Zoledronic acid Actavis

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Actavis 4 mg/5 ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial with 5 ml concentrate contains 4 mg zoledronic acid (as monohydrate). 
 
One ml concentrate contains 0.8 mg zoledronic acid (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear and colourless concentrate for solution for infusion. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
- Prevention of skeletal related events (pathological fractures, spinal compression, radiation or 

surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced 
malignancies involving bone. 

 
- Treatment of adult patients with tumour-induced hypercalcaemia (TIH).  
 
4.2 Posology and method of administration 
 
Zoledronic acid Actavis must only be prescribed and administered to patients by healthcare 
professionals experienced in the administration of intravenous bisphosphonates. Patients treated with 
Zoledronic acid Actavis should be given the package leaflet and the patient reminder card. 
 
Posology 
Prevention of skeletal related events in patients with advanced malignancies involving bone 
Adults and older people 
The recommended dose in the prevention of skeletal related events in patients with advanced 
malignancies involving bone is 4 mg zoledronic acid every 3 to 4 weeks.  
  
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D 
daily. 
 
The decision to treat patients with bone metastases for the prevention of skeletal related events should 
consider that the onset of treatment effect is 2-3 months. 
 
Treatment of TIH 
Adults and older people 
The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥ 12.0 mg/dl or 
3.0 mmol/l) is a single dose of 4 mg zoledronic acid.  
 



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Renal impairment 
TIH: 
Zoledronic acid Actavis treatment in TIH patients who also have severe renal impairment should be 
considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients 
with serum creatinine > 400 micromol/l or > 4.5 mg/dl were excluded. No dose adjustment is 
necessary in TIH patients with serum creatinine < 400 micromol/l or < 4.5 mg/dl (see section 4.4). 
 
Prevention of skeletal related events in patients with advanced malignancies involving bone: 
When initiating treatment with Zoledronic acid Actavis in patients with multiple myeloma or 
metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should 
be determined. CLcr is calculated from serum creatinine using the Cockcroft-Gault formula. 
Zoledronic acid Actavis is not recommended for patients presenting with severe renal impairment 
prior to initiation of therapy, which is defined for this population as CLcr < 30 ml/min. In clinical 
trials with zoledronic acid, patients with serum creatinine > 265 micromol/l or > 3.0 mg/dl were 
excluded. 
 
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation 
of therapy, which is defined for this population as CLcr 30-60 ml/min, the following Zoledronic acid 
Actavis dose is recommended (see also section 4.4): 
 

Baseline Creatinine Clearance (ml/min) Zoledronic acid Actavis recommended dose* 
> 60 4.0 mg zoledronic acid 

50-60 3.5 mg* zoledronic acid 
40-49 3.3 mg* zoledronic acid 
30-39 3.0 mg* zoledronic acid 

* Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr = 75 ml/min). The 
reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in 
patients with creatinine clearance of 75 ml/min. 
 
Following initiation of therapy, serum creatinine should be measured prior to each dose of Zoledronic 
acid Actavis and treatment should be withheld if renal function has deteriorated. In the clinical trials, 
renal deterioration was defined as follows: 
- For patients with normal baseline serum creatinine (< 1.4 mg/dl or < 124 micromol/l), an 

increase of 0.5 mg/dl or 44 micromol/l; 
- For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 micromol/l), an increase of 

1.0 mg/dl or 88 micromol/l. 
 
In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returned 
to within 10% of the baseline value (see section 4.4). Zoledronic acid Actavis treatment should be 
resumed at the same dose as that given prior to treatment interruption. 
 
Paediatric population 
The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been 
established. Currently available data are described in section 5.1 but no recommendation on a 
posology can be made. 
 
Method of administration 
Intravenous use. 
Zoledronic acid Actavis 4 mg/5 ml concentrate for solution for infusion, further diluted in 100 ml (see 
section 6.6), should be given as a single intravenous infusion in no less than 15 minutes. 
 
In patients with mild to moderate renal impairment, reduced zoledronic acid doses are recommended 
(see section “Posology” above and section 4.4). 
 



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Instructions for preparing reduced doses of Zoledronic acid Actavis 
Withdraw an appropriate volume of the concentrate needed, as follows: 
- 4.4 ml for 3.5 mg dose 
- 4.1 ml for 3.3 mg dose 
- 3.8 ml for 3.0 mg dose 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. The 
withdrawn amount of concentrate must be further diluted in 100 ml of sterile 0.9% w/v sodium 
chloride solution or 5% w/v glucose solution. The dose must be given as a single intravenous infusion 
over no less than 15 minutes. 
 
Zoledronic acid Actavis must not be mixed with calcium or other divalent cation-containing infusion 
solutions such as lactated Ringer’s solution, and should be administered as a single intravenous 
solution in a separate infusion line. 
 
Patients must be maintained well hydrated prior to and following administration of Zoledronic acid 
Actavis. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients 

listed in section 6.1  
• Breast-feeding (see section 4.6) 
 
4.4 Special warnings and precautions for use 
 
General 
Patients must be assessed prior to administration of Zoledronic acid Actavis to ensure that they are 
adequately hydrated. 
 
Overhydration should be avoided in patients at risk of cardiac failure. 
 
Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate 
and magnesium, should be carefully monitored after initiating Zoledronic acid Actavis therapy. If 
hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplemental therapy 
may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function 
impairment, therefore careful renal function monitoring should be considered. 
 
Other products containing zoledronic acid as active substances are available for osteoporosis 
indications and treatment of Paget´s disease of the bone. Patients being treated with Zoledronic acid 
Actavis should not be treated with such products or any other bisphosphonate concomitantly, since the 
combined effects of these agents are unknown. 
 
Renal insufficiency 
Patients with TIH and evidence of deterioration in renal function should be appropriately evaluated 
with consideration given as to whether the potential benefit of treatment with Zoledronic acid Actavis 
outweighs the possible risk. 
 
The decision to treat patients with bone metastases for the prevention of skeletal related events should 
consider that the onset of treatment effect is 2-3 months. 
 
Zoledronic acid, used as indicated in sections 4.1 and 4.2, has been associated with reports of renal 
dysfunction. Factors that may increase the potential for deterioration in renal function include 
dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid and other 
bisphosphonates as well as use of other nephrotoxic medicinal products. While the risk is reduced with 
a dose of 4 mg zoledronic acid administered over 15 minutes, deterioration in renal function may still 
occur. Renal deterioration, progression to renal failure and dialysis have been reported in patients after 



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the initial dose or a single dose of 4 mg zoledronic acid. Increases in serum creatinine also occur in 
some patients with chronic administration of zoledronic acid at recommended doses for prevention of 
skeletal related events, although less frequently. 
 
Patients should have their serum creatinine levels assessed prior to each dose of Zoledronic acid 
Actavis. Upon initiation of treatment in patients with bone metastases with mild to moderate renal 
impairment, lower doses of zoledronic acid are recommended. In patients who show evidence of renal 
deterioration during treatment, Zoledronic acid Actavis should be withheld. Zoledronic acid Actavis 
should only be resumed when serum creatinine returns to within 10% of baseline. Zoledronic acid 
Actavis treatment should be resumed at the same dose as that given prior to treatment interruption. 
 
In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data in 
patients with severe renal impairment (in clinical trials defined as serum creatinine ≥ 400 micromol/l 
or ≥ 4.5 mg/dl for patients with TIH and ≥ 265 micromol/l or ≥ 3.0 mg/dl for patients with cancer and 
bone metastases, respectively) at baseline and only limited pharmacokinetic data in patients with 
severe renal impairment at baseline (creatinine clearance < 30 ml/min), the use of Zoledronic acid 
Actavis is not recommended in patients with severe renal impairment. 
 
Hepatic insufficiency 
As only limited clinical data are available in patients with severe hepatic insufficiency, no specific 
recommendations can be given for this patient population. 
 
Osteonecrosis 
Osteonecrosis of the jaw 
Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials and in the 
post-marketing setting in patients receiving zoledronic acid. 
 
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, except in medical emergency situations. A dental examination 
with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior 
to treatment with bisphosphonates in patients with concomitant risk factors. 
 
The following risk factors should be considered when evaluating an individual’s risk of developing 
ONJ: 
- Potency of the bisphosphonate (higher risk for highly potent compounds), route of 

administration (higher risk for parenteral administration) and cumulative dose of 
bisphosphonate. 

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking. 
- Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to 

neck and head, corticosteroids. 
- History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures 

(e.g. tooth extractions) and poorly fitting dentures 
 
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, or non-healing of 
sores or discharge during treatment with Zoledronic acid Actavis. While on treatment, invasive dental 
procedures should be performed only after careful consideration and be avoided in close proximity to 
zoledronic acid administration. For patients who develop osteonecrosis of the jaw while on 
bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental 
procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment 
reduces the risk of osteonecrosis of the jaw.  
 
The 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. 
 



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Osteonecrosis of other anatomical sites 
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. 
 
Additionally, there have been sporadic reports of osteonecrosis of other sites, including the hip and 
femur, reported predominantly in adult cancer patients treated with zoledronic acid. 
 
Musculoskeletal pain 
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain 
have been reported in patients that were given zoledronic acid as indicated in sections 4.1 and 4.2. 
However, such reports have been infrequent. The time to onset of symptoms varied from one day to 
several months after starting treatment. Most patients had relief of symptoms after stopping treatment. 
A subset had recurrence of symptoms when rechallenged with zoledronic acid or another 
bisphosphonate. 
 
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. 
 
Hypocalcaemia 
Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and 
neurologic adverse events (including convulsions, hypoaesthesia and tetany) have been reported 
secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation 
have been reported. In some instances, the hypocalcaemia may be life-threatening (see section 4.8). 
Caution is advised when zoledronic acid is administered with medicinal products known to cause 
hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (see section 
4.5). Serum calcium should be measured and hypocalcaemia must be corrected before initiating 
zoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D. 
 
Zoledronic acid Actavis contains sodium 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
“sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In clinical studies, zoledronic acid, used as indicated in sections 4.1 and 4.2, has been administered 
concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without 
clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma 
proteins and does not inhibit human P450 enzymes in vitro (see section 5.2), but no formal clinical 
interaction studies have been performed. 
 



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Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop 
diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for 
longer periods than required (see section 4.4). 
 
Caution is indicated when Zoledronic acid Actavis is used with other potentially nephrotoxic 
medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing 
during treatment. 
 
In multiple myeloma patients, the risk of renal dysfunction may be increased when Zoledronic acid 
Actavis is used in combination with thalidomide. 
 
Caution is advised when Zoledronic acid Actavis is administered with anti-angiogenic medicinal 
products, as an increase in the incidence of ONJ has been observed in patients treated concomitantly 
with these medicinal products. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction 
studies with zoledronic acid have shown reproductive toxicity (see section 5.3). The potential risk for 
humans is unknown. Zoledronic acid Actavis should not be used during pregnancy. Women of child-
bearing potential should be advised to avoid becoming pregnant. 
 
Breast-feeding 
It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid Actavis is 
contraindicated in breast-feeding women (see section 4.3). 
 
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 to be related to the 
compound’s inhibition of skeletal calcium metabolisation, 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 and somnolence, may have influence on the ability to drive or use 
machines, therefore caution should be exercised with the use of Zoledronic acid Actavis along with 
driving and operating of machinery. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Within three days after zoledronic acid administration, used as indicated in sections 4.1 and 4.2, an 
acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, 
arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve 
within a few days (see description of selected adverse reactions). 
 
The following are the important identified risks with zoledronic acid in the approved indications: 
Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial 
fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are 
shown in Table 1. 
 
Tabulated list of adverse reactions 
The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and 
post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: 
 



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Table 1 
 
Adverse reactions are ranked under headings of frequency, the most frequent first, 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). 
 
Blood and lymphatic system disorders 

Common: Anaemia 
Uncommon: Thrombocytopenia, leukopenia 
Rare: Pancytopenia 

Immune system disorders 
Uncommon: Hypersensitivity reaction 
Rare: Angioneurotic oedema 

Psychiatric disorders 
Uncommon: Anxiety, sleep disturbance 
Rare: Confusion 

Nervous system disorders 
Common: Headache 
Uncommon: 
 
 
Very rare: 

Dizziness, paraesthesia,  dysgeusia, 
hypoaesthesia, hyperaesthesia, tremor, 
somnolence 
Convulsions, hypoaesthesia and tetany 
(secondary to hypocalcaemia) 

Eye disorders 
Common: Conjunctivitis 
Uncommon: 
Rare: 

Blurred vision, scleritis and orbital inflammation 
Uveitis 

Very rare: Episcleritis 
Cardiac disorders 

Uncommon: Hypertension, hypotension, atrial fibrillation, 
hypotension leading to syncope or circulatory 
collapse 

Rare: Bradycardia, cardiac arrhythmia (secondary to 
hypocalcaemia) 

Respiratory, thoracic and mediastinal disorders 
Uncommon: 
Rare: 

Dyspnoea, cough, bronchoconstriction 
Interstitial lung disease 

Gastrointestinal disorders 
Common: Nausea, vomiting, decreased appetite 
Uncommon: Diarrhoea, constipation, abdominal pain, 

dyspepsia, stomatitis, dry mouth 
Skin and subcutaneous tissue disorders 

Uncommon: Pruritus, rash (including erythematous and 
macular rash), increased sweating 

Musculoskeletal and connective tissue disorders 
Common: Bone pain, myalgia, arthralgia, generalised pain 
Uncommon: 
Very rare: 

Muscle spasms, osteonecrosis of the jaw 
Osteonecrosis of the external auditory canal 
(bisphosphonate class adverse reaction) and other 
anatomical sites including femur and hip 

Renal and urinary disorders 
Common: Renal impairment 
Uncommon: 
Rare: 

Acute renal failure, haematuria, proteinuria 
Acquired Fanconi syndrome 



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General disorders and administration site conditions 
Common: Fever, flu-like syndrome (including fatigue, 

rigors, malaise and flushing) 
Uncommon: 
 
 
 
Rare: 

Asthenia, peripheral oedema, injection site 
reactions (including pain, irritation, swelling, 
induration), chest pain, weight increase, 
anaphylactic reaction/shock, urticaria 
Arthritis and joint swelling as a symptom of acute 
phase reaction 

Investigations 
Very common: Hypophosphataemia 
Common: Blood creatinine and blood urea increased, 

hypocalcaemia 
Uncommon: Hypomagnesaemia, hypokalaemia 
Rare: Hyperkalaemia, hypernatraemia 

 
Description of selected adverse reactions 
Renal function impairment 
Zoledronic acid, used as indicated in sections 4.1 and 4.2, has been associated with reports of renal 
dysfunction. In a pooled analysis of safety data from zoledronic acid registration trials for the 
prevention of skeletal-related events in patients with advanced malignancies involving bone, the 
frequency of renal impairment adverse events suspected to be related to zoledronic acid (adverse 
reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), 
lung and other solid tumours (3.2%). Factors that may increase the potential for deterioration in renal 
function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or 
other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a 
shorter infusion time than currently recommended. Renal deterioration, progression to renal failure 
and dialysis have been reported in patients after the initial dose or a single dose of 4 mg zoledronic 
acid (see section 4.4). 
 
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, such as zoledronic acid (see section 4.4). Many of 
these patients were also receiving chemotherapy and corticosteroids and had signs of local infection 
including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions 
or other dental surgeries. 
 
Atrial fibrillation 
In one 3-year, randomised, double-blind controlled trial that evaluated the efficacy and safety of 
zoledronic acid 5 mg once yearly vs. placebo in the treatment of postmenopausal osteoporosis (PMO), 
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 5 mg and placebo, respectively. The rate of atrial fibrillation serious 
adverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) in patients receiving zoledronic 
acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in 
other trials with zoledronic acid, including those with zoledronic acid 4 mg every 3-4 weeks in 
oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single 
clinical trial is unknown. 
 
Acute phase reaction 
This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, 
headache, extremity pain, nausea, vomiting, diarrhoea, arthralgia and arthritis with subsequent joint 
swelling. The onset time is ≤ 3 days post-zoledronic acid infusion (used as indicated in sections 4.1 
and 4.2), and the reaction is also referred to using the terms “flu-like” or “post-dose” symptoms.  
 
Atypical fractures of the femur 
During post-marketing experience the following reactions have been reported (frequency rare): 
Atypical subtrochanteric and diaphyseal femoral fractures (bisphopsphonate class adverse reaction). 



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Hypocalcaemia-related ADRs 
Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Based 
on the review of both clinical trial and post-marketing cases, there is sufficient evidence to support an 
association between zoledronic acid therapy, the reported event of hypocalcaemia, and the secondary 
development of cardiac arrhythmia. Furthermore, there is evidence of an association between 
hypocalcaemia and secondary neurological events reported in these cases including; convulsions, 
hypoaesthesia and tetany (see section 4.4). 
 
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 of zoledronic acid is limited. The administration of doses up 
to 48 mg of zoledronic acid in error has been reported. Patients who have received doses higher than 
those recommended (see section 4.2) should be carefully monitored, since renal function impairment 
(including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) 
abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should 
be administered as clinically indicated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: 
M05BA08 
 
Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of 
osteoclastic bone resorption. 
 
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, 
but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In 
long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the 
formation, mineralisation or mechanical properties of bone. 
 
In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several 
anti-tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone 
disease. The following properties have been demonstrated in preclinical studies: 
- In vivo: Inhibition of osteoclastic bone resorption, which alters the bone 

marrow microenvironment, making it less conducive to tumour cell growth, anti-angiogenic 
activity and anti-pain activity. 

- In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on 
tumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti-adhesion/invasion 
activity. 

 
Clinical trial results in the prevention of skeletal related events in patients with advanced malignancies 
involving bone 
The first randomised, double-blind, placebo-controlled study compared zoledronic acid 4 mg to 
placebo for the prevention of skeletal related events (SREs) in prostate cancer patients. Zoledronic 
acid 4 mg significantly reduced the proportion of patients experiencing at least one skeletal related 
event (SRE), delayed the median time to first SRE by > 5 months, and reduced the annual incidence of 
events per patient - skeletal morbidity rate. Multiple event analysis showed a 36% risk reduction in 



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developing SREs in the zoledronic acid 4 mg group compared with placebo. Patients receiving 
zoledronic acid 4 mg reported less increase in pain than those receiving placebo, and the difference 
reached significance at months 3, 9, 21 and 24. Fewer zoledronic acid 4 mg patients suffered 
pathological fractures. The treatment effects were less pronounced in patients with blastic lesions. 
Efficacy results are provided in Table 2. 
 
In a second study including solid tumours other than breast or prostate cancer, zoledronic acid 4 mg 
significantly reduced the proportion of patients with an SRE, delayed the median time to first SRE by 
> 2 months, and reduced the skeletal morbidity rate. Multiple event analysis showed 30.7% risk 
reduction in developing SREs in the zoledronic acid 4 mg group compared with placebo. Efficacy 
results are provided in Table 3. 
 
Table 2: Efficacy results (prostate cancer patients receiving hormonal therapy) 
 
 Any SRE (+TIH) Fractures* Radiation therapy 

to bone 
 Zoledronic 

acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo 

N 214 208 214 208 214 208 
Proportion of 
patients with SREs 
(%) 

38 49 17 25 26 33 

p-value 0.028 0.052 0.119 
Median time to SRE 
(days) 

488 321 NR NR NR 640 

p-value 0.009 0.020 0.055 
Skeletal morbidity 
rate 

0.77 1.47 0.20 0.45 0.42 0.89 

p-value 0.005 0.023 0.060 
Risk reduction of 
suffering from 
multiple events** 
(%) 

36 - NA NA NA NA 

p-value 0.002 NA NA 
* Includes vertebral and non-vertebral fractures 
** Accounts for all skeletal events, the total number as well as time to each event during the trial  
NR Not Reached 
NA Not Applicable 
 
Table 3: Efficacy results (solid tumours other than breast or prostate cancer) 
 
 Any SRE (+TIH) Fractures* Radiation therapy 

to bone 
 Zoledronic 

acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo 

N 257 250 257 250 257 250 
Proportion of 
patients with SREs 
(%) 

39 48 16 22 29 34 

p-value 0.039 0.064 0.173 
Median time to SRE 
(days) 

236 155 NR NR 424 307 

p-value 0.009 0.020 0.079 



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 Any SRE (+TIH) Fractures* Radiation therapy 
to bone 

 Zoledronic 
acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo Zoledronic 
acid 
4 mg 

Placebo 

Skeletal morbidity 
rate 

1.74 2.71 0.39 0.63 1.24 1.89 

p-value 0.012 0.066 0.099 
Risk reduction of 
suffering from 
multiple events** 
(%) 

30.7 - NA NA NA NA 

p-value 0.003 NA NA 
* Includes vertebral and non-vertebral fractures 
** Accounts for all skeletal events, the total number as well as time to each event during the trial 
NR Not Reached 
NA Not Applicable 
 
In a third phase III randomised, double-blind trial, 4 mg zoledronic acid or 90 mg pamidronate every 
3 to 4 weeks were compared in patients with multiple myeloma or breast cancer with at least one bone 
lesion. The results demonstrated that 4 mg zoledronic acid showed comparable efficacy to 90 mg 
pamidronate in the prevention of SREs. The multiple event analysis revealed a significant risk 
reduction of 16% in patients treated with 4 mg zoledronic acid in comparison with patients receiving 
pamidronate. Efficacy results are provided in Table 4. 
 
Table 4: Efficacy results (breast cancer and multiple myeloma patients) 
 
 Any SRE (+TIH) Fractures* Radiation therapy 

to bone 
 Zoledronic 

acid 
4 mg 

Pam 
90 mg 

Zoledronic 
acid 
4 mg 

Pam 
90 mg 

Zoledronic 
acid 
4 mg 

Pam 
90 mg 

N 561 555 561 555 561 555 
Proportion of 
patients with SREs 
(%) 

48 52 37 39 19 24 

p-value 0.198 0.653 0.037 
Median time to SRE 
(days) 

376 356 NR 714 NR NR 

p-value 0.151 0.672 0.026 
Skeletal morbidity 
rate 

1.04 1.39 0.53 0.60 0.47 0.71 

p-value 0.084 0.614 0.015 
Risk reduction of 
suffering from 
multiple events** 
(%) 

16 - NA NA NA NA 

p-value 0.030 NA NA 
* Includes vertebral and non-vertebral fractures 
** Accounts for all skeletal events, the total number as well as time to each event during the trial 
NR Not Reached 
NA Not Applicable 
 
Zoledronic acid 4 mg was also studied in a double-blind, randomised, placebo-controlled trial in 
228 patients with documented bone metastases from breast cancer to evaluate the effect of 4 mg 
zoledronic acid on the skeletal related event (SRE) rate ratio, calculated as the total number of SRE 



13 

events (excluding hypercalcaemia and adjusted for prior fracture), divided by the total risk period. 
Patients received either 4 mg zoledronic acid or placebo every four weeks for one year. Patients were 
evenly distributed between zoledronic acid-treated and placebo groups. 
 
The SRE rate (events/person year) was 0.628 for zoledronic acid and 1.096 for placebo. The 
proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the zoledronic 
acid-treated group versus 49.6% in the placebo group (p=0.003). Median time to onset of the first SRE 
was not reached in the zoledronic acid-treated arm at the end of the study and was significantly 
prolonged compared to placebo (p=0.007). Zoledronic acid 4 mg reduced the risk of SREs by 41% in a 
multiple event analysis (risk ratio=0.59, p=0.019) compared with placebo. 
 
In the zoledronic acid-treated group, statistically significant improvement in pain scores (using the 
Brief Pain Inventory, BPI) was seen at 4 weeks and at every subsequent time point during the study, 
when compared to placebo (Figure 1). The pain score for zoledronic acid was consistently below 
baseline and pain reduction was accompanied by a trend in reduced analgesics score. 
 
Figure 1: Mean changes from baseline in BPI scores. Statistically significant differences are 
marked (*p<0.05) for between treatment comparisons (4 mg zoledronic acid vs. placebo) 
 

 
 
 
 
Clinical trial results in the treatment of TIH 
Clinical studies in tumour-induced hypercalcaemia (TIH) demonstrated that the effect of zoledronic 
acid is characterised by decreases in serum calcium and urinary calcium excretion. In Phase I dose 
finding studies in patients with mild to moderate tumour-induced hypercalcaemia (TIH), effective 
doses tested were in the range of approximately 1.2-2.5 mg. 
 
To assess the effects of 4 mg zoledronic acid versus pamidronate 90 mg, the results of two pivotal 
multicentre studies in patients with TIH were combined in a pre-planned analysis. There was faster 
normalisation of corrected serum calcium at day 4 for 8 mg zoledronic acid and at day 7 for 4 mg and 
8 mg zoledronic acid. The following response rates were observed: 
 

Placebo 
Zoledronic acid 

B
PI

 m
ea

n 
ch

an
ge

 fr
om

 b
as

el
in

e 

Time on study (weeks) 



14 

Table 5: Proportion of complete responders by day in the combined TIH studies 
 
 Day 4 Day 7 Day 10 
Zoledronic acid 4 mg (N=86) 45.3% (p=0.104) 82.6% (p=0.005)* 88.4% (p=0.002)* 
Zoledronic acid 8 mg (N=90) 55.6% (p=0.021)* 83.3% (p=0.010)* 86.7% (p=0.015)* 
Pamidronate 90 mg (N=99) 33.3% 63.6% 69.7% 
*p-values compared to pamidronate. 
 
Median time to normocalcaemia was 4 days. Median time to relapse (re-increase of albumin-corrected 
serum calcium ≥ 2.9 mmol/l) was 30 to 40 days for patients treated with zoledronic acid versus 
17 days for those treated with pamidronate 90 mg (p-values: 0.001 for 4 mg and 0.007 for 8 mg 
zoledronic acid). There were no statistically significant differences between the two zoledronic acid 
doses. 
 
In clinical trials 69 patients who relapsed or were refractory to initial treatment (zoledronic acid 4 mg, 
8 mg or pamidronate 90 mg) were retreated with 8 mg zoledronic acid. The response rate in these 
patients was about 52%. Since those patients were retreated with the 8 mg dose only, there are no data 
available allowing comparison with the 4 mg zoledronic acid dose. 
 
In clinical trials performed in patients with tumour-induced hypercalcaemia (TIH), the overall safety 
profile amongst all three treatment groups (zoledronic acid 4 and 8 mg and pamidronate 90 mg) was 
similar in types and severity. 
 
Paediatric population 
Clinical trial results in the treatment of severe osteogenesis imperfecta in paediatric patients aged 
1 to 17 years 
The effects of intravenous zoledronic acid in the treatment of paediatric patients (age 1 to 17 years) 
with severe osteogenesis imperfecta (types I, III and IV) were compared to intravenous pamidronate in 
one international, multicentre, randomised, open-label study with 74 and 76 patients in each treatment 
group, respectively. The study treatment period was 12 months preceded by a 4- to 9-week screening 
period during which vitamin D and elemental calcium supplements were taken for at least 2 weeks. In 
the clinical programme patients aged 1 to < 3 years received 0.025 mg/kg zoledronic acid (up to a 
maximum single dose of 0.35 mg) every 3 months and patients aged 3 to 17 years received 0.05 mg/kg 
zoledronic acid (up to a maximum single dose of 0.83 mg) every 3 months. An extension study was 
conducted in order to examine the long-term general and renal safety of once yearly or twice yearly 
zoledronic acid over the 12-month extension treatment period in children who had completed one year 
of treatment with either zoledronic acid or pamidronate in the core study. 
 
The primary endpoint of the study was the percent change from baseline in lumbar spine bone mineral 
density (BMD) after 12 months of treatment. Estimated treatment effects on BMD were similar, but 
the trial design was not sufficiently robust to establish non-inferior efficacy for zoledronic acid. In 
particular there was no clear evidence of efficacy on incidence of fracture or on pain. Fracture adverse 
events of long bones in the lower extremities were reported in approximately 24% (femur) and 14% 
(tibia) of zoledronic acid-treated patients vs 12% and 5% of pamidronate-treated patients with severe 
osteogenesis imperfecta, regardless of disease type and causality but overall incidence of fractures was 
comparable for the zoledronic acid and pamidronate-treated patients: 43% (32/74) vs 41% (31/76). 
Interpretation of the risk of fracture is confounded by the fact that fractures are common events in 
patients with severe osteogenesis imperfecta as part of the disease process. 
 
The type of adverse reactions observed in this population were similar to those previously seen in 
adults with advanced malignancies involving the bone (see section 4.8). The adverse reactions ranked 
under headings of frequency, are presented in Table 6. The following conventional classification is 
used: 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). 
 



15 

Table 6: Adverse reactions observed in paediatric patients with severe osteogenesis imperfecta1 
 
Nervous system disorders  

Common: Headache 
Cardiac disorders  

Common: Tachycardia 
Respiratory, thoracic and mediastinal disorders  

Common: Nasopharyngitis 
Gastrointestinal disorders  

Very common: Vomiting, nausea 
Common: Abdominal pain 

Musculoskeletal and connective tissue disorders  
Common: Pain in extremities, arthralgia, musculoskeletal 

pain 
General disorders and administration site conditions 

Very common: Pyrexia, fatigue 
Common: Acute phase reaction, pain 

Investigations  
Very common: Hypocalcaemia 
Common: Hypophosphataemia 

1Adverse events occurring with frequencies < 5% were medically assessed and it was shown that these 
cases are consistent with the well established safety profile of zoledronic acid as indicated in 
sections 4.1 and 4.2 (see section 4.8) 
 
In paediatric patients with severe osteogenesis imperfecta, zoledronic acid seems to be associated with 
more pronounced risks for acute phase reaction, hypocalcaemia and unexplained tachycardia, in 
comparison to pamidronate, but this difference declined after subsequent infusions. 
 
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 
the treatment of tumour-induced hypercalcaemia and prevention of skeletal-related events in patients 
with advanced malignancies involving bone (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 
with bone metastases yielded the following pharmacokinetic data, which were found to be dose 
independent. 
 
After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly 
increased, 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 prior to the second infusion of zoledronic acid on day 28. 
 
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic 
disappearance from the systemic circulation, with half-lives of t½ α 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 zoledronic acid in plasma after multiple doses given every 28 days. 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. 
 
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, and body weight. Increasing the infusion time from 5 to 15 minutes caused a 30% decrease 
in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the 
plasma concentration versus time curve. 



16 

 
The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen with 
other bisphosphonates. 
 
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in 
patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro, 
shows no biotransformation and in animal studies < 3% of the administered dose was recovered in the 
faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid. 
 
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 cancer patients studied. Population analysis showed that for a patient with 
creatinine clearance of 20 ml/min (severe renal impairment), or 50 ml/min (moderate impairment), the 
corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, of that of a 
patient showing creatinine clearance of 84 ml/min. Only limited pharmacokinetic data are available in 
patients with severe renal insufficiency (creatinine clearance < 30 ml/min). 
 
In an in vitro study, zoledronic acid showed low affinity for the cellular components of human blood, 
with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/ml to 
5000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at 
2 ng/ml to 77% at 2000 ng/ml of zoledronic acid. 
 
Special populations 
Paediatric patients 
Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic 
acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg 
dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic 
acid systemic exposure. 
 
5.3 Preclinical safety data 
 
Acute toxicity 
The highest non-lethal single intravenous dose was 10 mg/kg bodyweight in mice and 0.6 mg/kg in 
rats. 
 
Subchronic and chronic toxicity 
Zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to 
dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously 
in rats and 0.005 mg/kg intravenously once every 2-3 days in dogs for up to 52 weeks was also well 
tolerated. 
 
The most frequent finding in 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. 
 
The safety margins relative to renal effects were narrow in the long-term repeat-dose parenteral animal 
studies but the cumulative no adverse event levels (NOAELs) in the single dose (1.6 mg/kg) and 
multiple dose studies of up to one month (0.06-0.6 mg/kg/day) did not indicate renal effects at doses 
equivalent to or exceeding the highest intended human therapeutic dose. Longer-term repeat 
administration at doses bracketing the highest intended human therapeutic dose of zoledronic acid 
produced toxicological effects in other organs, including the gastrointestinal tract, liver, spleen and 
lungs, and at intravenous injection sites. 
 
Reproduction toxicity 
Zoledronic acid was teratogenic in the rat at subcutaneous doses ≥ 0.2 mg/kg. Although no 
teratogenicity or foetotoxicity was observed in the rabbit, maternal toxicity was found. Dystocia was 
observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat. 



17 

 
Mutagenicity and carcinogenic potential 
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did 
not provide any evidence of carcinogenic potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Sodium citrate 
Water for injections 
 
6.2 Incompatibilities 
 
To avoid potential incompatibilities,  Zoledronic acid Actavis 4 mg/5 ml concentrate for solution for 
infusion is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution. 
 
This medicinal product must not be mixed with calcium or other divalent cation-containing infusion 
solutions such as lactated Ringer’s solution, and should be administered as a single intravenous 
solution in a separate infusion line. 
 
6.3 Shelf life 
 
3 years. 
 
After dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C 
and at 25°C after dilution in 100 ml 0.9% w/v sodium chloride solution or 100 ml 5% w/v glucose. 
From a microbiological point of view, the solution for infusion should be used immediately after 
dilution. 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. 
If refrigerated, the solution must be allowed to reach room temperature before administration. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions of Zoledronic acid Actavis after dilution, see section 6.3. 
 
6.5 Nature and contents of container 
 
5 ml concentrate in a plastic vial made of clear, colourless oleofinic polymer closed with 
fluoropolymer-coated bromobutyl rubber stopper and aluminium cap with plastic flip-off component. 
 
Pack sizes: 1, 4 or 10 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Prior to administration, 5 ml concentrate from one vial or the volume of the concentrate withdrawn 
as required must be further diluted with 100 ml of calcium-free infusion solution (0.9% w/v sodium 
chloride solution or 5% w/v glucose solution).  
 
Additional information on handling of Zoledronic acid Actavis, including guidance on preparation of 
reduced doses, is provided in section 4.2. 



18 

 
Aseptic techniques must be followed during the preparation of the infusion. For single use only. 
 
Only clear solution free from particles and discolouration should be used. 
 
Healthcare professionals are advised not to dispose of unused Zoledronic acid Actavis via the 
domestic sewage system. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78 
220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/759/001 
EU/1/12/759/002 
EU/1/12/759/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 April 2012 
Date of latest renewal: 09 Desember 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



20 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Actavis Italy S.p.A 
Via Pasteur, 10 
20014 Nerviano (MI) 
Italy 
 
 
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 marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency, 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
Additional risk minimisation measures 
The MAH shall ensure that a patient reminder card regarding osteonecrosis of the jaw is implemented.  



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTONS FOR VIALS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid Actavis 4 mg/5 ml concentrate for solution for infusion 
zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 4 mg of zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol, sodium citrate and water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
1 x 5 ml vial   
4 x 5 ml vials 
10 x 5 ml vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use after dilution. 
 
 
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 
 
Shelf life after dilution: See leaflet. 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



24 

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 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/759/001 1vial 
EU/1/12/759/002 4 vials 
EU/1/12/759/003 10 vials 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
<Not applicable.>  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
< PC: {number}  
SN: {number}  
NN: {number} > 
 
<Not applicable.>



25 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Zoledronic acid Actavis 4 mg/5 ml sterile concentrate 
zoledronic acid 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
Dilute before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
4 mg/5 ml 
 
 
6. OTHER 
 
[Actavis logo] 

  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



27 

Package leaflet: Information for the user 
 

Zoledronic acid Actavis 4 mg/5 ml concentrate for solution for infusion 
zoledronic acid 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects , talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Zoledronic acid Actavis is and what it is used for 
2. What you need to know before you are given Zoledronic acid Actavis 
3. How Zoledronic acid Actavis is used 
4. Possible side effects 
5. How to store Zoledronic acid Actavis 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid Actavis is and what it is used for 
 
The active substance in Zoledronic acid Actavis is zoledronic acid, which belongs to a group of 
substances called bisphosphonates. Zoledronic acid works by attaching itself to the bone and slowing 
down the rate of bone change. It is used: 
• To prevent bone complications, e.g. fractures, in adult patients with bone metastases (spread 

of cancer from primary site to the bone). 
• To reduce the amount of calcium in the blood in adult patients where it is too high due to the 

presence of a tumour. Tumours can accelerate normal bone change in such a way that the 
release of calcium from bone is increased. This condition is known as tumour-induced 
hypercalcaemia (TIH). 

 
 
2. What you need to know before you are given Zoledronic acid Actavis 
 
Follow carefully all instructions given to you by your doctor. 
 
Your doctor will carry out blood tests before you start treatment with Zoledronic acid Actavis and will 
check your response to treatment at regular intervals. 
 
You should not be given Zoledronic acid Actavis: 
- if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which 

Zoledronic acid Actavis belongs), or any of the other ingredients of this medicine (listed in 
section 6). 

- if you are breast-feeding. 
 
Warnings and precautions 
Talk to your doctor before you are given Zoledronic acid Actavis: 
- if you have or have had a kidney problem. 
- if you have or have had pain, swelling or numbness of the jaw, a feeling of heaviness in the 

jaw or loosening of a tooth. Your doctor may recommend a dental examination before you start 
treatment with Zoledronic acid Actavis. 

- if you are having dental treatment or are due to undergo dental surgery, tell your dentist that 
you are being treated with Zoledronic acid Actavis and inform your doctor about your dental 
treatment. 



28 

 
While being treated with Zoledronic acid Actavis, you should maintain good oral hygiene (including 
regular teeth brushing) and receive routine dental check-ups. 
 
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 a 
condition called osteonecrosis of the jaw. 
 
Patients who are undergoing chemotherapy and/or radiotherapy, who are taking steroids, who are 
undergoing dental surgery, who do not receive routine dental care, who have gum disease, who are 
smokers, or who were previously treated with a bisphosphonate (used to treat or prevent bone 
disorders) may have a higher risk of developing osteonecrosis of the jaw. 
 
Reduced levels of calcium in the blood (hypocalcaemia), sometimes leading to muscle cramps, dry 
skin, burning sensation, have been reported in patients treated with zoledronic acid. Irregular heart 
beat (cardiac arrhythmia), seizures, spasm and twitching (tetany) have been reported as secondary to 
severe hypocalcaemia. In some instances the hypocalcaemia may be life-threatening. If any of these 
apply to you, tell your doctor straight away. If you have pre-existing hypocalcaemia, it must be 
corrected before initiating the first dose of Zoledronic acid Actavis. You will be given adequate 
calcium and vitamin D supplements. 
 
Patients aged 65 years and over 
Zoledronic acid Actavis can be given to people aged 65 years and over. There is no evidence to 
suggest that any extra precautions are needed. 
 
Children and adolescents 
Zoledronic acid Actavis is not recommended for use in adolescents and children below the age of 
18 years. 
 
Other medicines and Zoledronic acid Actavis 
Tell your doctor if you are taking, have recently taken or might take any other medicines. It is 
especially important that you tell your doctor if you are also taking: 
- Aminoglycosides (medicines used to treat severe infections), calcitonin (a type of medicine used 

to treat post-menopausal osteoporosis and hypercalcaemia), loop diuretics (a type of medicine to 
treat high blood pressure or oedema) or other calcium-lowering medicines, since the 
combination of these with bisphosphonates may cause the calcium level in the blood to become 
too low. 

- Thalidomide (a medicine used to treat a certain type of blood cancer involving the bone) or any 
other medicines which may harm your kidneys. 

- Other medicines that contain zoledronic acid which are used to treat osteoporosis and other non-
cancer diseases of the bone, or any other bisphosphonate, since the combined effects of these 
medicines taken together with Zoledronic acid Actavis are unknown. 

- Anti-angiogenic medicines (used to treat cancer), since the combination of these with zoledronic 
acid has been associated with an increased risk of osteonecrosis of the jaw (ONJ). 

 
Pregnancy and breast-feeding 
You should not be given Zoledronic acid Actavis if you are pregnant. Tell your doctor if you are or 
think that you may be pregnant. 
 
You must not be given Zoledronic acid Actavis if you are breast-feeding. 
 
Ask your doctor for advice before taking any medicine while you are pregnant or breast-feeding. 
 
Driving and using machines 
There have been very rare cases of drowsiness and sleepiness with the use of zoledronic acid. You 
should therefore be careful when driving, using machinery or performing other tasks that need full 
attention. 



29 

 
Zoledronic acid Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially “sodium-free”. 
 
 
3. How Zoledronic acid Actavis is used 
 
- Zoledronic acid Actavis must only be given by healthcare professionals trained in administering 

bisphosphonates intravenously, i.e. through a vein. 
- Your doctor will recommend that you drink enough water before each treatment to help prevent 

dehydration. 
- Carefully follow all the other instructions given to you by your doctor, pharmacist or nurse. 
 
How much Zoledronic acid Actavis is given 
- The usual single dose given is 4 mg. 
- If you have a kidney problem, your doctor will give you a lower dose depending on the severity 

of your kidney problem. 
 
How often Zoledronic acid Actavis is given 
- If you are being treated for the prevention of bone complications due to bone metastases, you 

will be given one infusion of Zoledronic acid Actavis every three to four weeks. 
- If you are being treated to reduce the amount of calcium in your blood, you will normally only 

be given one infusion of Zoledronic acid Actavis. 
 
How Zoledronic acid Actavis is given 
- Zoledronic acid Actavis is given as a drip (infusion) into a vein which should take at least 

15 minutes and should be administered as a single intravenous solution in a separate infusion 
line. 

 
Patients whose blood calcium levels are not too high will also be prescribed calcium and vitamin D 
supplements to be taken each day. 
 
If you are given more Zoledronic acid Actavis than you should be 
If you have received doses higher than those recommended, you must be carefully monitored by your 
doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of 
calcium, phosphorus and magnesium) and/or changes in kidney function, including severe kidney 
impairment. If your level of calcium falls too low, you may have to be given supplemental calcium by 
infusion. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The most 
common ones are usually mild and will probably disappear after a short time. 
 
Tell your doctor about any of the following serious side effects straight away: 
 
Common (may affect up to 1 in 10 people):  
- Severe kidney impairment (will normally be determined by your doctor with certain specific 

blood tests). 
- Low level of calcium in the blood. 
 
Uncommon (may affect up to 1 in 100 people):  
- Pain in the mouth, teeth and/or jaw, swelling or non-healing sores inside 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 



30 

you experience such symptoms while being treated with Zoledronic acid Actavis or after 
stopping treatment. 

- Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving zoledronic acid for 
postmenopausal osteoporosis. It is currently unclear whether zoledronic acid causes this 
irregular heart rhythm but you should report it to your doctor if you experience such symptoms 
after you have received zoledronic acid. 

- Severe allergic reaction: shortness of breath, swelling mainly of the face and throat. 
 
Rare (may affect up to 1 in 1,000 people): 
- As a consequence of low calcium values: irregular heart beat (cardiac arrhythmia; secondary to 

hypocalcaemia). 
- A kidney function disorder called Fanconi syndrome (will normally be determined by your 

doctor with certain urine tests). 
 
Very rare (may affect up to 1 in 10,000 people): 
- As a consequence of low calcium values: seizures, numbness and tetany (secondary to 

hypocalcaemia). 
- 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. 
- Osteonecrosis has also very rarely been seen occurring with other bones than the jaw, especially 

the hip or thigh. Tell your doctor immediately if you experience symptoms such as new onset or 
worsening of aches, pain or stiffness while being treated with Zoledronic acid Actavis or after 
stopping treatment. 

 
Tell your doctor about any of the following side effects as soon as possible: 
 
Very common (may affect more than 1 in 10 people): 
- Low level of phosphate in the blood. 
 
Common (may affect up to 1 in 10 people): 
- Headache and a flu-like syndrome consisting of fever, fatigue, weakness, drowsiness, chills and 

bone, joint and/or muscle ache. In most cases no specific treatment is required and the 
symptoms disappear after a short time (couple of hours or days). 

- Gastrointestinal reactions such as nausea and vomiting as well as loss of appetite. 
- Conjunctivitis. 
- Low level of red blood cells (anaemia). 
 
Uncommon (may affect up to 1 in 100 people): 
- Hypersensitivity reactions. 
- Low blood pressure. 
- Chest pain. 
- Skin reactions (redness and swelling) at the infusion site, rash, itching. 
- High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste 

disturbances, trembling, tingling or numbness of the hands or feet, diarrhoea, constipation, 
abdominal pain, dry mouth. 

- Low counts of white blood cells and blood platelets. 
- Low level of magnesium and potassium in the blood. Your doctor will monitor this and take any 

necessary measures. 
- Weight increase. 
- Increased sweating. 
- Sleepiness. 
- Blurred vision, tearing of the eye, eye sensitivity to light. 
- Sudden coldness with fainting, limpness or collapse. 
- Difficulty in breathing with wheezing or coughing. 
- Urticaria. 
 



31 

Rare (may affect up to 1 in 1,000 people): 
- Slow heart beat. 
- Confusion. 
- 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. 

- Interstitial lung disease (inflammation of the tissue around the air sacks of the lungs) 
- Flu-like symptoms including arthritis and joint swelling. 
- Painful redness and/or swelling of the eye. 
 
Very rare (may affect up to 1 in 10,000 people): 
- Fainting due to low blood pressure. 
- Severe bone, joint and/or muscle pain, occasionally incapacitating. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Zoledronic acid Actavis 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid Actavis properly. 
 
 
6. Contents of the pack and other information 
 
What Zoledronic acid Actavis contains 
- The active substance is zoledronic acid. One vial contains 4 mg zoledronic acid (as 

monohydrate). 
- The other ingredients are: mannitol, sodium citrate and water for injections. 
 
What Zoledronic acid Actavis looks like and contents of the pack 
Zoledronic acid Actavis is supplied as a clear and colourless concentrate for solution for infusion 
(sterile concentrate) in a plastic vial. One vial contains 5 ml of solution. 
Zoledronic acid Actavis is supplied as packs containing 1, 4 or 10 vials. Not all pack sizes may be 
marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78 
220 Hafnarfjörður 
Iceland 
 
Manufacturer 
Actavis Italy S.p.A. 
Via Pasteur 10  
20014 Nerviano (MI) 
Italy 
 



32 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Teva Baltics 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 

Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 

Nederland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Eesti 
UAB Teva Baltics Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 2118805000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Aurovitas Spain, S.A.U. 
Tel: +34 916308645 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: + 385 13720000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o 
Tel: +421 257267911 
 



33 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
Teva Finland Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE 
Ελλάδα 
Τηλ: +30 2118805000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Teva Baltics filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
This leaflet was last revised in {month 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 Actavis 
 
- To prepare an infusion solution containing 4 mg Zoledronic acid Actavis, further dilute the 

Zoledronic acid Actavis concentrate (5.0 ml) with 100 ml of calcium-free or other divalent 
cation-free infusion solution. If a lower dose of Zoledronic acid Actavis is required, first 
withdraw the appropriate volume as indicated below and then dilute it further with 100 ml of 
infusion solution. To avoid potential incompatibilities, the infusion solution used for dilution 
must be either 0.9% w/v sodium chloride or 5% w/v glucose solution. 

 
Do not mix Zoledronic acid Actavis concentrate with calcium-containing or other divalent 
cation containing solutions such as lactated Ringer’s solution. 

 
Instructions for preparing reduced doses of Zoledronic acid Actavis: 
Withdraw the appropriate volume of the liquid concentrate, as follows: 
- 4.4 ml for 3.5 mg dose 
- 4.1 ml for 3.3 mg dose 
- 3.8 ml for 3.0 mg dose 

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

particles and discolouration should be used. Aseptic techniques must be followed during the 
preparation of the infusion.  

 
- Shelf life after dilution: Chemical and physical in-use stability has been demonstrated for 

24 hours at 2°C - 8°C and at 25°C after dilution in 100 ml 0.9% w/v sodium chloride solution or 
100 ml 5% w/v glucose. From a microbiological point of view, the solution for infusion should 
be used immediately after dilution. 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. If refrigerated, the solution must be allowed to reach room temperature before 
administration. 

 



34 

- The solution containing zoledronic acid is given as a single 15-minute intravenous infusion in a 
separate infusion line. The hydration status of patients must be assessed prior to and following 
administration of Zoledronic acid Actavis to ensure that they are adequately hydrated. 

 
- Since no data are available on the compatibility of Zoledronic acid Actavis with other 

intravenously administered substances, Zoledronic acid Actavis must not be mixed with other 
medications/substances and should always be given through a separate infusion line. 

 
How to store Zoledronic acid Actavis 
 
- Keep Zoledronic acid Actavis out of the sight and reach of children. 
- Do not use Zoledronic acid Actavis after the expiry date stated on the vial and carton after EXP. 
- This medicinal product does not require any specific storage conditions. 
- For storage conditions of Zoledronic acid Actavis after dilution, see “Shelf life after dilution” 

above. 
 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET