Zoledronic acid medac

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One bottle with 100 ml solution contains 4 mg zoledronic acid (as monohydrate). 
 
One ml solution contains 0.04 mg zoledronic acid (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion 
Clear, colourless solution. 
 
 
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 medac must only be prescribed and administered to patients by healthcare 
professionals experienced in the administration of intravenous bisphosphonates. Patients treated with 
Zoledronic acid medac 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 elderly 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 elderly 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 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 µmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in TIH 
patients with serum creatinine < 400 µmol/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 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 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 µmol/l or > 3.0 mg/dl were excluded. 
 
For patients with normal renal function (defined as CLcr > 60 ml/min), zoledronic acid 4 mg/100 ml 
solution for infusion may be administered directly without any further preparation. 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 dose is 
recommended (see also section 4.4): 
 
Baseline creatinine clearance (ml/min) Zoledronic acid recommended dose* 
> 60 4.0 mg 
50 – 60 3.5 mg* 
40 – 49 3.3 mg* 
30 – 39 3.0 mg* 
*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 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 µmol/l), an increase of 

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

1.0 mg/dl or 88 µmol/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 treatment should be resumed at 
the same dose as that 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 medac 4 mg/100 ml solution for infusion should be given as a single intravenous 
infusion in no less than 15 minutes. 
 
In patients with normal renal function, defined as CLcr > 60 ml/min, zoledronic acid 4 mg/100 ml 
solution for infusion must not be further diluted.  
 



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In patients with mild to moderate renal impairment, reduced Zoledronic acid medac 4 mg/100 ml 
solution for infusion doses are recommended (see section “Posology” above and section 4.4). 
 
To prepare reduced doses for patients with baseline CLcr ≤ 60 ml/min, refer to Table 1 below. 
Remove the volume of Zoledronic acid medac 4 mg/100 ml solution indicated from the bottle and 
replace with an equal volume of sterile sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% 
glucose. 
 
Table 1: Preparation of reduced doses of Zoledronic acid medac 4 mg/100 ml solution for infusion 
 

Baseline creatinine 
clearance (ml/min)  

Remove the following 
amount of Zoledronic 
acid medac solution for 
infusion (ml)  

Replace with the 
following volume of 
sterile sodium chloride 
9 mg/ml (0.9%), or 5% 
glucose solution for 
injection (ml)  

Adjusted dose (mg 
zoledronic acid in 
100 ml)  

50-60 12.0 12.0 3.5 
40-49 18.0 18.0 3.3 
30-39 25.0 25.0 3.0 

 
Zoledronic acid medac 4 mg/100 ml solution for infusion must not be mixed with other infusion 
solutions 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. 
 
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 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 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 medicinal 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 medac should not be treated with such medicinal products concomitantly or any other 
bisphosphonate, 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 
outweighs the possible risk. 
 



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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 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 4 mg 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 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. 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 should be withheld. Zoledronic acid should only be resumed when 
serum creatinine returns to within 10 % of baseline. Zoledronic acid medac 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 µmol/l or 
≥ 4.5 mg/dl for patients with TIH and ≥ 265 µmol/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 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. 
 



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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 medac. 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. 
 
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 medac. 
 
Musculoskeletal pain 
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain 
have been reported in patients taking bisphosphonates, including zoledronic acid. 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. 



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Sodium 
Zoledronic acid medac contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially 
‘sodium-free’. 
 
4.5 Interactions with other medicinal products and other forms of interaction 
 
In clinical studies, zoledronic acid 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.  
 
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 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 is 
used in combination with thalidomide. 
 
Caution is advised when zoledronic acid 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 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 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 along with driving and 
operating of machinery.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 



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Within three days after zoledronic acid administration, an acute phase reaction has 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 2. 
 
Tabulated list of adverse reactions 
The following adverse reactions, listed in Table 2, have been accumulated from clinical studies and 
post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: 
 
Table 2 
 
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: 
  Uncommon: 
  Rare: 

 
Anaemia 
Thrombocytopenia, leukocytopenia 
Pancytopenia 

Immune system disorders 
  Uncommon: 
  Rare: 

 
Hypersensitivity reaction 
Angioneurotic oedema 

Psychiatric disorders 
  Uncommon: 
  Rare: 

 
Anxiety, sleep disturbance 
Confusion 

Nervous system disorders 
  Common:  
  Uncommon: 
   
 
  Very rare: 

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

Eye disorders 
  Common: 
  Uncommon: 
   

Rare: 
Very rare: 

 
Conjunctivitis 
Blurred vision, scleritis and orbital 
inflammation 
Uveitis 
Episcleritis  

Cardiac disorders 
  Uncommon: 
   
 

Rare: 
 

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



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  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: 
   
  Uncommon: 
  Very rare: 
   

 
Bone pain, myalgia, arthralgia, generalised 
pain 
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: 
  Uncommon: 
  Rare: 

 
Renal impairment 
Acute renal failure, haematuria, proteinuria 
Acquired Fanconi syndrome 

General disorders and administration site conditions 
  Common: 
 
  Uncommon: 
 
 
 
 
  Rare: 

 
Fever, flu-like syndrome (including fatigue, 
rigors, malaise and flushing) 
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: 
  Common: 
 
  Uncommon: 
  Rare: 

 
Hypophosphataemia 
Blood creatinine and blood urea increased, 
hypocalcaemia 
Hypomagnesaemia, hypokalaemia 
Hyperkalaemia, hypernatraemia 

 
Description of selected adverse reactions  
Renal function impairment  
Zoledronic acid 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 medac (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. 
 



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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, 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). 
 
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. 
 
 

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


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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 medicinal products, 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 
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 3. 
 
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 4. 
 



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Table 3: 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 4: 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 
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 
 



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In a third phase III randomised, double-blind trial, zoledronic acid 4 mg 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 zoledronic acid 4 mg 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 zoledronic acid 4 mg in comparison with patients receiving 
pamidronate. Efficacy results are provided in Table 5. 
 
Table 5: Efficacy results (breast cancer and multiple myeloma patients) 
 
 Any SRE (+TIH) Fractures* Radiation therapy 

to bone 
 Zoledronic 

acid 4 mg 
Pamidronate 

90 mg 
Zoledronic 
acid 4 mg 

Pamidronate 
90 mg 

Zoledronic 
acid 4 mg 

Pamidronate 
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 
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. 
 



 14 

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: 
 
Table 6: 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. 

Placebo    
Zoledronic acid 4 mg   



 15 

 
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 versus 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) 
versus 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 7. 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). 
 



 16 

Table 7: 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: 
  Common: 

 
Vomiting, nausea 
Abdominal pain 

Musculoskeletal and connective tissue disorders 
  Common: 

 
Pain in extremities, arthralgia, 
musculoskeletal pain 

General disorders and administration site conditions 
  Very common: 
  Common: 

 
Pyrexia, fatigue 
Acute phase reaction, pain 

Investigations 
  Very common: 
  Common: 

 
Hypocalcaemia 
Hypophosphataemia 

1 Adverse 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 (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 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 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. 
 



 17 

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 
5,000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at 
2 ng/ml to 77% at 2,000 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. 
 



 18 

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. 
 
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 and it must not be mixed or given intravenously with any other medicinal product in the 
same infusion line.  
 
6.3 Shelf life 
 
Unopened bottle: 3 years. 
 
After first opening: Chemical and physical in-use stability has been demonstrated for 4 days at 2 – 8°C 
and 25°C.  
 
Chemical and physical in-use stability has been demonstrated for glass bottles, polyethylene, 
polyvinylchloride and polypropylene infusion lines and infusion bags (prefilled with sodium chloride 
9 mg/ml (0.9 %) solution for injection or 5 % w/v glucose solution) for 96 hours at 2-8°C and 25°C. 
 
After first opening and dilution: From a microbiological point of view the medicinal 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 2-8°C unless dilution has 
taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Do not freeze. 
 
For storage conditions after first opening of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Colourless glass bottle type I with fluoropolymer coated halobutyl rubber stopper and aluminium flip-
off cap.  
 
Each vial contains 100 ml of solution 
 
Zoledronic acid medac is supplied as packs containing 1 bottle or multipacks of 4 cartons each 
containing 1 bottle. Not all pack sizes may be marketed.  
 



 19 

6.6 Special precautions for disposal and other handling  
 
Additional information on handling of Zoledronic acid medac 4 mg/100 ml solution for infusion, 
including guidance on the preparation of reduced doses using the Zoledronic acid medac ready-to-use 
bottle, is provided in section 4.2.  
 
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 medac 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 
 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/12/779/004 
EU/1/12/779/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 03 August 2012. 
Date of latest renewal: 28 April 2017. 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 

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


 20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 



 21 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
 
medac Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
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 the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 
 

 
 

• Additional risk minimisation measures 
The MAH shall ensure that a patient reminder card regarding osteonecrosis of the jaw is implemented.  
 



 22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 24 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR 1 BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
Zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 4 mg of zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium citrate, 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: 
Read the leaflet for the shelf life of the medicinal product after first opening. 
 
 



 25 

9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 
 
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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/779/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



 26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING (WITHOUT BLUE BOX) 
 
CARTON FOR 1 BOTTLE AS PART OF A MULTIPACK COMPRISING 4 BOTTLES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
Zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 4 mg of zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium citrate, 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: 
Read the leaflet for the shelf life of the medicinal product after first opening. 
 
 



 27 

9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 
 
 
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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/779/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 



 28 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
Zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 4 mg of zoledronic acid (as monohydrate). 
One ml solution contains 0.04 mg zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium citrate, 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: 
 
 



 29 

9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 
 
 
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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/779/004 
EU/1/12/779/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 



 30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL ON MULTIPACKS WITH 4 BOTTLES WRAPPED IN TRANSPARENT FOIL 
(INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
Zoledronic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 4 mg of zoledronic acid (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium citrate, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion. 
 
Multipack: 4 x 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: 
 
 



 31 

9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 
 
 
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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/779/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



 32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 33 

 Package leaflet: Information for the user 
 

Zoledronic acid medac 4 mg/100 ml 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 medac is and what it is used for 
2. What you need to know before you are given Zoledronic acid medac 
3. How Zoledronic acid medac is used 
4. Possible side effects 
5. How to store Zoledronic acid medac 
6. Contents of the pack and other information 
 
 
1. What Zoledronic acid medac is and what it is used for 
 
The active substance in Zoledronic acid medac 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 medac 
 
Follow carefully all instructions given to you by your doctor. 
 
Your doctor will carry out blood tests before you start treatment with Zoledronic acid medac and will 
check your response to treatment at regular intervals. 
 
You should not be given Zoledronic acid medac 
- if you are breast-feeding. 
- if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which 

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

 
Warnings and precautions 
Talk to your doctor before you are given Zoledronic acid medac, if you 
- have or have had a kidney problem. 
- 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 medac. 



 34 

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

 
While being treated with Zoledronic acid medac, 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 medac. You will be given adequate calcium 
and vitamin D supplements. 
 
Patients aged 65 years and over 
Zoledronic acid medac 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 medac is not recommended for use in adolescents and children below the age of 
18 years. 
 
Other medicines and Zoledronic acid medac 
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 also contain zoledronic acid and 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 medac 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 medac if you are pregnant. Tell your doctor if you are or 
think that you may be pregnant.  
 
You must not be given Zoledronic acid medac if you are breast-feeding.  
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 



 35 

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. 
 
Zoledronic acid medac contains sodium 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially ‘sodium-
free’.  
 
 
3. How Zoledronic acid medac is used 
 
- Zoledronic acid medac 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 medac 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 medac 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 medac 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 medac. 
 
How Zoledronic acid medac is given 
- Zoledronic acid medac 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 medac 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.  



 36 

 
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 you 
experience such symptoms while being treated with Zoledronic acid medac 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 medac 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, sleep disturbances, taste disturbances, 

trembling, tingling or numbness of the hands or feet, diarrhoea, 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.  



 37 

- Sudden coldness with fainting, limpness or collapse.  
- Difficulty in breathing with wheezing or coughing.  
- Urticaria.  
 
Rare (may affect up to 1 in 1,000 people): 
- Slow heartbeat. 
- 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 medac 
 
Your doctor, pharmacist or nurse knows how to store Zoledronic acid medac properly (see section 6). 
 
After first opening, Zoledronic acid medac solution for infusion should preferably be used 
immediately. If the solution is not used immediately, it should be stored in a refrigerator at 2°C – 8°C. 
 
6. Contents of the pack and other information 
 
What Zoledronic acid medac contains 
- The active substance is zoledronic acid. One bottle contains 4 mg zoledronic acid. 
- The other ingredients are: mannitol, sodium citrate, water for injections. 
 
What Zoledronic acid medac looks like and contents of the pack 
Zoledronic acid medac is supplied as solution for infusion in a 100 ml colourless glass bottle (type I) 
with rubber stoppers (halobutyl, fluoropolymer coated) and aluminium flip-off caps. One bottle 
contains 100 ml of solution. 
 
Zoledronic acid medac is supplied as packs containing 1 bottle or multipacks of 4 packs each 
containing 1 bottle. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 

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


 38 

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 medac 
 
• Zoledronic acid medac 4 mg/100 ml solution for infusion contains 4 mg zoledronic acid in 

100 ml of infusion solution for immediate use in patients with normal renal function.  
 
• 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.  

 
• From a microbiological point of view, the solution for infusion should be used immediately, 

after first opening. 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, 
unless dilution has taken place in controlled and validated aseptic conditions. The refrigerated 
solution should then be equilibrated to room temperature prior to administration.  

 
• The solution containing zoledronic acid must not be further diluted or mixed with other infusion 

solutions. It 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 medac to ensure that they are adequately hydrated.  

 
• Zoledronic acid medac 4 mg/100 ml solution for infusion can be used immediately without 

further preparation for patients with normal renal function. In patients with mild to moderate 
renal impairment, reduced doses should be prepared as instructed below.  

 
To prepare reduced doses for patients with baseline CLcr ≤ 60 ml/min, refer to Table 1 below. Remove 
the volume of Zoledronic acid medac solution indicated from the bottle and replace with an equal 
volume of sterile sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% w/v glucose solution 
for injection. 
 
Do not mix Zoledronic acid medac with calcium-containing or other divalent cation containing 
solutions such as lactated Ringer’s solution. 

 
Table 1: Preparation of reduced doses of Zoledronic acid medac 4 mg/100 ml solution for infusion 
 
Baseline creatinine 
clearance (ml/min)  

Remove the following 
amount of Zoledronic 
acid medac solution 
for infusion (ml)  

Replace with the 
following volume of 
sterile sodium 
chloride 9 mg/ml 
(0.9%), or 5% glucose 
solution for injection 
(ml)  

Adjusted dose (mg 
zoledronic acid in 
100 ml)  

50-60 12.0 12.0 3.5 
40-49 18.0 18.0 3.3 
30-39 25.0 25.0 3.0 
 

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


 39 

*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. 
 
• Studies with glass bottles, several types of infusion bags and infusion lines made from 

polyvinylchloride, polyethylene and polypropylene (prefilled with sodium chloride 9 mg/ml 
(0.9%) solution for injection or 5% w/v glucose solution) showed no incompatibility with 
zoledronic acid. 

 
• Since no data are available on the compatibility of Zoledronic acid medac with other 

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

 
How to store Zoledronic acid medac 
• Keep Zoledronic acid medac out of the sight and reach of children. 
• Do not use Zoledronic acid medac after the expiry date stated on the bottle and carton after 

EXP. 
• The readily prepared Zoledronic acid medac infusion solution should preferably be used 

immediately. If the solution is not used immediately, storage prior to use is the responsibility of 
the user and should be in a refrigerator at 2 °C – 8 °C. 

• The total time between dilution, storage in the refrigerator and end of administration must not 
exceed 96 hours. 

• Do not freeze. 
 
 
 


	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
	ANNEX III
	LABELLING AND PACKAGE LEAFLET
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	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
	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
	12. MARKETING AUTHORISATION NUMBER(S)
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	16. INFORMATION IN BRAILLE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	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
	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
	12. MARKETING AUTHORISATION NUMBER(S)
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	16. INFORMATION IN BRAILLE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	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
	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
	12. MARKETING AUTHORISATION NUMBER(S)
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	16. INFORMATION IN BRAILLE
	1. NAME OF THE MEDICINAL PRODUCT
	2. STATEMENT OF ACTIVE SUBSTANCE(S)
	3. LIST OF EXCIPIENTS
	4. PHARMACEUTICAL FORM AND CONTENTS
	5. METHOD AND ROUTE(S) OF ADMINISTRATION
	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
	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
	12. MARKETING AUTHORISATION NUMBER(S)
	13. BATCH NUMBER
	14. GENERAL CLASSIFICATION FOR SUPPLY
	15. INSTRUCTIONS ON USE
	16. INFORMATION IN BRAILLE