Zoledronic acid Teva Pharma

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 5 mg solution for infusion in bottles 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each bottle with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate). 
 
Each ml of the solution contains 0.05 mg zoledronic acid (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion. 
 
Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of osteoporosis  
• in post-menopausal women  
• in adult men  
at increased risk of fracture, including those with a recent low-trauma hip fracture. 
 
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy  
• in post-menopausal women  
• in adult men  
at increased risk of fracture.  
 
Treatment of Paget’s disease of the bone in adults. 
 
4.2 Posology and method of administration 
 
Posology  
Patients must be appropriately hydrated prior to administration of Zoledronic acid Teva Pharma. This 
is especially important for the elderly (≥ 65 years) and for patients receiving diuretic therapy. 
 
Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Teva 
Pharma 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 Teva Pharma 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 Teva Pharma 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-

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trauma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the 
intramuscular route is recommended prior to the first zoledronic acid infusion. 
 
Paget’s disease 
For the treatment of Paget’s disease, Zoledronic acid Teva Pharma 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 Teva Pharma. 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 Teva Pharma 
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 Teva Pharma 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 Teva Pharma is contraindicated in patients with creatinine clearance < 35 ml/min (see 
sections 4.3 and 4.4). 
 
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min. 
 
Patients with hepatic impairment 
No dose adjustment is required (see section 5.2). 
 
Elderly (≥ 65 years) 
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in 
elderly patients and younger subjects. 
 
Paediatric population 
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 Teva Pharma is administered via a vented infusion line and given slowly at a constant 
infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of 
Zoledronic acid Teva Pharma, see section 6.6. 
 
Patients treated with Zoledronic acid Teva Pharma should be given the package leaflet and the patient 
reminder card. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients, 

listed in section 6.1. 
 
- Patients with hypocalcaemia (see section 4.4). 
 
- Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4). 
 
- Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 

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Renal function 
The use of Zoledronic acid Teva Pharma in patients with severe renal impairment (creatinine clearance 
< 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. 
 
Renal impairment has been observed following the administration of zoledronic acid (see section 4.8), 
especially in patients with pre-existing renal dysfunction or other risks including advanced age, 
concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or 
dehydration occurring after zoledronic acid administration. Renal impairment has been observed in 
patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely 
occurred in patients with underlying renal impairment or with any of the risk factors described above. 
 
The following precautions should be taken into account to minimise the risk of renal adverse 
reactions: 
• Creatinine clearance should be calculated based on actual body weight using the 

Cockcroft-Gault formula before each Zoledronic acid Teva Pharma 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 Pharma 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 Pharma.  
• A single dose of Zoledronic acid Teva Pharma 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 Teva Pharma (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 Teva Pharma 
(see section 4.8). 
 
Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Teva 
Pharma 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 Teva Pharma 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 Teva Pharma is recommended for patients with Paget´s disease. 
 
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported 
in patients taking bisphosphonates, including zoledronic acid (see section 4.8). 
 
Osteonecrosis of the jaw (ONJ)  
ONJ has been reported in the post-marketing setting in patients receiving Zoledronic acid Teva 
Pharma for osteoporosis (see section 4.8). 
 
The start of treatment or of a new course of treatment should be delayed in patients with unhealed 
open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual 
benefit-risk assessment is recommended prior to treatment with Zoledronic acid Teva Pharma in 
patients with concomitant risk factors. 
 

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The following should be considered when evaluating a patient’s risk of developing ONJ: 
- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent 

compounds), route of administration (higher risk for parenteral administration) and cumulative 
dose of bone resorption therapy. 

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking. 
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to 

head and neck. 
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, 

invasive dental procedures, e.g. tooth extractions. 
 
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, 
and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of 
sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental 
procedures should be performed with caution and avoided in close proximity to zoledronic acid 
treatment. 
 
The management plan for patients who develop ONJ should be set up in close collaboration between 
the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of 
zoledronic acid treatment should be considered until the condition resolves and contributing risk 
factors are mitigated where possible. 
 
Osteonecrosis of the external auditory canal 
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in 
association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory 
canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The 
possibility of osteonecrosis of the external auditory canal should be considered in patients receiving 
bisphosphonates who present with ear symptoms including chronic ear infections. 
 
Atypical fractures of the femur 
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate 
therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short 
oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just 
above the supracondylar flare. These fractures occur after minimal or no trauma and some patients 
experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to 
months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the 
contralateral femur should be examined in bisphosphonate-treated patients who have sustained a 
femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of 
bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered 
pending evaluation of the patient, based on an individual benefit risk assessment. 
 
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and 
any patient presenting with such symptoms should be evaluated for an incomplete femur fracture. 
 
General 
The incidence of post-dose symptoms occuring within the first three days after administration of 
Zoledronic acid Teva Pharma can be reduced with the administration of paracetamol or ibuprofen 
shortly following Zoledronic acid Teva Pharma administration. 
 
Other products containing zoledronic acid as an active substance are available for oncology 
indications. Patients being treated with Zoledronic acid Teva Pharma should not be treated with such 
products or any other bisphosphonate concomitantly, since the combined effects of these agents are 
unknown. 
 
Excipients 
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially 
“sodium–free.” 
 

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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 Teva 
Pharma is administered in conjunction with medicinal products that can significantly impact renal 
function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4). 
 
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are 
primarily excreted via the kidney may increase. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Zoledronic acid Teva Pharma is not recommended in women of childbearing potential. 
 
Pregnancy 
Zoledronic acid Teva Pharma 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 Teva Pharma is contraindicated during breast-feeding (see section 4.3). It is unknown 
whether zoledronic acid is excreted into human milk. 
 
Fertility 
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 
generation. This resulted in exaggerated pharmacological effects considered related to the compound’s 
inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a 
bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded 
determining a definitive effect of zoledronic acid on fertility in humans. 
 
4.7 Effects on ability to drive and use machines 
 
Adverse reactions, such as dizziness, may affect the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% 
after the first, second and third infusion, respectively.  Incidence of individual adverse reactions 
following the first infusion was: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), 
arthralgia (4.8%) and headache (5.1%). 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. 
 
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); 

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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 Decreased appetite  
Psychiatric disorders  Uncommon  Insomnia  
Nervous system disorders  Common  Headache, dizziness  
 Uncommon Lethargy, paraesthesia, somnolence, 

tremor, syncope, dysgeusia  
Eye disorders  Common  Ocular hyperaemia  
 Uncommon  Conjunctivitis, eye pain  
 Rare  Uveitis, episcleritis, iritis  
 Not known**  Scleritis and parophthalmia 
Ear and labyrinth disorders  Uncommon  Vertigo  
Cardiac disorders  Common  Atrial fibrillation  
 Uncommon  Palpitations  
Vascular disorders  Uncommon  Hypertension, flushing  
 Not known** Hypotension (some of the patients had 

underlying risk factors)  
Respiratory, thoracic and mediastinal 
disorders  

Uncommon  Cough, dyspnoea  

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

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

 

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

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

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

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

 Very rare Osteonecrosis of the external auditory 
canal† (bisphosphonate class adverse 
reaction) 

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

Renal and urinary disorders Uncommon Blood creatinine increased, pollakiuria, 

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 proteinuria
 Not known** Renal impairment. Rare cases of renal 

failure requiring dialysis and rare cases 
with a fatal outcome have been reported 
in patients with pre-existing renal 
dysfunction or other risk factors such as 
advanced age, concomitant nephrotoxic 
medicinal products, concomitant diuretic 
therapy, or dehydration in the post 
infusion period (see sections 4.4 and 4.8 
Class effects)

General disorders and administration site 
conditions 

Very common Pyrexia 

 Common Influenza-like illness, chills, fatigue, 
asthenia, pain, malaise, infusion site 
reaction

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

 Not known** Dehydration secondary to 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. 
 
Description of selected adverse reactions 
 
Atrial fibrillation 
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial 
fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving 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. 
 
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 

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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  
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with 
medicinal products that inhibit bone resorption, including zoledronic acid (see section 4.4). In a large 
clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with 
zoledronic acid and one patient treated with placebo.  Cases of ONJ have been reported in the post-
marketing setting for Zoledronic acid Teva Pharma. 
 
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. 
 

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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) 
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 Placebo Absolute reduction Relative risk 

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acid 
(N=3,875) 
event rate 

(%) 

(N=3,861) 
event rate 

(%) 

in fracture event rate 
%  

(CI) 

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 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 treatment. 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 

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least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were not 
routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the 
intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants 
received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation 
per day. Ninety-five percent of the patients received their infusion two or more weeks after the hip 
fracture repair and the median timing of infusion was approximately six weeks after the hip fracture 
repair. The primary efficacy variable was the incidence of clinical fractures over the duration of the 
study. 
 
Effect on all clinical fractures 
The incidence rates of key clinical fracture variables are presented in Table 4. 
 
Table 4 Between treatment comparisons of the incidence of key clinical fracture variables 
 
Outcome Zoledronic 

acid 
(N=1,065) 
event rate 

(%) 

Placebo 
(N=1,062) 
event rate 

(%) 

Absolute reduction 
in fracture event 

rate % 
(CI) 

Relative risk 
reduction in 

fracture incidence 
% (CI) 

Any clinical fracture (1) 8.6 13.9 5.3 (2.3, 8.3) 35 (16, 50)** 
Clinical vertebral fracture (2) 1.7 3.8 2.1 (0.5, 3.7) 46 (8, 68)* 
Non-vertebral fracture (1) 7.6 10.7 3.1 (0.3, 5.9) 27 (2, 45)* 
*p-value <0.05, **p-value <0.01 
(1) Excluding finger, toe and facial fractures 
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
 
The study was not designed to measure significant differences in hip fracture, but a trend was seen 
towards reduction in new hip fractures. 
 
All cause mortality was 10% (101 patients) in the zoledronic acid-treated group compared to 13% 
(141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause 
mortality (p=0.01). 
 
The incidence of delayed hip fracture healing was comparable between zoledronic acid (34 [3.2%]) 
and placebo (29 [2.7%]). 
 
Effect on bone mineral density (BMD) 
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip 
and femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid 
resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months 
as compared to placebo. 
 
Clinical efficacy in men  
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD 
assessed at 24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was 
observed for patients treated with zoledronic acid as compared to the effects observed in post-
menopausal women in the HORIZON-PFT study. The study was not powered to show a reduction in 
clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with zoledronic 
acid versus 8.7% for placebo. 
 
In another study in men (study CZOL446M2308) an annual infusion of zoledronic acid was non-
inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to 
baseline. 
 
Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy  
The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated 
with long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-

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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 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 

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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 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 Pharma 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 

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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 
 
6.2 Incompatibilities 
 
This medicinal product must not be allowed to come into contact with any calcium-containing 
solutions. It must not be mixed or given intravenously with any other medicinal products. 
 
6.3 Shelf life 
 
18 months 
 
After opening: Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C 
and 25ºC. 
 

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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 solution. 
 
Zoledronic acid Teva Pharma is supplied in packs of 1 bottle and multipacks of 5 (5 x 1) or 
10 (10 x 1) bottles. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
For single use only. 
Only clear solution free from particles and discoloration should be used. 
 
If refrigerated, allow the refrigerated solution to reach room temperature before administration. 
Aseptic techniques must be followed during the preparation of the infusion. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/772/001 
EU/1/12/772/002 
EU/1/12/772/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 August 2012 
Date of latest renewal:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
 

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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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http://www.ema.europa.eu/�


18 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 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 Teva Pharma. This 
is especially important for the elderly (≥ 65 years) and for patients receiving diuretic therapy. 
 
Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Teva 
Pharma 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 Teva Pharma 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 Teva Pharma on an individual patient basis, particularly after 5 or more years of use. 
 
 

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In patients with a recent low-trauma hip fracture, it is recommended to give the zoledronic acid 
infusion at least two weeks after hip fracture repair (see section 5.1). In patients with a recent low-
trauma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the 
intramuscular route is recommended prior to the first zoledronic acid infusion. 
 
Paget’s disease 
For the treatment of Paget’s disease, Zoledronic acid Teva Pharma 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 Teva Pharma. 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 Teva Pharma 
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 Teva Pharma 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 Teva Pharma is contraindicated in patients with creatinine clearance < 35 ml/min (see 
sections 4.3 and 4.4). 
 
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min. 
 
Patients with hepatic impairment  
No dose adjustment is required (see section 5.2). 
 
Elderly (≥ 65 years) 
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in 
elderly patients and younger subjects. 
 
Paediatric population  
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 Teva Pharma is administered via a vented infusion line and given slowly at a constant 
infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of 
Zoledronic acid Teva Pharma, see section 6.6.  
 
Patients treated with Zoledronic acid Teva Pharma should be given the package leaflet and the patient 
reminder card. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients 

listed in section 6.1. 
 
- Patients with hypocalcaemia (see section 4.4). 
 
- Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4). 
 
- Pregnancy and breast-feeding (see section 4.6). 
 

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4.4 Special warnings and precautions for use 
 
Renal function 
The use of Zoledronic acid Teva Pharma in patients with severe renal impairment (creatinine clearance 
< 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. 
 
Renal impairment has been observed following the administration of zoledronic acid (see section 4.8), 
especially in patients with pre-existing renal dysfunction or other risks including advanced age, 
concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or 
dehydration occurring after zoledronic acid administration. Renal impairment has been observed in 
patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely 
occurred in patients with underlying renal impairment or with any of the risk factors described above. 
 
The following precautions should be taken into account to minimise the risk of renal adverse 
reactions:  
• Creatinine clearance should be calculated based on actual body weight using the 

Cockcroft-Gault formula before each Zoledronic acid Teva Pharma 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 Pharma 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 Pharma.  
• A single dose of Zoledronic acid Teva Pharma 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 Teva Pharma (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 Teva Pharma 
(see section 4.8). 
 
Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Teva 
Pharma 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 Teva Pharma 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 Teva Pharma is recommended for patients with Paget´s disease. 
 
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported 
in patients taking bisphosphonates, including zoledronic acid (see section 4.8). 
 
Osteonecrosis of the jaw (ONJ)  
ONJ has been reported in the post-marketing setting in patients receiving Zoledronic acid Teva 
Pharma for osteoporosis (see section 4.8). 
 
The start of treatment or of a new course of treatment should be delayed in patients with unhealed 
open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual 
benefit-risk assessment is recommended prior to treatment with Zoledronic acid Teva Pharma in 

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patients with concomitant risk factors. 
 
The following should be considered when evaluating a patient’s risk of developing ONJ: 
- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent 

compounds), route of administration (higher risk for parenteral administration) and cumulative 
dose of bone resorption therapy. 

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking. 
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to 

head and neck. 
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, 

invasive dental procedures, e.g. tooth extractions. 
 
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, 
and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of 
sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental 
procedures should be performed with caution and avoided in close proximity to zoledronic acid 
treatment. 
 
The management plan for patients who develop ONJ should be set up in close collaboration between 
the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of 
zoledronic acid treatment should be considered until the condition resolves and contributing risk 
factors are mitigated where possible. 
 
Osteonecrosis of the external auditory canal 
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in 
association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory 
canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The 
possibility of osteonecrosis of the external auditory canal should be considered in patients receiving 
bisphosphonates who present with ear symptoms including chronic ear infections. 
 
Atypical fractures of the femur 
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate 
therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short 
oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just 
above the supracondylar flare. These fractures occur after minimal or no trauma and some patients 
experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to 
months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the 
contralateral femur should be examined in bisphosphonate-treated patients who have sustained a 
femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of 
bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered 
pending evaluation of the patient, based on an individual benefit risk assessment. 
 
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and 
any patient presenting with such symptoms should be evaluated for an incomplete femur fracture. 
 
General 
The incidence of post-dose symptoms occuring within the first three days after administration of 
Zoledronic acid Teva Pharma can be reduced with the administration of paracetamol or ibuprofen 
shortly following Zoledronic acid Teva Pharma administration. 
 
Other products containing zoledronic acid as an active substance are available for oncology 
indications. Patients being treated with Zoledronic acid Teva Pharma should not be treated with such 
products or any other bisphosphonate concomitantly, since the combined effects of these agents are 
unknown. 
 
Excipients 

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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 Teva 
Pharma is administered in conjunction with medicinal products that can significantly impact renal 
function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4). 
 
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are 
primarily excreted via the kidney may increase. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Zoledronic acid Teva Pharma is not recommended in women of childbearing potential. 
 
Pregnancy  
Zoledronic acid Teva Pharma 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 Teva Pharma is contraindicated during breast-feeding (see section 4.3). It is unknown 
whether zoledronic acid is excreted into human milk. 
 
Fertility 
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 
generation. This resulted in exaggerated pharmacological effects considered related to the compound’s 
inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a 
bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded 
determining a definitive effect of zoledronic acid on fertility in humans. 
 
4.7 Effects on ability to drive and use machines 
 
Adverse reactions, such as dizziness, may affect the ability to drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% 
after the first, second and third infusion, respectively. Incidence of individual adverse reactions 
following the first infusion was: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), 
arthralgia (4.8%) and headache (5.1%). 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. 
 
Tabulated list of adverse reactions 

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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 Decreased appetite  
Psychiatric disorders  Uncommon  Insomnia  
Nervous system disorders  Common  Headache, dizziness  
 Uncommon Lethargy, paraesthesia, somnolence, 

tremor, syncope, dysgeusia  
Eye disorders  Common  Ocular hyperaemia  
 Uncommon  Conjunctivitis, eye pain  
 Rare  Uveitis, episcleritis, iritis  
 Not known**  Scleritis and parophthalmia  
Ear and labyrinth disorders  Uncommon  Vertigo  
Cardiac disorders  Common  Atrial fibrillation  
 Uncommon  Palpitations  
Vascular disorders  Uncommon  Hypertension, flushing  
 Not known** Hypotension (some of the patients had 

underlying risk factors)  
Respiratory, thoracic and mediastinal 
disorders  

Uncommon  Cough, dyspnoea  

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

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

 

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

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

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

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

 Very rare Osteonecrosis of the external auditory 
canal† (bisphosphonate class adverse 
reaction) 

 Not known** Osteonecrosis of the jaw (see 

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sections 4.4 and 4.8 Class effects)
Renal and urinary disorders 
 

Uncommon Blood creatinine increased, pollakiuria, 
proteinuria

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

General disorders and administration site 
conditions 

Very common Pyrexia 

 Common Influenza-like illness, chills, fatigue, 
asthenia, pain, malaise, infusion site 
reaction

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

 Not known** Dehydration secondary to 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. 
 
Description of selected adverse reactions 
 
Atrial fibrillation 
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial 
fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving 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. 
 
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.  

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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  
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with 
medicinal products that inhibit bone resorption, including zoledronic acid (see section 4.4). In a large 
clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with 
zoledronic acid and one patient treated with placebo. Cases of ONJ have been reported in the post-
marketing setting for Zoledronic acid Teva Pharma. 
 
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 

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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) 
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.  
 

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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 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). 
 

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

acid 
(N=1,065) 
event rate 

(%) 

Placebo 
(N=1,062) 
event rate 

(%) 

Absolute reduction 
in fracture event 

rate % 
(CI) 

Relative risk 
reduction in 

fracture incidence 
% (CI) 

Any clinical fracture (1) 8.6 13.9 5.3 (2.3, 8.3) 35 (16, 50)** 
Clinical vertebral fracture (2) 1.7 3.8 2.1 (0.5, 3.7) 46 (8, 68)* 
Non-vertebral fracture (1) 7.6 10.7 3.1 (0.3, 5.9) 27 (2, 45)* 
*p-value <0.05, **p-value <0.01 
(1) Excluding finger, toe and facial fractures 
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
 
The study was not designed to measure significant differences in hip fracture, but a trend was seen 
towards reduction in new hip fractures. 
 
All cause mortality was 10% (101 patients) in the zoledronic acid-treated group compared to 13% 
(141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause 
mortality (p=0.01). 
 
The incidence of delayed hip fracture healing was comparable between zoledronic acid (34 [3.2%]) 
and placebo (29 [2.7%]). 
 
Effect on bone mineral density (BMD) 
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip 
and femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid 
resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months 
as compared to placebo. 
 
Clinical efficacy in men  
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD 
assessed at 24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was 
observed for patients treated with zoledronic acid as compared to the effects observed in post-
menopausal women in the HORIZON-PFT study. The study was not powered to show a reduction in 
clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with zoledronic 
acid versus 8.7% for placebo. 
 

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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 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). 
 

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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 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 

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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 Pharma 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 
 
6.2 Incompatibilities 
 
This medicinal product must not be allowed to come into contact with any calcium-containing 
solutions. It must not be mixed or given intravenously with any other medicinal products. 
 
6.3 Shelf life 
 

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18 months  
 
After opening: 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 solution. 
 
Zoledronic acid Teva Pharma is supplied in multipacks  of 5 (5 x 1) or 10 (10 x 1) bags . 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
For single use only. 
Only clear solution free from particles and discoloration should be used.  
 
If refrigerated, allow the refrigerated solution to reach room temperature before administration. 
Aseptic techniques must be followed during the preparation of the infusion.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/772/003 
EU/1/12/772/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 August 2012 
Date of latest renewal:  
 
 
10. DATE OF REVISION OF THE TEXT 

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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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34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 manufacturers responsible for batch release 
 
Teva Pharmaceutical Works Private Limited Company 
Táncsics Mihály út 82 
HU-2100 Godollo 
Hungary 
 
Pharmachemie B.V. 
Swensweg 5  
2031 GA Haarlem 
The Netherland 
 
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 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The 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 a result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Additional risk minimisation measures 
 
The Marketing Authorisation Holder (MAH) shall provide an educational programme targeting all 
physicians who are expected to prescribe/use Zoledronic acid Teva Pharma for the treatment of 
osteoporosis prior to the launch in Member States. The MAH must agree the content and format of the 
educational material, together with a communication plan, with the national competent authorities in 

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Member States prior to distribution of the educational programme. The educational programme 
contains the following: 
• Physician educational material  
• Patient educational material 
 
The physician educational material should contain the following key messages:  
 Need to calculate creatinine clearance based on actual body weight using the Cockcroft-Gault 

formula before each treatment with Zoledronic acid Teva Pharma 
 Contraindication in patients with creatinine clearance < 35 ml/min  
 Contraindication in pregnancy and in breast-feeding women due to potential teratogenicity  
 Need to ensure appropriate hydration of the patient especially those at an advanced age and 

those receiving diurectic therapy 
 Need to infuse Zoledronic acid Teva Pharma slowly over a period of no less than 15 minutes  
 Once-yearly dosing regime  
 That all patients should be provided with the educational material and be counselled about:  

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

o Key signs and symptoms of serious adverse events  
o When to seek attention from the health care provider  

 
The patient educational material should contain the following key messages:  
 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  
 
In addition, the following documents should be included in the patient information pack: 
 Package leaflet 
 Patient reminder card on osteonecrosis of the jaw 
 

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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 
 
IMMEDIATE CARTON (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 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 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After opening: 24 hours at 2°C - 8°C 
 
 

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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 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/001 multipack with 5 bottles 
EU/1/12/772/002 multipack with 10 bottles 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 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 
 
Multipack: 5 bottles of 100 ml 
Multipack: 10 bottles of 100 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After opening: 24 hours at 2°C - 8°C 
 
 

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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 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/001 multipack with 5 bottles 
EU/1/12/772/002 multipack with 10 bottles 
 
 
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. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
PC: 
SN: 
NN: 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF UNIT PACK (with blue box) 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 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. 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After opening: 24 hours at 2°C - 8°C 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/005 1 bottle 
 
 
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. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
PC: 
SN: 
NN:

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 5 mg solution for infusion  
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 
 
100 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
 
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 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/001 multipack with 5 bottles 
EU/1/12/772/002 multipack with 10 bottles 
EU/1/12/772/005 1 bottle 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BAG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 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 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After opening: 24 hours at 2°C - 8°C 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C.  
 
 
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 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/003 multipack with 5 bags 
EU/1/12/772/004 multipack with 10 bags 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Me

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OVERPOUCH  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 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 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After opening: 24 hours at 2°C - 8°C 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C.  
 
 
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 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/003 multipack with 5 bags 
EU/1/12/772/004 multipack with 10 bags 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA Me

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Teva Pharma 5 mg solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 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 of 100 ml 
Multipack: 10 bags of 100 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After opening: 24 hours at 2°C - 8°C 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
 
 
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 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/772/003 multipack with 5 bags 
EU/1/12/772/004 multipack with 10 bags 
 
 
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. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the user 

 
Zoledronic acid Teva Pharma 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 Pharma is and what it is used for 
2. What you need to know before you are given Zoledronic acid Teva Pharma 
3. How Zoledronic acid Teva Pharma is given 
4. Possible side effects 
5. How to store Zoledronic acid Teva Pharma 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid Teva Pharma is and what it is used for 
 
Zoledronic acid Teva Pharma contains the active substance zoledronic acid. It belongs to a group of 
medicines called bisphosphonates and is used to treat post-menopausal women and adult men with 
osteoporosis or osteoporosis caused by treatment with corticosteroids used to treat inflammation, and 
Paget’s disease of the bone in adults. 
 
Osteoporosis  
Osteoporosis is a disease that involves the thinning and weakening of the bones and is common in 
women after the menopause, but can also occur in men. At the menopause, a woman’s ovaries stop 
producing the female hormone oestrogen, which helps keep bones healthy. Following the menopause 
bone loss occurs, bones become weaker and break more easily. Osteoporosis could also occur in men 
and women because of the long term use of steroids, which can affect the strength of bones. Many 
patients with osteoporosis have no symptoms but they are still at risk of breaking bones because 
osteoporosis has made their bones weaker. Decreased circulating levels of sex hormones, mainly 
oestrogens converted from androgens, also play a role in the more gradual bone loss observed in men. 
In both women and men, Zoledronic acid Teva Pharma strengthens the bone and therefore makes it 
less likely to break. Zoledronic acid Teva Pharma 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 Pharma 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 Pharma 
 
Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given 
Zoledronic acid Teva Pharma. 
 
You must not be given Zoledronic acid Teva Pharma:  

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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, pharmacist or nurse before you are given Zoledronic acid Teva Pharma:  
-  if you are being treated with any medicine containing zoledronic acid, which is also the active 

substance of Zoledronic acid Teva Pharma (zoledronic acid is used in adult patients with certain 
types of cancer to prevent bone complications or to reduce the amount of calcium). 

-  if you have a kidney problem, or used to have one.  
-  if you are unable to take daily calcium supplements.  
-  if you have had some or all of the parathyroid glands in your neck surgically removed.  
-  if you have had sections of your intestine removed.  
 
A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported in the 
post-marketing setting in patients receiving Zoledronic acid Teva Pharma for osteoporosis. ONJ can 
also occur after stopping treatment. 
 
It is important to try and prevent ONJ developing as it a painful condition that can be difficult to treat. 
In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions you 
should take. 
 
Before receiving Zoledronic acid Teva Pharma treatment, tell your doctor, pharmacist or nurse if 
- you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

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

disorders); 
- you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
- you have cancer. 
 
Your doctor may ask you to undergo a dental examination before you start treatment with Zoledronic 
acid Teva Pharma. 
 
While being treated with Zoledronic acid Teva Pharma, you should maintain good oral hygiene 
(including regular teeth brushing) and receive routine dental check-ups. If you wear dentures you 
should make sure these fit properly. If you are under dental treatment or are due to undergo dental 
surgery (e.g. tooth extractions), inform your doctor about your dental treatment and tell your dentist 
that you are being treated with Zoledronic acid Teva Pharma. Contact your doctor and dentist 
immediately if you experience any problems with your mouth or teeth such as loose teeth, pain or 
swelling, or non-healing of sores or discharge, as these could be signs of osteonecrosis of the jaw. 
 
Monitoring test 
Your doctor should do a blood test to check your kidney function (levels of creatinine) before each 
dose of Zoledronic acid Teva Pharma. 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 Pharma, as directed by your 
healthcare provider. 
 
Children and adolescents 
Zoledronic acid Teva Pharma is not recommended for anyone under 18 years of age. The use of 
Zoledronic acid Teva Pharma in children and adolescents has not been studied. 
 
Other medicines and Zoledronic acid Teva Pharma 

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Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
It is important for your doctor to know all the medicines you are taking, especially if you are taking 
any medicines known to be harmful to your kidneys (e.g. aminoglycosides) or diuretics (“waterpills”) 
that may cause dehydration. 
 
Pregnancy and breast-feeding 
You must not be given Zoledronic acid Teva Pharma 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 using this medicine.  
 
Driving and using machines  
If you feel dizzy while taking Zoledronic acid Teva Pharma, do not drive or use machines until you 
feel better. 
 
Zoledronic acid Teva Pharma contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially “sodium–free.” 
 
 
3. How Zoledronic acid Teva Pharma 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 Pharma 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 Pharma works for one year. Your doctor will let you know 
when to return for your next dose.  
 
Paget’s disease 
For the treatment of Paget’s disease, Zoledronic acid Teva Pharma should be prescribed only by 
physicians with experience in the treatment of Paget’s disease of the bone. 
 
The usual dose is 5 mg, given to you as one initial infusion into a vein by your doctor or nurse. The 
infusion will take at least 15 minutes. Zoledronic acid Teva Pharma 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 Pharma. 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 Pharma 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 Pharma, as directed by your doctor. This will help prevent dehydration. You 
may eat normally on the day you are treated with Zoledronic acid Teva Pharma. This is especially 
important in patients who take diuretics (“water pills”) and in elderly patients (age 65 years or over). 

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If you missed a dose of Zoledronic acid Teva Pharma  
Contact your doctor or hospital as soon as possible to re-schedule your appointment.  
 
Before stopping Zoledronic acid Teva Pharma therapy  
If you are considering stopping Zoledronic acid Teva Pharma 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 Pharma. 
 
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 Pharma. 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 Pharma. 
 
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 
Pharma for the treatment of postmenopausal osteoporosis. It is currently unclear whether Zoledronic 
acid Teva Pharma 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 Pharma. 
 
Uncommon (may affect up to 1 in 100 people) 
Swelling, redness, pain and itching to the eyes or eye sensitivity to light. 
 
Very rare (may affect up to 1 in 10,000 people) 
Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These could 
be signs of bone damage in the ear. 
 
Not known (frequency cannot be estimated from the available data) 
Pain in the mouth, and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness 
or a feeling of heaviness in the jaw, or loosening of a tooth; these could be signs of bone damage in 
the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms 
while being treated with Zoledronic acid Teva Pharma or after stopping treatment. 
 
Kidney disorders (e.g. decreased urine output) may occur. Your doctor should do a blood test to check 
your kidney function before each dose of Zoledronic acid Teva Pharma. 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 Pharma, as directed by your healthcare provider. 
 
If you experience any of the above side effects, you should contact your doctor immediately. 
 
Zoledronic acid Teva Pharma 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 

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Headache, dizziness, sickness, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or 
joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain), 
chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, swelling and/or pain at 
the infusion site. 
 
In patients with Paget’s disease symptoms due to low blood calcium, such as muscle spasms, or 
numbness, or a tingling sensation especially in the area around the mouth have been reported.  
 
Uncommon: may affect up to 1 in 100 people 
Flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness, 
sleepiness which may include reduced alertness and awareness, tingling sensation or numbness, 
extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or 
inflammation with pain and redness, spinning sensation, increased blood pressure, flushing, cough, 
shortness of breath, upset stomach, abdominal pain, constipation, dry mouth, heartburn, skin rash, 
excessive sweating, itching, skin reddening, neck pain, stiffness in muscles, bones and/or joints, joint 
swelling, muscle spasms, shoulder pain, pain in your chest muscles and rib cage, joint inflammation, 
muscular weakness, abnormal kidney test results, abnormal frequent urination, swelling of hands, 
ankles or feet, thirst, toothache, taste disturbances.  
 
Rare (may affect up to 1 in 1,000 people) 
Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may 
occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or 
groin as this may be an early indication of a possible fracture of the thigh bone. 
 
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. 
 
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 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 Pharma 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid Teva Pharma properly. 
 
Keep this medicine out of the sight and reach of children. 
 
-  Do not use this medicine after the expiry date which is stated on the carton and bottle 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 

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59 

 
What Zoledronic acid Teva Pharma 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 Pharma looks like and contents of the pack 
Zoledronic acid Teva Pharma is a clear and colourless solution. 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 
Netherlands  
Manufacturer 
Teva Pharmaceutical Works Private Limited Company 
Táncsics Mihály út 82 
H-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: 
 
België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG 
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 N.V./S.A./AG, 
Belgique/Belgien 
Tél/Tel: +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  
Teva Pharmaceuticals Ireland, L-Irlanda 
Tel: +353 51 321740 

 
Deutschland 
TEVA GmbH 
Tel: +49 731 402 08 

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

 
Eesti 
UAB "Sicor Biotech" Eesti filiaal 
Tel: +372 661 0801 

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

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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: +351 214 235 910 

 
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, Finnland 
Sími: +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 

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

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

Latvija 
UAB "Sicor Biotech" filiāle Latvijā  
Tel: +371 673 23 666 

United Kingdom 
Teva UK Limited 
Tel: +44 1323 501 111 

 
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.. 
 
-------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
How to prepare and administer Zoledronic acid Teva Pharma  
 
-  Zoledronic acid Teva Pharma 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 Pharma 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 

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61 

Teva Pharma 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 Pharma  
 
-  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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Package leaflet: Information for the user 

 
Zoledronic acid Teva Pharma 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 Pharma is and what it is used for 
2. What you need to know before you are given Zoledronic acid Teva Pharma 
3. How Zoledronic acid Teva Pharma is given 
4. Possible side effects 
5. How to store Zoledronic acid Teva Pharma 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid Teva Pharma is and what it is used for 
 
Zoledronic acid Teva Pharma contains the active substance zoledronic acid. It belongs to a group of 
medicines called bisphosphonates and is used to treat post-menopausal women and adult men with 
osteoporosis or osteoporosis caused by treatment with corticosteroids used to treat inflammation, and 
Paget’s disease of the bone in adults. 
 
Osteoporosis  
Osteoporosis is a disease that involves the thinning and weakening of the bones and is common in 
women after the menopause, but can also occur in men. At the menopause, a woman’s ovaries stop 
producing the female hormone oestrogen, which helps keep bones healthy. Following the menopause 
bone loss occurs, bones become weaker and break more easily. Osteoporosis could also occur in men 
and women because of the long term use of steroids, which can affect the strength of bones. Many 
patients with osteoporosis have no symptoms but they are still at risk of breaking bones because 
osteoporosis has made their bones weaker. Decreased circulating levels of sex hormones, mainly 
oestrogens converted from androgens, also play a role in the more gradual bone loss observed in men. 
In both women and men, Zoledronic acid Teva Pharma strengthens the bone and therefore makes it 
less likely to break. Zoledronic acid Teva Pharma 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 Pharma 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 Pharma 
 
Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given 
Zoledronic acid Teva Pharma.  
 
You must not be given Zoledronic acid Teva Pharma:  

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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, pharmacist or nurse before you are given Zoledronic acid Teva Pharma:  
-  if you are being treated with any medicine containing zoledronic acid, which is also the active 

substance of Zoledronic acid Teva Pharma (zoledronic acid is used in adult patients with certain 
types of cancer to prevent bone complications or to reduce the amount of calcium). 

-  if you have a kidney problem, or used to have one.  
-  if you are unable to take daily calcium supplements.  
-  if you have had some or all of the parathyroid glands in your neck surgically removed.  
-  if you have had sections of your intestine removed.  
 
A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported in the 
post-marketing setting in patients receiving Zoledronic acid Teva Pharma for osteoporosis. ONJ can 
also occur after stopping treatment. 
 
It is important to try and prevent ONJ developing as it a painful condition that can be difficult to treat. 
In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions you 
should take. 
 
Before receiving Zoledronic acid Teva Pharma treatment, tell your doctor, pharmacist or nurse if 
- you have any problems with your mouth or teeth such as poor dental health, gum disease, or a 

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

disorders); 
- you are taking medicines called corticosteroids (such as prednisolone or dexamethasone) 
- you have cancer. 
 
Your doctor may ask you to undergo a dental examination before you start treatment with Zoledronic 
acid Teva Pharma. 
 
While being treated with Zoledronic acid Teva Pharma, you should maintain good oral hygiene 
(including regular teeth brushing) and receive routine dental check-ups. If you wear dentures you 
should make sure these fit properly. If you are under dental treatment or are due to undergo dental 
surgery (e.g. tooth extractions), inform your doctor about your dental treatment and tell your dentist 
that you are being treated with Zoledronic acid Teva Pharma. Contact your doctor and dentist 
immediately if you experience any problems with your mouth or teeth such as loose teeth, pain or 
swelling, or non-healing of sores or discharge, as these could be signs of osteonecrosis of the jaw. 
 
Monitoring test 
Your doctor should do a blood test to check your kidney function (levels of creatinine) before each 
dose of Zoledronic acid Teva Pharma. 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 Pharma, as directed by your 
healthcare provider. 
 
Children and adolescents 
Zoledronic acid Teva Pharma is not recommended for anyone under 18 years of age. The use of 
Zoledronic acid Teva Pharma in children and adolescents has not been studied.  
 
Other medicines and Zoledronic acid Teva Pharma 

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Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
 
It is important for your doctor to know all the medicines you are taking, especially if you are taking 
any medicines known to be harmful to your kidneys (e.g. aminoglycosides) or diuretics (“waterpills”) 
that may cause dehydration.  
 
Pregnancy and breast-feeding 
You must not be given Zoledronic acid Teva Pharma 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 using this medicine.  
 
Driving and using machines  
If you feel dizzy while taking Zoledronic acid Teva Pharma, do not drive or use machines until you 
feel better. 
 
Zoledronic acid Teva Pharma contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per 100 ml; i.e. essentially “sodium –free.” 
 
 
3. How Zoledronic acid Teva Pharma 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 Pharma 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 Pharma works for one year. Your doctor will let you know 
when to return for your next dose.  
 
Paget’s disease  
For the treatment of Paget’s disease, Zoledronic acid Teva Pharma should be prescribed only by 
physicians with experience in the treatment of Paget’s disease of the bone. 
 
The usual dose is 5 mg, given to you as one initial infusion into a vein by your doctor or nurse. The 
infusion will take at least 15 minutes. Zoledronic acid Teva Pharma 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 Pharma. 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 Pharma 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 Pharma, as directed by your doctor. This will help prevent dehydration. You 
may eat normally on the day you are treated with Zoledronic acid Teva Pharma, This is especially 
important in patients who take diuretics (“water pills”) and in elderly patients (age 65 years or over). 

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If you missed a dose of Zoledronic acid Teva Pharma  
Contact your doctor or hospital as soon as possible to re-schedule your appointment.  
 
Before stopping Zoledronic acid Teva Pharma therapy  
If you are considering stopping Zoledronic acid Teva Pharma 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 Pharma. 
 
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 Pharma. 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 Pharma.  
 
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 
Pharma for the treatment of postmenopausal osteoporosis. It is currently unclear whether Zoledronic 
acid Teva Pharma 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 Pharma. 
 
Uncommon (may affect up to 1 in 100 people)  
Swelling, redness, pain and itching to the eyes or eye sensitivity to light. 
 
Very rare (may affect up to 1 in 10,000 people) 
Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These could 
be signs of bone damage in the ear. 
 
Not known (frequency cannot be estimated from the available data) 
Pain in the mouth, and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness 
or a feeling of heaviness in the jaw, or loosening of a tooth; these could be signs of bone damage in 
the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms 
while being treated with Zoledronic acid Teva Pharma or after stopping treatment. 
 
Kidney disorders (e.g. decreased urine output) may occur. Your doctor should do a blood test to check 
your kidney function before each dose of Zoledronic acid Teva Pharma. 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 Pharma, as directed by your healthcare provider. 
 
If you experience any of the above side effects, you should contact your doctor immediately. 
 
Zoledronic acid Teva Pharma 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  

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66 

Headache, dizziness, sickness, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or 
joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain), 
chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, swelling and/or pain at 
the infusion site. 
 
In patients with Paget’s disease: symptoms due to low blood calcium, such as muscle spasms, or 
numbness, or a tingling sensation especially in the area around the mouth have been reported.  
 
Uncommon: may affect up to 1 in 100 people 
Flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness, 
sleepiness which may include reduced alertness and awareness, tingling sensation or numbness, 
extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or 
inflammation with pain and redness, spinning sensation, increased blood pressure, flushing, cough, 
shortness of breath, upset stomach, abdominal pain, constipation, dry mouth, heartburn, skin rash, 
excessive sweating, itching, skin reddening, neck pain, stiffness in muscles, bones and/or joints, joint 
swelling, muscle spasms, shoulder pain, pain in your chest muscles and rib cage, joint inflammation, 
muscular weakness, abnormal kidney test results, abnormal frequent urination, swelling of hands, 
ankles or feet, thirst, toothache, taste disturbances.  
 
Rare (may affect up to 1 in 1,000 people) 
Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may 
occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or 
groin as this may be an early indication of a possible fracture of the thigh bone. 
 
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. 
 
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 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 Pharma 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid Teva Pharma properly. 
 
Keep this medicine out of the sight and reach of children. 
 
-  Do not use this medicine after the expiry date which is stated on the carton and bag after EXP. 

The expiry date refers to the last day of that month. 
-  Store below 30°C.  
-  After opening the bag, 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 

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67 

 
What Zoledronic acid Teva Pharma 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 Pharma looks like and contents of the pack 
Zoledronic acid Teva Pharma is a clear and colourless solution. 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 
Netherlands  
 
Manufacturer 
Teva Pharmaceutical Works Private Limited Company 
Táncsics Mihály út 82 
H-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: 
 
België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG 
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 N.V./S.A./AG, 
Belgique/Belgien 
Tél/Tel: +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  
Teva Pharmaceuticals Ireland, L-Irlanda 
Tel: +353 51 321740 

 
Deutschland 
TEVA GmbH 
Tel: +49 731 402 08 

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

 
Eesti 
UAB "Sicor Biotech" Eesti filiaal 

 
Norge 
Teva Norway AS 

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68 

Tel: +372 661 0801 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: +351 214 235 910 

 
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, Finnland 
Sími: +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 

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

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

Latvija 
UAB "Sicor Biotech" filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1323 501 111 

 
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.. 
 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
How to prepare and administer Zoledronic acid Teva Pharma 
 
-  Zoledronic acid Teva Pharma 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 Pharma must not be mixed or given 

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69 

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 Pharma 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 Pharma  
 
-  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 bag after EXP.  
-  Store below 30°C.  
-  After opening the bag, 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