markers with repeated annual dosing.  
 
Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)  
The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years were demonstrated in 
post-menopausal women (7,736 women aged 65-89 years) with either: a femoral neck bone mineral density 
(BMD) with a T-score ≤ –1.5 and at least two mild or one moderate existing vertebral fracture(s); or a 
femoral neck BMD T-score ≤ –2.5 with or without evidence of existing vertebral fracture(s). 85% of patients 
were bisphosphonate-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  
Zoledronic acid significantly decreased the incidence of one or more new vertebral fractures over three years 
and as early as the one year timepoint (see Table 2). 
 

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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  Zoledronic 
acid (%)  

Placebo 
(%)  

Absolute reduction 
in fracture 

incidence % (CI)  

Relative reduction 
in fracture 

incidence % (CI)  
At least one new vertebral 
fracture (0–1 year)  

1.5  3.7  2.2 (1.4, 3.1)  60 (43, 72)**  

At least one new vertebral 
fracture (0–2 year)  

2.2  7.7  5.5 (4.4, 6.6)  71 (62, 78)**  

At least one new vertebral 
fracture (0–3 year)  

3.3  10.9  7.6 (6.3, 9.0)  70 (62, 76)**  

** p <0.0001  
 
Zoledronic acid-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral 
fractures compared to placebo patients (p<0.0001). 
 
Effect on hip fractures  
Zoledronic acid demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip 
fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for zoledronic acid-treated patients 
compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-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 Zoledronic 

acid 
(N=3,875) 
event rate 

(%) 

Placebo 
(N=3,861) 
event rate 

(%) 

Absolute reduction 
in fracture event rate 

%  
(CI) 

Relative risk 
reduction in 

fracture incidence 
% (CI) 

Any clinical fracture (1) 8.4 12.8 4.4 (3.0, 5.8) 33 (23, 42)** 
Clinical vertebral fracture (2) 0.5 2.6 2.1 (1.5, 2.7) 77 (63, 86)** 
Non-vertebral fracture (1) 8.0 10.7 2.7 (1.4, 4.0) 25 (13, 36)* 
*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)  
Zoledronic acid significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment 
with placebo at all timepoints (6, 12, 24 and 36 months). Treatment with zoledronic acid resulted in a 6.7% 
increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal 
radius over 3 years as compared to placebo. 
 
Bone histology  
Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post-menopausal 
patients with osteoporosis treated with zoledronic acid (N=82) or placebo (N=70). Histomorphometric 
analysis showed a 63% reduction in bone turnover. In patients treated with zoledronic acid, no osteomalacia, 
marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 
82 biopsies obtained from patients on zoledronic acid. Microcomputed tomography (μCT) analysis 
demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients 
treated with zoledronic acid 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 zoledronic acid significantly reduced 
BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 
36 months.  P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 
52% below baseline levels at 36 months. B-CTx was significantly reduced by 61% below baseline levels at 
12 months and was sustained at 55% below baseline levels at 36 months. During this entire time period bone 
turnover markers were within the pre-menopausal range at the end of each year. Repeat dosing did not lead 
to further reduction of bone turnover markers. 
 
Effect on height  
In the three-year osteoporosis study standing height was measured annually using a stadiometer. The 
zoledronic acid group revealed approximately 2.5 mm less height loss compared to placebo (95% 
CI: 1.6 mm, 3.5 mm) [p<0.0001]. 
 
Days of disability  
Zoledronic acid significantly reduced the mean days of limited activity and the days of bed rest due to back 
pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days 
of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to 
placebo (all p<0.01). 

Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip 
fracture (RFT) 
The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 
2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low-trauma 
hip fracture who were followed for an average of 2 years on study medication. Approximately 42% of 
patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral 
neck BMD T-score above -2.5. zoledronic acid was administered once a year, until at least 211 patients in 
the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a 
loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the 
majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental 
calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients 
received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was 
approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of 
clinical fractures over the duration of the study. 
 
Effect on all clinical fractures 
The incidence rates of key clinical fracture variables are presented in Table 4. 
 
Table 4 Between treatment comparisons of the incidence of key clinical fracture variables 
 
Outcome Zoledronic acid  

(N = 1,065) event 
rate (%) 

Placebo (N = 
1,062) event rate 

(%) 

Absolute 
reduction in 

fracture event 
rate % 
(CI) 

Relative risk 
reduction in 

fracture 
incidence 

% (CI) 
Any clinical fracture (1) 8.6 13.9 5.3 (2.3, 8.3) 35 (16, 50)** 
Clinical vertebral fracture 
(2) 

1.7 3.8 2.1 (0.5, 3.7) 46 (8, 68)* 

Non-vertebral fracture (1) 7.6 10.7 3.1 (0.3, 5.9) 27 (2, 45)* 
*p-value <0.05, **p-value <0.01 
(1) Excluding finger, toe and facial fractures 
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
 

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

All cause mortality was 10% (101 patients) in the zoledronic acid-treated group compared to 13% (141 
patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality 
(p=0.01). 
 
The incidence of delayed hip fracture healing was comparable between zoledronic acid (34 [3.2%]) and 
placebo (29 [2.7%]). 
 
Effect on bone mineral density (BMD) 
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip and 
femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid resulted in 
an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to 
placebo. 
 
Clinical efficacy in men  
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 
24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients 
treated with zoledronic acid as compared to the effects observed in post-menopausal women in the 
HORIZON-PFT study. The study was not powered to show a reduction in clinical fractures in men; the 
incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus 8.7% for placebo. 
 
In another study in men (study CZOL446M2308) an annual infusion of zoledronic acid was non-inferior to 
weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline. 
 
Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy  
The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated with 
long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, 
stratified, active-controlled study of 833 men and women aged 18-85 years (mean age for men 56.4 years; 
for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified 
with respect to duration of glucocorticoid use prior to randomisation (≤ 3 months versus > 3 months). The 
duration of the trial was one year. Patients were randomised to either zoledronic acid 5 mg single infusion or 
to oral risedronate 5 mg daily for one year.  All participants received 1,000 mg elemental calcium plus 400 to 
1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if 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 zoledronic acid-treated group at the lumbar spine and 
femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving 
glucocorticoids for more than 3 months prior to randomisation, zoledronic acid increased lumbar spine BMD 
by 4.06% versus 2.71% for risedronate (mean difference: 1.36%; p<0.001). In the subpopulation of patients 
that had received glucocorticoids for 3 months or less prior to randomisation, zoledronic acid increased 
lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96%; p<0.001). The study 
was not powered to show a reduction in clinical fractures compared to risedronate. The incidence of fractures 
was 8 for zoledronic acid-treated patients versus 7 for risedronate-treated patients (p=0.8055). 
 
Clinical efficacy in the treatment of Paget’s disease of the bone 
Zoledronic acid was studied in male and female patients aged above 30 years with primarily mild to 
moderate Paget’s disease of the bone (median serum alkaline phosphatase level 2.6-3.0 times the upper limit 
of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence. 
 
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months 
was demonstrated in two 6-month comparative trials. After 6 months, zoledronic acid showed 96% 
(169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared 
to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001). 

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In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were 
observed over 6 months for zoledronic acid and risedronate. 
 
Patients who were classified as responders at the end of the 6 month core study were eligible to enter an 
extended follow-up period. Of the 153 zoledronic acid-treated patients and 115 risedronate-treated patients 
who entered an extended observation study, after a mean duration of follow-up of 3.8 years from time of 
dosing, the proportion of patients ending the Extended Observation Period due to the need for 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 zoledronic acid and later 
experienced disease relapse during the extended follow-up period were re-treated with zoledronic acid after a 
mean time of 6.5 years from initial treatment to re-treatment. 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. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with the 
reference medicinal product containing zoledronic acid 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 t½α 0.24 and t½β 1.87 hours, followed by a long elimination 
phase with a terminal elimination half-life of t½γ 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. 
 

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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 drugs are unlikely. 
 
Special populations (see section 4.2)  
Renal impairment 
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 
75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in 
the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate 
renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with 
multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50-80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not 
necessary. The use of zoledronic acid in patients with severe renal impairment (creatinine clearance 
< 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. 
 
5.3 Preclinical safety data 
 
Acute toxicity 
The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In 
the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based 
on AUC) administered over 15 minutes was well tolerated with no renal effects. 
 
Subchronic and chronic toxicity  
In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 
0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that 
corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions 
of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to 7 times the human 
therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were 
well-tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 
4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, 
when given for 52 weeks. 
 
Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended 
human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, 
and at the site of intravenous administration. The clinical relevance of these findings is unknown. The most 
frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of 
long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological 
antiresorptive activity. 
 
Reproduction toxicity  
Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was 
observed in rats at doses ≥ 0.2 mg/kg and was manifested by external, visceral and skeletal malformations.  
Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or 
embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to 
decreased serum calcium levels.  
 
Mutagenicity and carcinogenic potential  
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not 
provide any evidence of carcinogenic potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 

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6.1 List of excipients 
 
Mannitol  
Sodium citrate  
Water for injections 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial, i.e. essentially “sodium 
free”. 
 
6.2 Incompatibilities 
 
This medicinal product must not be allowed to come into contact with any calcium-containing solutions. The 
medicinal product must not be mixed or given intravenously with any other medicinal products. 
 
6.3 Shelf life 
 
18 months 
 
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C and 25ºC. 
 
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 to 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 
 
Cyclic Olefin Polymer (COP) plastic bottle, fitted with a chlorobutyl/butyl rubber stopper and aluminium cap 
fitted with violet plastic flip off disc. 
Each bottle contains 100 ml of solution 
Zoledronic acid Teva Generics is supplied in packs of 1, 5 or 10 bottles. The pack sizes of 5 and 10 bottles 
are only available in multipacks. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
For single use only.  
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. Only clear solution free from particles and discoloration should be used. 
 
If refrigerated, allow the refrigerated solution to reach room temperature before administration. 
Aseptic techniques must be followed during the preparation of the infusion. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 

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8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/912/001 
EU/1/14/912/002 
EU/1/14/912/003 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
01/04/2014 

 
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. 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion in bags 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each bag 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 zoledronic acid. This is especially 
important for the elderly and for patients receiving diuretic therapy. 
 
Adequate calcium and vitamin D intake are recommended in association with zoledronic acid administration. 
 
Osteoporosis 
For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis 
associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous 
infusion of 5 mg zoledronic acid administered once a year. 
 
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for 
continued treatment should be re-evaluated periodically based on the benefits and potential risks of 
zoledronic acid on an individual patient basis, particularly after 5 or more years of use. 
 
In patients with a recent low-trauma hip fracture, it is recommended to give the zoledronic acid infusion at 
least two weeks after hip fracture repair (see section 5.1). In patients with a recent low-trauma hip fracture, a 

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loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is 
recommended prior to the first zoledronic acid infusion. 
 
Paget’s disease 
For the treatment of Paget’s disease, zoledronic acid should be prescribed only by physicians with 
experience in the treatment of Paget’s disease of the bone. The recommended dose is a single intravenous 
infusion of 5 mg zoledronic acid. In patients with Paget’s disease, it is strongly advised that adequate 
supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 
10 days following zoledronic acid administration (see section 4.4). 
 
Re-treatment of Paget’s disease: After initial treatment with zoledronic acid in Paget’s disease an extended 
remission period is observed in responding patients. Re-treatment consists of an additional intravenous 
infusion of 5 mg zoledronic acid after an interval of one year or longer from initial treatment in patients who 
have relapsed. Limited data on re-treatment of Paget’s disease are available (see section 5.1). 
 
Special populations 
Patients with renal impairment 
Zoledronic acid is contraindicated in patients with creatinine clearance < 35 ml/min (see 
sections 4.3 and 4.4). 
 
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min. 
 
Patients with hepatic impairment  
No dose adjustment is required (see section 5.2). 
 
Older people (≥ 65 years)  
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly 
patients and younger subjects. 
 
Paediatric population  
The safety and efficacy of zoledronic acid in children and adolescents below 18 years of age have not been 
established. No data are available. 
 
Method of administration  
Intravenous use.  
Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and 
given at a constant infusion rate. The infusion time must not be less than 15 minutes.  For information on the 
infusion of Zoledronic acid Teva Generics, see section 6.6.  
 
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). 
 
4.4 Special warnings and precautions for use 
 
Renal function 
The use of zoledronic acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is 
contraindicated due to an increased risk of renal failure in this population. 
 

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Renal impairment has been observed following the administration of zoledronic acid (see section 4.8), 
especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant 
nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring 
after zoledronic acid administration.  Renal impairment has been observed in patients after a single 
administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with 
underlying renal impairment or with any of the risk factors described above. 
 
The following precautions should be taken into account to minimise the risk of renal adverse reactions: 
• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault 

formula before each zoledronic acid dose. 
• Transient increase in serum creatinine may be greater in patients with underlying impaired renal 

function. 
• Monitoring of serum creatinine should be considered in at-risk patients. 
• Zoledronic acid Teva Generics should be used with caution when concomitantly used with other 

medicinal products that could impact renal function (see section 4.5). 
• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately 

hydrated prior to administration of Zoledronic acid Teva Generics. 
• A single dose of Zoledronic acid Teva Generics should not exceed 5 mg and the duration of infusion 

should be at least 15 minutes (see section 4.2). 
 
Hypocalcaemia 
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating 
therapy with zoledronic acid (see section 4.3). Other disturbances of mineral metabolism must also be 
effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should 
consider clinical monitoring for these patients. 
 
Elevated bone turnover is a characteristic of Paget’s disease of the bone.  Due to the rapid onset of effect of 
zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is 
usually maximal within the first 10 days after infusion of zoledronic acid (see section 4.8). 
 
Adequate calcium and vitamin D intake are recommended in association with zoledronic acid administration. 
In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium 
corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following 
zoledronic acid administration (see section 4.2). 
 
Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring 
during the period of risk. Measurement of serum calcium before infusion of zoledronic acid is recommended 
for patients with Paget´s disease. 
 
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in 
patients taking bisphosphonates, including zoledronic acid (see section 4.8). 
 
Osteonecrosis of the jaw (ONJ)  
Osteonecrosis of the jaw has been reported in patients treated with zoledronic acid. Many of the reported 
cases have been associated with dental procedures such as tooth extraction. A dental examination with 
appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients 
with concomitant risk factors (e.g. cancer, chemotherapy, anti-angiogenic medicinal products, 
corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental 
procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, 
dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data 
available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of 
the jaw. The clinical judgement of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessment. 
 
Atypical fractures of the femur 
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, 
primarily in patients receiving long-term treatment for osteoporosis.  These transverse or short oblique 

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fractures can occur anywhere along the femur from just below the lesser trochanter to just above the 
supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or 
groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with 
a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be 
examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of 
these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to 
have an atypical femur fracture should be considered pending evaluation of the patient, based on an 
individual benefit risk assessment. 
 
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any 
patient presenting with such symptoms should be evaluated for an incomplete femur fracture. 
 
General 
Other products containing zoledronic acid as active substances are available for oncology indications. 
Patients being treated with zoledronic acid should not be treated with such products or any other 
bisphosphonate concomitantly, since the combined effects of these agents are unknown. 
 
The incidence of post-dose symptoms occuring within the first three days after administration of zoledronic 
acid can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid 
administration. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml; i.e. essentially “sodium –
free.” 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies with other medicinal products have been performed. Zoledronic acid is not 
systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). 
Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions 
resulting from displacement of highly protein-bound drugs are therefore unlikely. 
 
Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered 
in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or 
diuretics that may cause dehydration) (see section 4.4). 
 
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are 
primarily excreted via the kidney may increase. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy  
Zoledronic acid is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use 
of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive 
toxicological effects including malformations (see section 5.3). The potential risk for humans is unknown. 
 
Breast-feeding 
Zoledronic acid is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic 
acid is excreted into human milk. 
 
Women of childbearing potential  
Zoledronic acid is not recommended in women of childbearing potential. 
 
Fertility  
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 
generation.  This resulted in exaggerated pharmacological effects considered related to the compound’s 
inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class 

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effect, dystocia and early termination of the study. Thus these results precluded determining a definitive 
effect of zoledronic acid on fertility in humans. 
 
4.7 Effects on ability to drive and use machines 
 
Zoledronic acid Teva Generics has no or negligible influence on the abililty to drive and use machines. 
Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no studies on 
this effect with zoledronic acid have been performed. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after 
the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first 
infusion was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache 
(5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of zoledronic 
acid. The majority of these reactions occur within the first three days following zoledronic acid 
administration. The majority of these reactions were mild to moderate and resolved within three days of the 
event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study 
(19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against 
adverse reactions was used. 
 
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation 
was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid and placebo, 
respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving 
zoledronic acid (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852).  
The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials 
(PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable 
between zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled 
incidences were 1.3% for zoledronic acid and 0.8% for placebo. 
 
Tabulated list of adverse reactions 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. 
Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to 
<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known 
(cannot be estimated from the available data). Within each frequency grouping, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1  
 

Infections and infestations  Uncommon  Influenza, nasopharyngitis  
Blood and lymphatic system disorders  Uncommon  Anaemia  
Immune system disorders  Not known**  Hypersensitivity reactions including rare 

cases of bronchoconstriction, urticaria 
and angioedema, and very rare cases of 
anaphylactic reaction/shock  

Metabolism and nutrition disorders  Common  Hypocalcaemia*  
 Uncommon Anorexia, decreased appetite  
Psychiatric disorders  Uncommon  Insomnia  
Nervous system disorders  Common  Headache, dizziness  
 Uncommon Lethargy, paraesthesia, somnolence, 

tremor, syncope, dysgeusia  
Eye disorders  Common  Ocular hyperaemia  
 Uncommon  Conjunctivitis, eye pain  
 Rare  Uveitis, episcleritis, iritis  

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 Not known**  Scleritis and orbital inflammation  
Ear and labyrinth disorders  Uncommon  Vertigo  
Cardiac disorders  Common  Atrial fibrillation  
 Uncommon  Palpitations  
Vascular disorders  Uncommon  Hypertension, flushing  
 Not known** Hypotension (some of the patients had 

underlying risk factors)  
Respiratory, thoracic and mediastinal 
disorders  

Uncommon  Cough, dyspnoea  

Gastrointestinal disorders  Common  Nausea, vomiting, diarrhoea  
 Uncommon Dyspepsia, abdominal pain upper, 

abdominal pain, gastroesophageal reflux 
disease, constipation, dry mouth, 
oesophagitis, toothache, gastritis#

 

Skin and subcutaneous tissue disorders  Uncommon  Rash, hyperhydrosis, pruritus, erythema  
Musculoskeletal and connective tissue 
disorders 

Common  Myalgia, arthralgia, bone pain, back 
pain, pain in extremity 

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

 Rare Atypical subtrochanteric and diaphyseal 
fermoral fractures† (bisphosphonate 
class adverse reaction) 

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

Renal and urinary disorders 
 

Uncommon Blood creatinine increased, pollakiuria, 
proteinuria 

 Not known** Renal impairment. Rare cases of renal 
failure requiring dialysis and rare cases 
with a fatal outcome have been reported 
in patients with pre-existing renal 
dysfunction or other risk factors such as 
advanced age, concomitant nephrotoxic 
medicinal products, concomitant diuretic 
therapy, or dehydration in the post 
infusion period (see sections 4.4 and 4.8 
Class effects) 

General disorders and administration site 
conditions 

Very common Fever 

 Common Flu-like symptoms, chills, fatigue, 
asthenia, pain, malaise, infusion site 
reaction 

 Uncommon Peripheral oedema, thirst, acute phase 
reaction, non-cardiac chest pain 

 Not known** Dehydration secondary to post-dose 
symptoms such as fever, vomiting and 
diarrhoea 

Investigations Common C-reactive protein increased 
 Uncommon Blood calcium decreased 

#  
Observed in patients taking concomitant glucocorticosteroids.  

*  Common in Paget’s disease only.  
**  Based on post-marketing reports. Frequency cannot be estimated from available data. 
† Identified in post-marketing experience. 

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Description of selected adverse reactions 
Class effects:  
Renal impairment  
Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. 
increased serum creatinine) and in rare cases acute renal failure.  Renal impairment has been observed 
following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or 
additional risk factors (e.g. advanced age, oncology patients with chemotherapy, concomitant nephrotoxic 
medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 
4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration. 
 
In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and 
the incidence of renal failure and impairment was comparable for both the zoledronic acid and placebo 
treatment groups over three years.  There was a transient increase in serum creatinine observed within 
10 days in 1.8% of zoledronic acid-treated patients versus 0.8% of placebo-treated patients. 
 
Hypocalcaemia  
In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels 
(less than 1.87 mmol/l) following zoledronic acid administration. No symptomatic cases of hypocalcaemia 
were observed. 
 
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in 
all of whom it resolved. 
 
Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range 
(less than 2.10 mmol/l) occurred in 2.3% of zoledronic acid-treated patients in a large clinical trial compared 
to 21% of zoledronic acid-treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was 
much lower following subsequent infusions.  
 
All patients received adequate supplementation with vitamin D and calcium in the post-menopausal 
osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials 
(see also section 4.2). In the trial for the prevention of clinical fractures following a recent hip fracture, 
vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin 
D prior to zoledronic acid administration (see section 4.2). 
 
Local reactions  
In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were 
reported (0.7%) following the administration of zoledronic acid. 
 
Osteonecrosis of the jaw  
Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer 
patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local 
infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth 
extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors 
including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, anti-angiogenic medicinal 
products, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, 
pre-existing dental disease). It is prudent to avoid dental surgery as recovery may be prolonged (see 
section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one 
patient treated with zoledronic acid and one patient treated with placebo. Both cases resolved. 
 
Atypical fractures of the femur 
During post-marketing experience the following reactions have been reported (frequency rare): Atypical 
subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction). 
 

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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. 
 
Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels 
with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter 
bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone 
turnover markers with repeated annual dosing. 
 
Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)  
The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years were demonstrated in 
post-menopausal women (7,736 women aged 65–89 years) with either: a femoral neck bone mineral density 
(BMD) with a T-score ≤ –1.5 and at least two mild or one moderate existing vertebral fracture(s); or a 
femoral neck BMD T-score ≤ –2.5 with or without evidence of existing vertebral fracture(s). 85% of patients 
were bisphosphonate-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  
Zoledronic acid significantly decreased the incidence of one or more new vertebral fractures over three years 
and as early as the one year timepoint (see Table 2).  
 
Table 2  Summary of vertebral fracture efficacy at 12, 24 and 36 months 
 

Outcome  Zoledronic 
acid (%)  

Placebo 
(%)  

Absolute reduction 
in fracture 

incidence % (CI)  

Relative reduction 
in fracture 

incidence % (CI)  

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25 

At least one new vertebral 
fracture (0–1 year)  

1.5  3.7  2.2 (1.4, 3.1)  60 (43, 72)**  

At least one new vertebral 
fracture (0–2 year)  

2.2  7.7  5.5 (4.4, 6.6)  71 (62, 78)**  

At least one new vertebral 
fracture (0–3 year)  

3.3  10.9  7.6 (6.3, 9.0)  70 (62, 76)**  

** p <0.0001  
 
Zoledronic acid-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral 
fractures compared to placebo patients (p<0.0001). 
 
Effect on hip fractures  
Zoledronic acid demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip 
fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for zoledronic acid-treated patients 
compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-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 Zoledronic 

acid 
(N=3,875) 
event rate 

(%) 

Placebo 
(N=3,861) 
event rate 

(%) 

Absolute reduction 
in fracture event rate 

%  
(CI) 

Relative risk 
reduction in 

fracture incidence 
% (CI) 

Any clinical fracture (1) 8.4 12.8 4.4 (3.0, 5.8) 33 (23, 42)** 
Clinical vertebral fracture (2) 0.5 2.6 2.1 (1.5, 2.7) 77 (63, 86)** 
Non-vertebral fracture (1) 8.0 10.7 2.7 (1.4, 4.0) 25 (13, 36)* 
*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)  
Zoledronic acid significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment 
with placebo at all timepoints (6, 12, 24 and 36 months).  Treatment with zoledronic acid resulted in a 6.7% 
increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal 
radius over 3 years as compared to placebo. 
 
Bone histology  
Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post-menopausal 
patients with osteoporosis treated with zoledronic acid (N=82) or placebo (N=70). Histomorphometric 
analysis showed a 63% reduction in bone turnover. In patients treated with zoledronic acid, no osteomalacia, 
marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 
82 biopsies obtained from patients on zoledronic acid. Microcomputed tomography (μCT) analysis 
demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients 
treated with zoledronic acid compared to placebo. 
 
Bone turnover markers  
Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and 
serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic 
intervals throughout the study. Treatment with a 5 mg annual dose of zoledronic acid significantly reduced 
BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 

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36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 
52% below baseline levels at 36 months.  B-CTx was significantly reduced by 61% below baseline levels at 
12 months and was sustained at 55% below baseline levels at 36 months. During this entire time period bone 
turnover markers were within the pre-menopausal range at the end of each year. Repeat dosing did not lead 
to further reduction of bone turnover markers. 
 
Effect on height  
In the three-year osteoporosis study standing height was measured annually using a stadiometer. The 
zoledronic acid group revealed approximately 2.5 mm less height loss compared to placebo (95% CI: 
1.6 mm, 3.5 mm) [p<0.0001]. 
 
Days of disability  
Zoledronic acid significantly reduced the mean days of limited activity and the days of bed rest due to back 
pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days 
of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to 
placebo (all p<0.01). 
 
Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip 
fracture (RFT) 
The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 
2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low-trauma 
hip fracture who were followed for an average of 2 years on study medication. Approximately 42% of 
patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral 
neck BMD T-score above -2.5. zoledronic acid was administered once a year, until at least 211 patients in 
the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a 
loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the 
majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental 
calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients 
received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was 
approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of 
clinical fractures over the duration of the study. 
 
Effect on all clinical fractures 
The incidence rates of key clinical fracture variables are presented in Table 4. 
 
Table 4 Between treatment comparisons of the incidence of key clinical fracture variables 
 
Outcome Zoledronic acid  

(N = 1,065) event 
rate (%) 

Placebo (N = 
1,062) event rate 

(%) 

Absolute 
reduction in 

fracture event 
rate % 
(CI) 

Relative risk 
reduction in 

fracture 
incidence 

% (CI) 
Any clinical fracture (1) 8.6 13.9 5.3 (2.3, 8.3) 35 (16, 50)** 
Clinical vertebral fracture 
(2) 

1.7 3.8 2.1 (0.5, 3.7) 46 (8, 68)* 

Non-vertebral fracture (1) 7.6 10.7 3.1 (0.3, 5.9) 27 (2, 45)* 
*p-value <0.05, **p-value <0.01 
(1) Excluding finger, toe and facial fractures 
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
 
The study was not designed to measure significant differences in hip fracture, but a trend was seen towards 
reduction in new hip fractures. 
 
All cause mortality was 10% (101 patients) in the zoledronic acid-treated group compared to 13% (141 
patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality 
(p=0.01). 
 

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The incidence of delayed hip fracture healing was comparable between zoledronic acid (34 [3.2%]) and 
placebo (29 [2.7%]). 
 
Effect on bone mineral density (BMD) 
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip and 
femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid resulted in 
an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to 
placebo. 
 
Clinical efficacy in men  
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 
24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients 
treated with zoledronic acid as compared to the effects observed in post-menopausal women in the 
HORIZON-PFT study. The study was not powered to show a reduction in clinical fractures in men; the 
incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus 8.7% for placebo. 
 
In another study in men (study CZOL446M2308) an annual infusion of zoledronic acid was non-inferior to 
weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline.  
 
Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy  
The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated with 
long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, 
stratified, active-controlled study of 833 men and women aged 18-85 years (mean age for men 56.4 years; 
for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified 
with respect to duration of glucocorticoid use prior to randomisation (≤ 3 months versus > 3 months). The 
duration of the trial was one year. Patients were randomised to either zoledronic acid 5 mg single infusion or 
to oral risedronate 5 mg daily for one year. All participants received 1,000 mg elemental calcium plus 400 to 
1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if 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 zoledronic acid-treated group at the lumbar spine and 
femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving 
glucocorticoids for more than 3 months prior to randomisation, zoledronic acid increased lumbar spine BMD 
by 4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the subpopulation of patients 
that had received glucocorticoids for 3 months or less prior to randomisation, zoledronic acid increased 
lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96% ; p<0.001).  The study 
was not powered to show a reduction in clinical fractures compared to risedronate. The incidence of fractures 
was 8 for zoledronic acid-treated patients versus 7 for risedronate-treated patients (p=0.8055).  
 
Clinical efficacy in the treatment of Paget’s disease of the bone  
Zoledronic acid was studied in male and female patients aged above 30 years with primarily mild to 
moderate Paget’s disease of the bone (median serum alkaline phosphatase level 2.6-3.0 times the upper limit 
of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.  
 
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months 
was demonstrated in two 6-month comparative trials. After 6 months, zoledronic acid showed 96% 
(169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared 
to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001). 
 
In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were 
observed over 6 months for zoledronic acid and risedronate. 
 
Patients who were classified as responders at the end of the 6 month core study were eligible to enter an 
extended follow-up period. Of the 153 zoledronic acid-treated patients and 115 risedronate-treated patients 

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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 zoledronic acid and later 
experienced disease relapse during the extended follow-up period were re-treated with zoledronic acid after a 
mean time of 6.5 years from initial treatment to re-treatment. 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. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with the 
reference medicinal product containing zoledronic acid 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 t½α 0.24 and t½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½γ 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.  
 
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 

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binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-
bound drugs are unlikely. 
 
Special populations (see section 4.2)  
Renal impairment 
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 
75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in 
the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate 
renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with 
multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50–80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not 
necessary. The use of Zoledronic acid Teva Generics in patients with severe renal impairment (creatinine 
clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. 
 
5.3 Preclinical safety data 
 
Acute toxicity 
The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In 
the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based 
on AUC) administered over 15 minutes was well tolerated with no renal effects. 
 
Subchronic and chronic toxicity  
In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 
0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that 
corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions 
of 0.25 mg/kg administered at 2–3-week intervals (a cumulative dose that corresponded to 7 times the human 
therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were well-
tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks 
in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when 
given for 52 weeks.  
 
Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended 
human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, 
and at the site of intravenous administration.  The clinical relevance of these findings is unknown. The most 
frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of 
long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological 
antiresorptive activity. 
 
Reproduction toxicity  
Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was 
observed in rats at doses ≥ 0.2 mg/kg and was manifested by external, visceral and skeletal malformations. 
Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or 
embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to 
decreased serum calcium levels. 
 
Mutagenicity and carcinogenic potential  
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not 
provide any evidence of carcinogenic potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Sodium citrate 
Water for injections 

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This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial, i.e. essentially “sodium 
free”. 
 
6.2 Incompatibilities 
 
This medicinal product must not be allowed to come into contact with any calcium-containing solutions. The 
medicinal product must not be mixed or given intravenously with any other medicinal products. 
 
6.3 Shelf life 
 
18 months  
 
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C and 25ºC. 
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 to 8°C. 
 
6.4 Special precautions for storage 
 
Store below 30°C. For storage conditions after first opening of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
multilayer polyolefin/styrene-ethylene-butylene (SEB) bag with SFC polypropylene infusion port closed 
with rubber stopper and snap cap.  
Each bag contains 100 ml of solution. 
Zoledronic acid Teva Generics is supplied in multipacks containing 5 or 10 bags. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
For single use only.  
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. Only clear solution free from particles and discoloration should be used. 
 
If refrigerated, allow the refrigerated solution to reach room temperature before administration. 
Aseptic techniques must be followed during the preparation of the infusion. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/912/004 
EU/1/14/912/005 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
01/04/2014 

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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. 
 
 

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ANNEX II 
 

A.          MANUFACTURERS 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 

 
 
 

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A.  MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Pharmachemie B.V. 
Swensweg 5  
2031 GA Haarlem 
The Netherlands 
 
TEVA Gyógyszergyár Zrt. 
Táncsics Mihály út 82., 
Gödöllő 2100 
Hungary 
 
The printed package leaflet of the medicinal product must state the name and address of the manufacturer 
responsible for the release of the concerned batch. 
 
 
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  
 

At the time of granting the marketing authorisation, the submission of periodic safety update reports is not 
required for this medicinal product.  However, the marketing authorisation holder shall submit periodic 
safety update reports for this medicinal product if the product is included in the list of Union reference 
dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 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 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.  

 
 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. 

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• Additional risk minimisation measures 
The Marketing Authorisation Holder (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 

 
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 Zoledronic acid Teva Generics 

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 Zoledronic acid Teva Generics 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 zoledronic 

acid 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: 

• Package leaflet 
• 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 events 
• When to seek attention from the health care provider 

 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion in bottles 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each bottle contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
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, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/001 
EU/1/14/912/002 
EU/1/14/912/003 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR MULTIPACKS (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion in bottles 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol, sodium citrate and water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
multipack: 5 bottles x 100 ml 
multipack: 10 bottles x 100 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
 
 
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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/001 
EU/1/14/912/002 
EU/1/14/912/003 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion in bottles 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
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 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 
 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/001 
EU/1/14/912/002 
EU/1/14/912/003 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion  
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
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 
 
Intravenous use. 
For single use only. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 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 
 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/001 
EU/1/14/912/002 
EU/1/14/912/003 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BAG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bag contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
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 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 
Store below 30°C.  
 
 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/004 
EU/1/14/912/005 

13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 

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PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING  
 
OVERPOUCH (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bag contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol, sodium citrate and water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
1 bag of 100 ml 
Component of a multipack, can’t be sold separately. 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 
Store below 30°C.  
 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/004 
EU/1/14/912/005 

 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Generics 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bag contains 5 mg zoledronic acid (as monohydrate). 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol, sodium citrate and water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
multipack: 5 bags x 100 ml 
multipack: 10 bags x 100 ml 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use. 
For single use only. 
Read the package leaflet before 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 
 
Store below 30°C. 

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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 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/912/004 
EU/1/14/912/005 

 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the user 

 
Zoledronic acid Teva Generics 5 mg solution for infusion in bottles 

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 Zoledronic acid Teva Generics is and what it is used for 
2. What you need to know before you are given Zoledronic acid Teva Generics 
3. How Zoledronic acid Teva Generics is given 
4. Possible side effects 
5. How to store Zoledronic acid Teva Generics 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid Teva Generics is and what it is used for 
 
Zoledronic acid Teva Generics 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 steroids, 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, Zoledronic acid Teva Generics 
strengthens the bone and therefore makes it less likely to break.  Zoledronic acid Teva Generics 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.  Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics 
 
Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given 
Zoledronic acid Teva Generics.  
 
You must not be given Zoledronic acid Teva Generics:  
 

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- 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 Zoledronic acid Teva Generics:  
-  if you are being treated with any other bisphosphonate medicine, since the combined effects of these 

medicines taken together with Zoledronic acid Teva Generics are unknown. This includes e.g. Zometa 
or Aclasta (medicines that also contain zoledronic acid and are used to treat the same disease or 
osteoporosis and other non-cancer diseases of the bone).  

-  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.  
 
Before you receive treatment with Zoledronic acid Teva Generics, tell your doctor if you have (or have had) 
pain, swelling or numbness in your gums, jaw or both, if your jaw feels heavy, or if you have lost a tooth.   
Before you receive dental treatment or undergo dental surgery, tell your dentist you are receiving treatment 
with Zoledronic acid Teva Generics.  
 
Monitoring test 
Your doctor should do a blood test to check your kidney function (levels of creatinine) before each dose of 
Zoledronic acid Teva Generics. It is important for you to drink at least 2 glasses of fluid (such as water), 
within a few hours before receiving Zoledronic acid Teva Generics, as directed by your healthcare provider. 
 
Children and adolescents 
Zoledronic acid Teva Generics is not recommended for anyone under 18 years of age.  The use of Zoledronic 
acid Teva Generics in children and adolescents has not been studied.  
 
Other medicines and Zoledronic acid Teva Generics 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
 
It is especially 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 Zoledronic acid Teva Generics 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  
Zoledronic acid Teva Generics has no or negligible influence on the ability to drive and use machines. If you 
feel dizzy while taking Zoledronic acid Teva Generics, do not drive or use machines until you feel better. 
 
Zoledronic acid Teva Generics contains sodium 
 This medicine contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially “sodium-free.” 
 
 

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3. How Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics 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, Zoledronic acid Teva Generics works for one year.  Your doctor will let you know when to 
return for your next dose.  
 
Paget’s disease  
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.  Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics.  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.  
 
Zoledronic acid Teva Generics with food and drink 
Make sure you drink enough fluids (at least one or two glasses) before and after the treatment with 
Zoledronic acid Teva Generics, as directed by your doctor. This will help prevent dehydration. You 
may eat normally on the day you are treated with Zoledronic acid Teva Generics. This is especially 
important in patients who take diuretics (“water pills”) and in elderly patients. 
 
If you missed a dose of Zoledronic acid Teva Generics  
Contact your doctor or hospital as soon as possible to re-schedule your appointment.  
 
Before stopping Zoledronic acid Teva Generics therapy  
If you are considering stopping Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics. 
 
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 Zoledronic acid 
Teva Generics.  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 Zoledronic acid Teva Generics.  
 

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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 Zoledronic acid Teva Generics 
for the treatment of postmenopausal osteoporosis. It is currently unclear whether Zoledronic acid Teva 
Generics causes this irregular heart rhythm but you should report it to your doctor if you experience such 
symptoms after you have received Zoledronic acid Teva Generics. 
Swelling and/or pain at the infusion site may occur. 
 
Uncommon (may affect up to 1 in 100 people) 
Skin reactions such as redness. 
Swelling, redness, pain and itching to the eyes or eye sensitivity to light. 
 
Not known (frequency cannot be estimated from the available data) 
Pain in the mouth, teeth and jaw, swelling or sores inside the mouth, 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 
dentist immediately if you experience such symptoms. 
 
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 Zoledronic acid Teva Generics. It is important for you to drink at least 
2 glasses of fluid (such as water), within a few hours before receiving Zoledronic acid Teva Generics, as 
directed by your healthcare provider. 
 
If you experience any of the above side effects, you should contact your doctor immediately. 
 
Zoledronic acid Teva Generics 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.  
 
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. 
 
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 post-dose symptoms such as fever, vomiting and 
diarrhoea.  
 

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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 Zoledronic acid Teva Generics 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid Teva Generics 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 bottle and carton label after EXP.  

The expiry date refers to the last day of that month. 
-  The unopened bottle does not require any special storage conditions.  
-  After opening the bottle, chemical and physical in-use stability has been demonstrated for 24 hours at 

2 to 8ºC and 25ºC. 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 to 8°C. Allow the refrigerated solution to reach 
room temperature before administration. 

- Do not use this medicine if you notice any discolouration or particles in the solution. 
- Do not throw away any medicines via wastewater (or household waste). Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment.  
 
 
6. Contents of the pack and other information 
 
What Zoledronic acid Teva Generics contains  
- The active substance is zoledronic acid.  One bottle contains 5 mg zoledronic acid (as monohydrate).  

Each ml of solution contains 0.05 mg zoledronic acid (as monohydrate). 
- The other ingredients are mannitol, sodium citrate and water for injections. 
 
What Zoledronic acid Teva Generics looks like and contents of the pack 
Zoledronic acid Teva Generics is a clear and colourless solution for infusion. It comes in a clear plastic 
bottle.  Each bottle contains 100 ml of solution. It is supplied in packs sizes of 1, 5 and 10. The pack sizes of 
5 and 10 are only available as multipacks comprising of 5 or 10 packs, each containing 1 bottle.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
Manufacturer 
 
Teva Pharmaceutical Works Private Limited Company 
Táncsics Mihály út 82 
2100 Gödöllő 
Hungary 
 
Pharmachemie B.V. 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 

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


57 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Teva Pharma Belgium N.V. 
Tel/Tél: +32 3 820 73 73  
 

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 
 

България  
Тева Фармасютикълс България ЕООД 
Teл: +359 2 489 95 82  

 Luxembourg/Luxemburg  
Teva Pharma Belgium S.A.  
Tél: +32 3 820 73 73 
 

 
Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251 007 111  
 

 
Magyarország 
Teva Gyógyszergyár Zrt 
Tel.: +36 1 288 64 00 
 

 
Danmark  
Teva Denmark A/S  
Tlf: +45 44 98 55 11  
 

 
 Malta  
Drugsales Ltd 
Τel: +356 21 419 070/1/2 
 

 
Deutschland 
Teva GmbH 
Tel: +49 731 402 08 

 
Nederland  
Teva Nederland B.V. 
Tel: +31 800 0228400  

 
Eesti 
Teva Eesti esindus UAB Sicor Biotech Eesti 
filiaal 
Tel: +372 661 0801 

 
Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 

 
Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

 
Österreich 
ratiopharm Arzenimittel 
Vertriebs-GmbH 
Tel: +43 1 97007-0 

 
España 
Teva Pharma S.L.U. 
Tél: +34 91 387 32 80   

 
Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 22 345 93 00 

 
France 
Teva Santé 
Tél: +33 1 55 91 7800 

 
Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: +351 21 476 75 50 

 
Hrvatska 
Novartis Hrvatska d.o.o. 
Tel. +385 1 6274 220 
 

 
România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 

 
Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 51 321 740 

 
Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 

 
Ísland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 

 
Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +421 2 5726 7911 

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58 

 
Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 

 
Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 

 
Κύπρος 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

 
Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 

 
Latvija 
Sicor Biotech filiāle Latvijā  
Tel: +371 67 323 666 

United Kingdom 
Teva UK Limited 
Tel: +44 1977 628 500 

 
 
 
This leaflet was last revised in {MM/YYYY}  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
-------------------------------------------------------------------------------------------------------------------------- 
 
INFORMATION FOR THE HEALTHCARE PROESSIONAL 
 
The following information is intended for healthcare professionals only: 
 
How to prepare and administer Zoledronic acid Teva Generics  
 
-  Zoledronic acid Teva Generics 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. Zoledronic acid Teva Generics 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.  Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics  
 
-  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. 

 
 

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59 

 
Package leaflet: Information for the user 

 
Zoledronic acid Teva Generics 5 mg solution for infusion in bags 

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 Zoledronic acid Teva Generics is and what it is used for 
2. What you need to know before you are given Zoledronic acid Teva Generics 
3. How Zoledronic acid Teva Generics is given 
4. Possible side effects 
5. How to store Zoledronic acid Teva Generics 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid Teva Generics is and what it is used for 
 
Zoledronic acid Teva Generics 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 steroids, 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, Zoledronic acid Teva Generics 
strengthens the bone and therefore makes it less likely to break. Zoledronic acid Teva Generics  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.  Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics 
 
Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given 
Zoledronic acid Teva Generics.  
 
You must not be given Zoledronic acid Teva Generics:  
 

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- 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 Zoledronic acid Teva Generics:  
-  if you are being treated with any other bisphosphonate medicine, since the combined effects of these 

medicines taken together with Zoledronic acid Teva Generics are unknown.  This includes e.g. Zometa 
or Aclasta (medicines that also contain zoledronic acid and are used to treat the same disease or 
osteoporosis and other non-cancer diseases of the bone).  

-  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.  
 
Before you receive treatment with Zoledronic acid Teva Generics, tell your doctor if you have (or have had) 
pain, swelling or numbness in your gums, jaw or both, if your jaw feels heavy, or if you have lost a tooth.   
Before you receive dental treatment or undergo dental surgery, tell your dentist you are receiving treatment 
with Zoledronic acid Teva Generics.  
 
Monitoring test 
Your doctor should do a blood test to check your kidney function (levels of creatinine) before each dose of 
Zoledronic acid Teva Generics. It is important for you to drink at least 2 glasses of fluid (such as water), 
within a few hours before receiving Zoledronic acid Teva Generics, as directed by your healthcare provider. 
 
Children and adolescents 
Zoledronic acid Teva Generics is not recommended for anyone under 18 years of age.  The use of Zoledronic 
acid Teva Generics in children and adolescents has not been studied.  
 
Other medicines and Zoledronic acid Teva Generics 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
 
It is especially 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 Zoledronic acid Teva Generics 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 any medicine.  
 
Driving and using machines  
Zoledronic acid Teva Generics has no or negligible influence on the ability to drive and use machines. If you 
feel dizzy while taking Zoledronic acid Teva Generics, do not drive or use machines until you feel better. 
 
Zoledronic acid Teva Generics contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per 100 ml; i.e. essentially “sodium-free.” 
 
 

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3. How Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics 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, Zoledronic acid Teva Generics works for one year.  Your doctor will let you know when to 
return for your next dose.  
 
Paget’s disease  
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.  Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics.  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.  
 
Zoledronic acid Teva Generics with food and drink 
Make sure you drink enough fluids (at least one or two glasses) before and after the treatment with 
Zoledronic acid Teva Generics, as directed by your doctor. This will help to prevent dehydration. You may 
eat normally on the day you are treated with Zoledronic acid Teva Generics. This is especially important in 
patients who take diuretics (“water pills”) and in elderly patients. 
 
If  you missed a dose of Zoledronic acid Teva Generics  
Contact your doctor or hospital as soon as possible to re-schedule your appointment.  
 
Before stopping Zoledronic acid Teva Generics therapy  
If you are considering stopping Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics. 
  
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 Zoledronic acid 
Teva Generics.  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 Zoledronic acid Teva Generics.  
 

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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 Zoledronic acid Teva Generics 
for the treatment of postmenopausal osteoporosis. It is currently unclear whether Zoledronic acid Teva 
Generics causes this irregular heart rhythm but you should report it to your doctor if you experience such 
symptoms after you have received Zoledronic acid Teva Generics. 
Swelling and/or pain at the infusion site may occur. 
 
Uncommon (may affect up to 1 in 100 people) 
Skin reactions such as redness. 
Swelling, redness, pain and itching to the eyes or eye sensitivity to light. 
 
Not known (frequency cannot be estimated from the available data) 
Pain in the mouth, teeth and jaw, swelling or sores inside the mouth, 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 
dentist immediately if you experience such symptoms. 
 
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 Zoledronic acid Teva Generics. It is important for you to drink at least 
2 glasses of fluid (such as water), within a few hours before receiving Zoledronic acid Teva Generics, as 
directed by your healthcare provider. 
 
If you experience any of the above side effects, you should contact your doctor immediately. 
 
Zoledronic acid Teva Generics 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.  
 
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. 
 
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 post-dose symptoms such as fever, vomiting and 
diarrhoea. 
 

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63 

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 Zoledronic acid Teva Generics 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid Teva Generics 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 bag and carton after EXP. The 

expiry date refers to the last day of that month. 
-  Store below 30°C.  
-  After opening the bottle, chemical and physical in-use stability has been demonstrated for 24 hours at 

2 to 8ºC and 25ºC.  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 to 8°C.  Allow the refrigerated solution to reach 
room temperature before administration.  

- Do not use this medicine if you notice any discolouration or particles in the solution. 
- Do not throw away any medicines via wastewater (or household waste).  Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Zoledronic acid Teva Generics contains  
- The active substance is zoledronic acid. One bag contains 5 mg zoledronic acid (as monohydrate).  

Each ml of solution contains 0.05 mg zoledronic acid (as monohydrate). 
- The other ingredients are mannitol, sodium citrate and water for injections. 
 
What Zoledronic acid Teva Generics looks like and contents of the pack 
Zoledronic acid Teva Generics is a clear and colourless solution for infusion. It comes in a 
polyolefin/styrene-ethylene-butylene (SEB) foil bag with a foil over pouch.  Each bag contains 100 ml of 
solution.  It is supplied in multipacks containing 5 or 10 bags. 
 
Not all pack size may be marketed. 
 
Marketing Authorisation Holder 
 
Teva B.V. 
Swensweg 5, 2031GA Haarlem 
The Netherlands 
 
Manufacturer 
Teva Pharmaceutical Works Private Limited Company 
Táncsics Mihály út 82 
2100 Gödöllő 
Hungary 
 
Pharmachemie B.V. 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

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


64 

 
België/Belgique/Belgien  
Teva Pharma Belgium N.V. 
Tel/Tél: +32 3 820 73 73  

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 

 
България  
Тева Фармасютикълс България ЕООД 
Teл: +359 2 489 95 82  

 
Luxembourg/Luxemburg  
Teva Pharma Belgium S.A.  
Tél: +32 3 820 73 73 
 

 
Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251 007 111  

 
Magyarország 
Teva Gyógyszergyár Zrt 
Tel.: +36 1 288 64 00 

 
Danmark  
Teva Denmark A/S  
Tlf: +45 44 98 55 11  

 
 Malta  
Drugsales Ltd 
Τel: +356 21 419 070/1/2 

 
Deutschland 
Teva GmbH 
Tel: +49 731 402 08 

 
Nederland  
Teva Nederland B.V. 
Tel: +31 800 0228400  

 
Eesti 
Teva Eesti esindus UAB Sicor Biotech Eesti 
filiaal 
Tel: +372 661 0801 

 
Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 

 
Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

 
Österreich 
ratiopharm Arzenimittel 
Vertriebs-GmbH 
Tel: +43 1 97007-0 

 
España 
Teva Pharma S.L.U. 
Tél: +34 91 387 32 80   

 
Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 22 345 93 00 

 
France 
Teva Santé 
Tél: +33 1 55 91 7800 

 
Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: +351 21 476 75 50 

 
Hrvatska 
Pliva Hrvatska d.o.o 
Tel: + 385 1 37 20 000 

 
România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 

 
Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 51 321 740 

 
Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 

 
Ísland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 

 
Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +421 2 5726 7911 

Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 
 

 
Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 

  

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65 

Κύπρος 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 

 
Latvija 
Sicor Biotech filiāle Latvijā  
Tel: +371 67 323 666 

 
United Kingdom 
Teva UK Limited 
Tel: +44 1977 628500 

 
 
This leaflet was last revised in {MM/YYYY}  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
------------------------------------------------------------------------------------------------------------------------- 
 
INFORMATION FOR THE HEALTHCARE PROFESSIONAL 
 
The following information is intended for healthcare professionals only: 
 
How to prepare and administer Zoledronic acid Teva Generics in bags 
 
-  Zoledronic acid Teva Generics 5 mg solution for infusion in bags 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. Zoledronic acid Teva Generics 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. Zoledronic acid Teva Generics 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 Zoledronic acid Teva Generics  
 
-  Keep this medicine out of the sight and reach of children.  
-  Do not use Zoledronic acid Teva Generics after the expiry date which is stated on the bag. 
-  Store below 30°C.  
-  Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8ºC and 25ºC. 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 to 8°C. 

 
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	SUMMARY OF PRODUCT CHARACTERISTICS
	A.  MANUFACTURERS 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