Zometa
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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg powder and solvent for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One vial contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Powder and solvent for solution for infusion 

 

White to off-white powder and clear, colourless solvent. 

 

 

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 

 

Zometa must only be prescribed and administered to patients by healthcare professionals experienced 

in the administration of intravenous bisphosphonates. Patients treated with Zometa 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: 

Zometa 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 Zometa 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. Zometa 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 Zometa, patients with serum creatinine 

> 265 µmol/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 Zometa dose is 

recommended (see also section 4.4): 

 

Baseline creatinine clearance (ml/min) Zometa 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 Zometa 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, Zometa treatment was resumed only when the creatinine level returned to 

within 10% of the baseline value (see section 4.4). Zometa 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. 

Zometa 4 mg powder and solvent for solution for infusion, reconstituted and 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 Zometa doses are recommended (see 

section “Posology” above and section 4.4). 

 



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Instructions for preparing reduced doses of Zometa 

 

Withdraw an appropriate volume of the reconstituted solution (4 mg/5 ml) as needed: 

- 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 reconstitution and dilution of the medicinal product before administration, see 

section 6.6. The withdrawn amount of reconstituted solution must be 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. 

 

Zometa reconstituted solution 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 Zometa. 

 

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 Zometa 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 Zometa 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. 

 

Zometa contains the same active substance as found in Aclasta (zoledronic acid). Patients being 

treated with Zometa should not be treated with Aclasta 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 Zometa 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. 

 

  



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Zometa 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 Zometa 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 Zometa 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 Zometa. 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, Zometa should be withheld. Zometa should only be resumed when serum creatinine 

returns to within 10% of baseline. Zometa 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 Zometa 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 in patients receiving 

Zometa. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ 

based on tumour type (advanced breast cancer, multiple myeloma). A study showed that ONJ was 

higher in myeloma patients when compared to other cancers (see section 5.1). 

 

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 Zometa. 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 Zometa. 

 

Musculoskeletal pain 

 

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain 

have been reported in patients taking Zometa. 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 Zometa 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. 

 

  



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Hypocalcaemia 

 

Hypocalcaemia has been reported in patients treated with Zometa. 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 Zometa 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 Zometa therapy. Patients 

should be adequately supplemented with calcium and vitamin D. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

In clinical studies, Zometa 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 Zometa 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 Zometa is used in 

combination with thalidomide. 

 

Caution is advised when Zometa 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. Zometa 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. Zometa 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. 

 

  



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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 Zometa along with driving and 

operating of machinery. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Within three days after Zometa administration, 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 Zometa 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: 

 

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: Dizziness, paraesthesia, dysgeusia, 

hypoaesthesia, hyperaesthesia, tremor, 

somnolence 

 Very rare: Convulsions, hypoaesthesia and tetany 

(secondary to hypocalcaemia) 

Eye disorders 

 Common: Conjunctivitis 

 Uncommon: Blurred vision, scleritis and orbital 

inflammation 

 Rare: Uveitis 

 Very rare: Episcleritis 



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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: Dyspnoea, cough, bronchoconstriction 

 Rare: 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: Muscle spasms, osteonecrosis of the jaw 

 Very rare: 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: Acute renal failure, haematuria, proteinuria 

 Rare:  Acquired Fanconi syndrome 

General disorders and administration site conditions 

 Common: Fever, flu-like syndrome (including fatigue, 

rigors, malaise and flushing) 

 Uncommon: Asthenia, peripheral oedema, injection site 

reactions (including pain, irritation, swelling, 

induration), chest pain, weight increase, 

anaphylactic reaction/shock, urticaria 

 Rare: 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 

Zometa has been associated with reports of renal dysfunction. In a pooled analysis of safety data from 

Zometa 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 Zometa (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 

Zometa 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). 

 



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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 Zometa (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 Zometa (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-Zometa 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 Zometa 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 Zometa 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 Zometa 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 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 

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. 

 



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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 

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 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 

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) 

 

 
 

CZOL446EUS122/SWOG study 

 

The primary objective of this observational study was to estimate the cumulative incidence of 

osteonecrosis of the jaw (ONJ) at 3 years in cancer patients with bone metastasis receiving zoledronic 

acid. The osteoclast inhibition therapy, other cancer therapy, and dental care was performed as 

clinically indicated in order to best represent academic and community-based care. A baseline dental 

examination was recommended but was not mandatory. 

 

Among the 3491 evaluable patients, 87 cases of ONJ diagnosis were confirmed. The overall estimated 

cumulative incidence of confirmed ONJ at 3 years was 2.8% (95% CI: 2.3-3.5%). The rates were 0.8% 

at year 1 and 2.0% at year 2. Rates of 3-year confirmed ONJ were highest in myeloma patients (4.3%) 

and lowest in breast cancer patients (2.4%). Cases of confirmed ONJ were statistically significantly 

higher in patients with multiple myeloma (p=0.03) than other cancers combined. 

 

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: 

 

Time on study (weeks) 

Placebo ∆ 

Zometa  
B

P
I 

m
ea

n
 c

h
an

g
e 

fr
o

m
 b

as
el

in
e 

 

 



15 

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). 

 



16 

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 
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 Zometa (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 

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 0.24 and t½ 1.87 hours, followed by 

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

accumulation of 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 

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. 

 



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 

 

Powder vial: Mannitol 

 Sodium citrate 

Solvent ampoule: Water for injections 

 

6.2 Incompatibilities 

 

To avoid potential incompatibilities, Zometa reconstituted solution 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 reconstitution and dilution: From a microbiological point of view, the reconstituted and diluted 

solution for infusion should be used immediately. If not used immediately, in-use storage times and 

conditions prior to use are the responsibility of the user and would normally not be longer than 

24 hours at 2°C – 8°C. The refrigerated solution should then be equilibrated to room temperature prior 

to administration. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

For storage conditions of the reconstituted solution for infusion, see section 6.3. 

 

6.5 Nature and contents of container 

 

Powder vial: 6 ml colourless glass vial, hydrolytic glass type I (Ph. Eur.). 

 

Solvent ampoule: 5-ml colourless glass ampoule. 

 

Unit packs containing 1 or 4 vials and 1 or 4 ampoules of water for injections, respectively. 

 

Multi-packs containing 10 (10 packs of 1+1) vials and ampoules of water for injections. 

 

Not all pack sizes may be marketed. 

 



19 

6.6 Special precautions for disposal and other handling 

 

The powder must first be reconstituted in the vial using 5 ml water for injections from the ampoule 

supplied. Dissolution must be complete before the solution is withdrawn. The amount of reconstituted 

solution as required is then 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 Zometa, including guidance on preparation of reduced doses, 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 Zometa 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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBERS 

 

EU/1/01/176/001-003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 20.03.2001 

Date of latest renewal: 20.03.2006 

 

 

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 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 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, corresponding to 4.264 mg zoledronic 

acid 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 

 

Clear and 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 

 

Zometa must only be prescribed and administered to patients by healthcare professionals experienced 

in the administration of intravenous bisphosphonates. Patients treated with Zometa 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. 

 



21 

Renal impairment 

TIH: 

Zometa 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 Zometa 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. Zometa 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 Zometa, patients with serum creatinine 

> 265 µmol/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 Zometa dose is 

recommended (see also section 4.4): 

 

Baseline creatinine clearance (ml/min) Zometa 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 Zometa 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, Zometa treatment was resumed only when the creatinine level returned to 

within 10% of the baseline value (see section 4.4). Zometa 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. 

Zometa 4 mg 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 Zometa doses are recommended (see 

section “Posology” above and section 4.4). 

 



22 

Instructions for preparing reduced doses of Zometa 

 

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 the 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. 

 

Zometa concentrate 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 Zometa. 

 

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 Zometa 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 Zometa 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. 

 

Zometa contains the same active substance as found in Aclasta (zoledronic acid). Patients being 

treated with Zometa should not be treated with Aclasta 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 Zometa 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. 

 

  



23 

Zometa 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 Zometa 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 Zometa 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 Zometa. 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, Zometa should be withheld. Zometa should only be resumed when serum creatinine 

returns to within 10% of baseline. Zometa 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 Zometa 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 in patients receiving 

Zometa. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ 

based on tumour type (advanced breast cancer, multiple myeloma). A study showed that ONJ was 

higher in myeloma patients when compared to other cancers (see section 5.1). 

 

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. 

 

  



24 

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 Zometa. 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 Zometa. 

 

Musculoskeletal pain 

 

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain 

have been reported in patients taking Zometa. 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 Zometa 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. 

 

  



25 

Hypocalcaemia 

 

Hypocalcaemia has been reported in patients treated with Zometa. 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 Zometa 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 Zometa therapy. Patients 

should be adequately supplemented with calcium and vitamin D. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

In clinical studies, Zometa 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 Zometa 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 Zometa is used in 

combination with thalidomide. 

 

Caution is advised when Zometa 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. Zometa 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. Zometa 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. 

 

  



26 

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 Zometa along with driving and 

operating of machinery. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Within three days after Zometa administration, 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 Zometa 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: 

 

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: Dizziness, paraesthesia, dysgeusia, 

hypoaesthesia, hyperaesthesia, tremor, 

somnolence 

 Very rare: Convulsions, hypoaesthesia and tetany 

(secondary to hypocalcaemia) 

Eye disorders 

 Common: Conjunctivitis 

 Uncommon: Blurred vision, scleritis and orbital 

inflammation 

 Rare: Uveitis 

 Very rare: Episcleritis 

 



27 

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: Dyspnoea, cough, bronchoconstriction 

 Rare: 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: Muscle spasms, osteonecrosis of the jaw 

 Very rare: 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: Acute renal failure, haematuria, proteinuria 

 Rare: Acquired Fanconi syndrome 

General disorders and administration site conditions 

 Common: Fever, flu-like syndrome (including fatigue, 

rigors, malaise and flushing) 

 Uncommon: Asthenia, peripheral oedema, injection site 

reactions (including pain, irritation, swelling, 

induration), chest pain, weight increase, 

anaphylactic reaction/shock, urticaria 

 Rare: 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 

Zometa has been associated with reports of renal dysfunction. In a pooled analysis of safety data from 

Zometa 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 Zometa (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 

Zometa 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). 

 



28 

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 Zometa (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 Zometa (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-Zometa 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 Zometa 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 Zometa 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 Zometa 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


29 

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 

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. 

 



30 

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 

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 

 

  



31 

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 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 

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. 

 



32 

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) 

 

 
 

CZOL446EUS122/SWOG study 

 

The primary objective of this observational study was to estimate the cumulative incidence of 

osteonecrosis of the jaw (ONJ) at 3 years in cancer patients with bone metastasis receiving zoledronic 

acid. The osteoclast inhibition therapy, other cancer therapy, and dental care was performed as 

clinically indicated in order to best represent academic and community-based care. A baseline dental 

examination was recommended but was not mandatory. 

 

Among the 3491 evaluable patients, 87 cases of ONJ diagnosis were confirmed. The overall estimated 

cumulative incidence of confirmed ONJ at 3 years was 2.8% (95% CI: 2.3-3.5%). The rates were 0.8% 

at year 1 and 2.0% at year 2. Rates of 3-year confirmed ONJ were highest in myeloma patients (4.3%) 

and lowest in breast cancer patients (2.4%). Cases of confirmed ONJ were statistically significantly 

higher in patients with multiple myeloma (p=0.03) than other cancers combined. 

 

  

Time on study (weeks) 

Placebo ∆ 

Zometa  
B

P
I 

m
ea

n
 c

h
an

g
e 

fr
o

m
 b

as
el

in
e 

 

 



33 

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 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. 

 

  



34 

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). 

 

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 
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 Zometa (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 

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). 

 

  



35 

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 0.24 and t½ 1.87 hours, followed by 

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

accumulation of 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. 

 

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. 

 

  



36 

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. 

 

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, Zometa concentrate 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. 

 



37 

6.3 Shelf life 

 

3 years. 

 

After dilution: From a microbiological point of view, the diluted solution for infusion should be used 

immediately. If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. The 

refrigerated solution should then be equilibrated to room temperature prior to administration. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

For storage conditions of the reconstituted solution for infusion, see section 6.3. 

 

6.5 Nature and contents of container 

 

Vial: 5-ml plastic vial made of clear, colourless cycloolefine copolymer with fluoropolymer-coated 

bromobutyl rubber stopper and aluminium cap with plastic flip-off component. 

 

Unit packs containing 1 or 4 vials. 

 

Multi-packs containing 10 (10 packs of 1) vials. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

Prior to administration, 5.0 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 Zometa, including guidance on preparation of reduced doses, 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 Zometa via the domestic sewage system. 

 

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

requirements. 

 

 

  



38 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBERS 

 

EU/1/01/176/004-006 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 24.03.2003 

Date of latest renewal: 20.03.2006 

 

 

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/


39 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg/100 ml solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One bottle contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for infusion 

 

Clear and colourless solution 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

- 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 

 

Zometa must only be prescribed and administered to patients by healthcare professionals experienced 

in the administration of intravenous bisphosphonates. Patients treated with Zometa 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. 

 

  



40 

Renal impairment 

TIH: 

Zometa 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 Zometa 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. Zometa 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 Zometa, 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, reduced Zometa doses are recommended 

(see also section 4.4). 

 

Baseline creatinine clearance (ml/min) Zometa 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 Zometa 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, Zometa treatment was resumed only when the creatinine level returned to 

within 10% of the baseline value (see section 4.4). Zometa 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. 

Zometa 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. 

 

  



41 

In patients with mild to moderate renal impairment, reduced Zometa 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 Zometa 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 solution for injection. 

 

Table 1 Preparation of reduced doses of Zometa 4 mg/100 ml solution for infusion 

 

Baseline creatinine 

clearance (ml/min) 

Remove the following 

amount of Zometa 

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 

 

Zometa 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 Zometa. 

 

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 Zometa 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 Zometa 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. 

 

Zometa contains the same active substance as found in Aclasta (zoledronic acid). Patients being 

treated with Zometa should not be treated with Aclasta or any other bisphosphonate concomitantly, 

since the combined effects of these agents are unknown. 

 

  



42 

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 Zometa 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. 

 

Zometa 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 Zometa 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 Zometa 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 Zometa. 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, Zometa should be withheld. Zometa should only be resumed when serum creatinine 

returns to within 10% of baseline. Zometa 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 Zometa 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 in patients receiving 

Zometa. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ 

based on tumour type (advanced breast cancer, multiple myeloma). A study showed that ONJ was 

higher in myeloma patients when compared to other cancers (see section 5.1). 

 

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. 

 

  



43 

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 Zometa. 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 Zometa. 

 

Musculoskeletal pain 

 

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain 

have been reported in patients taking Zometa. 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 Zometa 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. 

 

  



44 

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 Zometa. 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 Zometa 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 Zometa therapy. Patients 

should be adequately supplemented with calcium and vitamin D. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

In clinical studies, Zometa 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 Zometa 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 Zometa is used in 

combination with thalidomide. 

 

Caution is advised when Zometa 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. Zometa 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. Zometa 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. 

 



45 

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 Zometa along with driving and 

operating of machinery. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Within three days after Zometa administration, 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 Zometa 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: 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: Dizziness, paraesthesia, dysgeusia, 

hypoaesthesia, hyperaesthesia, tremor, 

somnolence 

 Very rare: Convulsions, hypoaesthesia and tetany 

(secondary to hypocalcaemia) 

Eye disorders 

 Common: Conjunctivitis 

 Uncommon: Blurred vision, scleritis and orbital 

inflammation 

 Rare: Uveitis 

 Very rare: Episcleritis 



46 

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: Dyspnoea, cough, bronchoconstriction 

 Rare: 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: Muscle spasms, osteonecrosis of the jaw 

 Very rare: 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: Acute renal failure, haematuria, proteinuria 

 Rare: Acquired Fanconi syndrome 

General disorders and administration site conditions 

 Common: Fever, flu-like syndrome (including fatigue, 

rigors, malaise and flushing) 

 Uncommon: Asthenia, peripheral oedema, injection site 

reactions (including pain, irritation, swelling, 

induration), chest pain, weight increase, 

anaphylactic reaction/shock, urticaria 

 Rare: 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 

Zometa has been associated with reports of renal dysfunction. In a pooled analysis of safety data from 

Zometa 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 Zometa (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 

Zometa 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). 

 



47 

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 Zometa (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 Zometa (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-Zometa 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 Zometa 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 Zometa 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 Zometa 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


48 

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 

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. 

 



49 

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 

Placeb

o 

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 

 

  



50 

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 

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 

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. 

 



51 

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) 

 
 

CZOL446EUS122/SWOG study 

 

The primary objective of this observational study was to estimate the cumulative incidence of 

osteonecrosis of the jaw (ONJ) at 3 years in cancer patients with bone metastasis receiving zoledronic 

acid. The osteoclast inhibition therapy, other cancer therapy, and dental care was performed as 

clinically indicated in order to best represent academic and community-based care. A baseline dental 

examination was recommended but was not mandatory. 

 

Among the 3491 evaluable patients, 87 cases of ONJ diagnosis were confirmed. The overall estimated 

cumulative incidence of confirmed ONJ at 3 years was 2.8% (95% CI: 2.3-3.5%). The rates were 0.8% 

at year 1 and 2.0% at year 2. Rates of 3-year confirmed ONJ were highest in myeloma patients (4.3%) 

and lowest in breast cancer patients (2.4%). Cases of confirmed ONJ were statistically significantly 

higher in patients with multiple myeloma (p=0.03) than other cancers combined. 

 

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: 

 

 

 

Time on study (weeks) 

Placebo ∆ 

Zometa  

B
P

I 
m

ea
n
 c

h
an

g
e 

fr
o

m
 b

as
el

in
e 

 

 



52 

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. 

 

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 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). 

 



53 

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: 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 
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 Zometa (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 

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 0.24 and t½ 1.87 hours, followed by 

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

accumulation of 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. 

 

  



54 

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. 

 



55 

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

immediately. If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. The 

refrigerated solution should then be equilibrated to room temperature prior to administration. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

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

 

6.5 Nature and contents of container 

 

100 ml solution in a transparent, colourless, plastic (cycloolefinic copolymer) bottle closed with a 

fluorocarbon polymer coated bromobutyl rubber stopper and an aluminum cap with a flip-off 

component of polypropylene. 

 

Unit packs containing 1 bottle. 

 

Multi-packs containing 4 (4x 1) or 5 (5x 1) bottles. 

 

Not all pack sizes may be marketed. 

 

  



56 

6.6 Special precautions for disposal and other handling 

 

Additional information on handling of Zometa, including guidance on the preparation of reduced 

doses using the Zometa 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 Zometa 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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBERS 

 

EU/1/01/176/007-9 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 20.03.2001 

Date of latest renewal: 20.03.2006 

 

 

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/


57 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 

 



58 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

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

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 
 

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. 

 

  



59 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



60 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



61 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX FOR 1 VIAL AND 1 AMPOULE AS UNIT PACK (INCLUDING BLUE BOX) 

FOLDING BOX FOR 4 VIALS AND 4 AMPOULES AS UNIT PACK (INCLUDING BLUE 

BOX 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg powder and solvent for solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial contains 4 mg of zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol and sodium citrate. 

The solvent ampoule contains water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder and solvent for solution for infusion 

 

One vial 4 mg 

One ampoule of solvent 5 ml 

Four vials 4 mg 

Four ampoules of solvent 5 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 

 

Use immediately after reconstitution and dilution. 



62 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/001 1 vial and 1 ampoule 

EU/1/01/176/002 4 vials and 4 ampoules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

Please open here 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



63 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX FOR 1 VIAL AND 1 AMPOULE AS INTERMEDIATE PACK (WITHOUT 

BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg powder and solvent for solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial contains 4 mg of zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol and sodium citrate. 

The solvent ampoule contains water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder and solvent for solution for infusion 

 

One vial 4 mg 

One ampoule of solvent 5 ml 

Component of a multipack comprising ten packs, each containing one vial and one ampoule 

 

 

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 

 

Use immediately after reconstitution and dilution. 

 

 



64 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

Please open here 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



65 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

WRAPPER LABEL ON MULTIPACKS WRAPPED IN FOIL (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg powder and solvent for solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One vial contains 4 mg of zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol and sodium citrate. 

The solvent ampoule contains water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder and solvent for solution for infusion 

 

Multipack comprising ten packs, each containing one vial and one ampoule of solvent 5 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 

 

Use immediately after reconstitution and dilution. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



66 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



67 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Zometa 4 mg powder for solution for infusion 

zoledronic acid 

For intravenous use only 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

The reconstituted solution is stable for 24 hours at 2°C – 8°C. 

 

MAH logo 

 

 

  



68 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

AMPOULE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Solvent for Zometa 

Water for injections 5 ml 

 

 

2. METHOD OF ADMINISTRATION 

 

Use the entire contents. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

 

  



69 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX FOR 1 VIAL AS UNIT PACK (INCLUDING BLUE BOX) 

FOLDING BOX FOR 4 VIALS AS UNIT PACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 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, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

One vial with 5 ml concentrate for solution for infusion 

Four vials with 5 ml concentrate for solution for infusion 

 

 

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 

 

Use immediately after dilution. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



70 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/004 1 vial 

EU/1/01/176/005 4 vials 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

Please open here 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



71 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX FOR 1 VIAL AS INTERMEDIATE PACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 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, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

One vial with 5 ml concentrate for solution for infusion 

Component of a multipack comprising ten packs, each containing one vial 

 

 

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 

 

Use immediately after dilution. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



72 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/006 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

Please open here 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



73 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

WRAPPER LABEL ON MULTIPACKS WRAPPED IN FOIL (INCLUDING BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 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, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

One vial with 5 ml concentrate for solution for infusion. 

Multipack comprising ten packs, each containing one vial. 

 

 

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 

 

Use immediately after dilution. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

  



74 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/006 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



75 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Zometa 4 mg/5 ml concentrate for solution for infusion 

zoledronic acid 

For intravenous use only 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

Stable for 24 hours at 2C – 8C after further dilution in 100 ml physiological saline or 5% w/v 

glucose solution. 

 

MAH logo 

 

  



76 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX - UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg/100 ml solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One bottle contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

1 bottle, 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 

 

Use immediately after first opening. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

  



77 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/007 1 bottle 

 

 

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: 

 

  



78 

PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS 

 

BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg/100 ml solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

1 bottle contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

100 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use. 

 

 

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

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



79 

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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/007 1 bottle 

EU/1/01/176/008 Multipack (4x1 bottle) 

EU/1/01/176/009 Multipack (5x1 bottle) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 

  



80 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX – OUTER CONTAINER OF MULTIPACK (WITH BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg/100 ml solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One bottle contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

Multipack comprising 4 packs, each containing 1 bottle. 

Multipack comprising 5 packs, each containing 1 bottle. 

 

 

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 

 

Use immediately after first opening. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



81 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/008 Multipack (4x1 bottle) 

EU/1/01/176/009 Multipack (5x1 bottle) 

 

 

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: 

 

  



82 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

FOLDING BOX – INTERMEDIATE CONTAINER OF MULTIPACK (WITHOUT BLUE 

BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zometa 4 mg/100 ml solution for infusion 

zoledronic acid 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One bottle contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. 

 

 

3. LIST OF EXCIPIENTS 

 

It also contains mannitol, sodium citrate and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for infusion 

 

100 ml 

Component of a multipack comprising 4 packs, each containing 1 bottle. 

Component of a multipack comprising 5 packs, each containing 1 bottle. 

Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only. 

Read the package leaflet before use. 

Intravenous use. 

 

 

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

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

Use immediately after first opening. 

 

 



83 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/176/008 Multipack (4x1 bottle) 

EU/1/01/176/009 Multipack (5x1 bottle) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 

  



84 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



85 

Package leaflet: Information for the user 

 

Zometa 4 mg powder and solvent 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 Zometa is and what it is used for 

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

3. How Zometa is used 

4. Possible side effects 

5. How to store Zometa 

6. Contents of the pack and other information 

 

 

1. What Zometa is and what it is used for 

 

The active substance in Zometa 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 Zometa 

 

Follow carefully all instructions given to you by your doctor. 

 

Your doctor will carry out blood tests before you start treatment with Zometa and will check your 

response to treatment at regular intervals. 

 

You should not be given Zometa: 

 if you are breast-feeding. 

 if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which 
Zometa 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 Zometa: 

 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 Zometa. 

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

 

  



86 

While being treated with Zometa, 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 Zometa. 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 Zometa. You will be given adequate calcium and vitamin D 

supplements. 

 

Patients aged 65 years and over 

Zometa 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 

Zometa is not recommended for use in adolescents and children below the age of 18 years. 

 

Other medicines and Zometa 

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. 

– Aclasta (a medicine that also contains zoledronic acid and is 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 Zometa are unknown. 

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

 

Pregnancy and breast-feeding 

You should not be given Zometa if you are pregnant. Tell your doctor if you are or think that you may 

be pregnant. 

 

You must not be given Zometa 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 Zometa. You should 

therefore be careful when driving, using machinery or performing other tasks that need full attention. 

 

 



87 

3. How Zometa is used 

 

 Zometa 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 Zometa 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 Zometa is given 

– If you are being treated for the prevention of bone complications due to bone metastases, you 
will be given one infusion of Zometa 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 Zometa. 

 

How Zometa is given 

– Zometa 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 Zometa 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 

you experience such symptoms while being treated with Zometa 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. 
 



88 

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 Zometa 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. 
 

  



89 

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 Zometa 

 

Your doctor, pharmacist or nurse knows how to store Zometa properly (see section 6). 

 

 

6. Contents of the pack and other information 

 

What Zometa contains 

 The active substance of Zometa is zoledronic acid. One vial contains 4 mg zoledronic acid, 
corresponding to 4.264 mg zoledronic acid monohydrate. 

 The other ingredients are mannitol, sodium citrate. 
 

What Zometa looks like and contents of the pack 

Zometa is supplied as a powder in a vial. One vial contains 4 mg of zoledronic acid. 

 

Each pack contains the vial with powder, together with an ampoule of 5 ml water for injections, which 

is used to dissolve the powder. 

 

  

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


90 

Zometa is supplied as unit packs containing 1 or 4 vials and 1 or 4 ampoules, respectively, and as 

multi-packs containing 10 (10x 1+1) vials and ampoules. Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

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

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

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

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 



91 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

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

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 

 

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

http://www.ema.europa.eu 

 

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


92 

INFORMATION FOR THE HEALTHCARE PROFESSIONAL 

 

How to prepare and administer Zometa 

 

 To prepare an infusion solution containing 4 mg zoledronic acid, add 5 ml of water for 
injections from the ampoule supplied in the pack to the vial containing the Zometa powder 

under aseptic conditions. Shake the vial gently to dissolve the powder. 

 

 Further dilute the Zometa reconstituted solution (5 ml) with 100 ml of calcium-free or other 
divalent cation-free infusion solution. If a lower dose of Zometa is required, first withdraw the 

appropriate volume of the reconstituted solution (4 mg/5 ml) 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 Zometa reconstituted solution with calcium-containing or other divalent 

cation-containing solutions such as lactated Ringer’s solution. 

 

Instructions for preparing reduced doses of Zometa: 

Withdraw the appropriate volume of the reconstituted solution (4 mg/5 ml), 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. 

 

 From a microbiological point of view, the reconstituted and diluted solution for infusion should 
be used immediately. If not used immediately, in-use storage times and conditions prior to use 

are the responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. 

The refrigerated solution should then be equilibrated to room temperature prior to 

administration. 

 

 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 Zometa to assure that they are adequately hydrated. 

 

 Studies with several types of infusion lines made from polyvinylchloride, polyethylene and 
polypropylene showed no incompatibility with Zometa. 

 

 Since no data are available on the compatibility of Zometa with other intravenously 
administered substances, Zometa must not be mixed with other medications/substances and 

should always be given through a separate infusion line. 

 

How to store Zometa 

 

 Keep Zometa out of the reach and sight of children. 

 Do not use Zometa after the expiry date stated on the pack. 

 The unopened vial does not require any specific storage conditions. 

 The diluted Zometa infusion solution should be used immediately in order to avoid microbial 
contamination. 



93 

Package leaflet: Information for the user 

 

Zometa 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 Zometa is and what it is used for 

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

3. How Zometa is used 

4. Possible side effects 

5. How to store Zometa 

6. Contents of the pack and other information 

 

 

1. What Zometa is and what it is used for 

 

The active substance in Zometa 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 Zometa 

 

Follow carefully all instructions given to you by your doctor. 

 

Your doctor will carry out blood tests before you start treatment with Zometa and will check your 

response to treatment at regular intervals. 

 

You should not be given Zometa: 

 if you are breast-feeding. 

 if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which 
Zometa 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 Zometa: 

 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 Zometa. 

if you are having dental treatment or are due to undergo dental surgery, tell your dentist that 

you are being treated with Zometa and inform your doctor about your dental treatment. 

 

  



94 

While being treated with Zometa, 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 Zometa. 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 Zometa. You will be given adequate calcium and vitamin D 

supplements. 

 

Patients aged 65 years and over 

Zometa 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 

Zometa is not recommended for use in adolescents and children below the age of 18 years. 

 

Other medicines and Zometa 

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. 

– Aclasta (a medicine that also contains zoledronic acid and is 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 Zometa are unknown. 

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

 

Pregnancy and breast-feeding 

You should not be given Zometa if you are pregnant. Tell your doctor if you are or think that you may 

be pregnant. 

 

You must not be given Zometa 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 Zometa. You should 

therefore be careful when driving, using machinery or performing other tasks that need full attention. 

 

 



95 

3. How Zometa is used 

 

 Zometa 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 Zometa 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 Zometa is given 

– If you are being treated for the prevention of bone complications due to bone metastases, you 
will be given one infusion of Zometa 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 Zometa. 

 

How Zometa is given 

– Zometa 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 Zometa 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 

you experience such symptoms while being treated with Zometa 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. 
 



96 

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 Zometa 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. 
 

  



97 

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 Zometa 

 

Your doctor, pharmacist or nurse knows how to store Zometa properly (see section 6). 

 

 

6. Contents of the pack and other information 

 

What Zometa contains 

 The active substance of Zometa is zoledronic acid. One vial contains 4 mg zoledronic acid, 
corresponding to 4.264 mg zoledronic acid monohydrate. 

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

What Zometa looks like and contents of the pack 

Zometa is supplied as a liquid concentrate in a vial. One vial contains 4 mg of zoledronic acid. 

 

Each pack contains the vial with concentrate. Zometa is supplied as unit packs containing 1 or 4 vials 

and as multi-packs containing 10 (10x1) vials. Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

  

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


98 

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

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

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

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

  



99 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

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

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency we bsite: 

http://www.ema.europa.eu 

 

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


100 

INFORMATION FOR THE HEALTHCARE PROFESSIONAL 

 

How to prepare and administer Zometa 

 

 To prepare an infusion solution containing 4 mg zoledronic acid, further dilute the Zometa 
concentrate (5.0 ml) with 100 ml of calcium-free or other divalent cation-free infusion solution. 

If a lower dose of Zometa 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 Zometa concentrate with calcium-containing or other divalent cation-

containing solutions such as lactated Ringer’s solution. 

 

Instructions for preparing reduced doses of Zometa: 

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. 

 

 From a microbiological point of view, the diluted solution for infusion should be used 
immediately. If not used immediately,in-use storage times and conditions prior to use are the 

responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. The 

refrigerated solution should then be equilibrated to room temperature prior to administration. 

 

 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 Zometa to ensure that they are adequately hydrated. 

 

 Studies with several types of infusion lines made from polyvinylchloride, polyethylene and 
polypropylene showed no incompatibility with Zometa. 

 

 Since no data are available on the compatibility of Zometa with other intravenously 
administered substances, Zometa must not be mixed with other medications/substances and 

should always be given through a separate infusion line. 

 

 

How to store Zometa 

 

 Keep Zometa out of the reach and sight of children. 

 Do not use Zometa after the expiry date stated on the pack. 

 The unopened vial does not require any specific storage conditions. 

 The diluted Zometa infusion solution should be used immediately in order to avoid microbial 
contamination. 



101 

Package leaflet: Information for the user 

 

Zometa 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 Zometa is and what it is used for 

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

3. How Zometa is used 

4. Possible side effects 

5. How to store Zometa 

6. Contents of the pack and other information 

 

 

1. What Zometa is and what it is used for 

 

The active substance in Zometa 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 Zometa 

 

Follow carefully all instructions given to you by your doctor. 

 

Your doctor will carry out blood tests before you start treatment with Zometa and will check your 

response to treatment at regular intervals. 

 

You should not be given Zometa: 

 if you are breast-feeding. 

 if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which 
Zometa 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 Zometa: 

 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 Zometa. 

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

 

  



102 

While being treated with Zometa, 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 Zometa. 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 Zometa. You will be given adequate calcium and vitamin D 

supplements. 

 

Patients aged 65 years and over 

Zometa 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 

Zometa is not recommended for use in adolescents and children below the age of 18 years. 

 

Other medicines and Zometa 

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. 

– Aclasta (a medicine that also contains zoledronic acid and is 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 Zometa are unknown. 

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

 

Pregnancy and breast-feeding 

You should not be given Zometa if you are pregnant. Tell your doctor if you are or think that you may 

be pregnant. 

 

You must not be given Zometa 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 Zometa. You should 

therefore be careful when driving, using machinery or performing other tasks that need full attention. 

 

 



103 

3. How Zometa is used 

 

 Zometa 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 Zometa 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 Zometa is given 

– If you are being treated for the prevention of bone complications due to bone metastases, you 
will be given one infusion of Zometa 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 Zometa. 

 

How Zometa is given 

– Zometa 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 Zometa 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 

you experience such symptoms while being treated with Zometa 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. 
 



104 

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 Zometa 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. 
 

  



105 

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 Zometa 

 

Your doctor, pharmacist or nurse knows how to store Zometa properly (see section 6). 

 

After first opening, Zometa 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 Zometa contains 

 The active substance of Zometa is zoledronic acid. One bottle contains 4 mg zoledronic acid, 
corresponding to 4.264 mg zoledronic acid monohydrate. 

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

What Zometa looks like and contents of the pack 

Zometa is supplied as a solution in a clear, colourless plastic bottle. One bottle contains 100 ml 

solution. 

 

Zometa is supplied as a unit pack containing one bottle or as multipacks comprising 4 or 5 cartons, 

each containing 1 bottle. Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

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


106 

 

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

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

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

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

  



107 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

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

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 

 

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

http://www.ema.europa.eu 

 

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


108 

INFORMATION FOR THE HEALTHCARE PROFESSIONAL 

 

How to prepare and administer Zometa 

 

 Zometa 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 then 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 Zometa to 

assure that they are adequately hydrated. 

 

 Zometa 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 Zometa 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 solution for injection. 

 

Table 1 Preparation of reduced doses of Zometa 4 mg/100 ml solution for infusion 

 

Baseline creatinine 

clearance (ml/min) 

Remove the following 

amount of Zometa 

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 

 

*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 several types of infusion lines made from polyvinylchloride, polyethylene and 
polypropylene showed no incompatibility with Zometa. 

 

 Since no data are available on the compatibility of Zometa with other intravenously 
administered substances, Zometa must not be mixed with other medications/substances and 

should always be given through a separate infusion line. 

 



109 

How to store Zometa 

 

 Keep Zometa out of the reach and sight of children. 

 Do not use Zometa after the expiry date stated on the pack. 

 The unopened bottle does not require any special storage conditions. 

 After opening the bottle, the product should be used immediately in order to avoid microbial 
contamination. 

 


	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
{'Title': '1. what zometa is and what it is used for', 'Section_Content': 'the active substance in zometa 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).', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 8, 'BeginOffset': 24, 'EndOffset': 30, 'Score': 0.9866895079612732, 'Text': 'zometa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.4036901295185089}]}, {'Id': 9, 'BeginOffset': 34, 'EndOffset': 49, 'Score': 0.9951530694961548, 'Text': 'zoledronic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'bisphosphonates', 'Type': 'TREATMENT', 'BeginOffset': 97, 'EndOffset': 112}, {'Id': 10, 'BeginOffset': 114, 'EndOffset': 129, 'Score': 0.9611112475395203, 'Text': 'zoledronic acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 0, 'BeginOffset': 163, 'EndOffset': 167, 'Score': 0.8814564943313599, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'bone change', 'Type': 'PROBLEM', 'BeginOffset': 197, 'EndOffset': 208}, {'Id': 13, 'BeginOffset': 233, 'EndOffset': 251, 'Score': 0.7834480404853821, 'Text': 'bone complications', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6376751065254211}]}, {'Text': 'e.g. fractures', 'Type': 'PROBLEM', 'BeginOffset': 253, 'EndOffset': 267}, {'Id': 15, 'BeginOffset': 292, 'EndOffset': 307, 'Score': 0.8861036896705627, 'Text': 'bone metastases', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9513230919837952}]}, {'Id': 16, 'BeginOffset': 319, 'EndOffset': 325, 'Score': 0.9615296721458435, 'Text': 'cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9517066478729248}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.42018619179725647, 'RelationshipScore': 0.9966127276420593, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 331, 'EndOffset': 343, 'Text': 'primary site', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9591646194458008, 'RelationshipScore': 0.993907630443573, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 5, 'BeginOffset': 351, 'EndOffset': 355, 'Text': 'bone', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 4, 'BeginOffset': 331, 'EndOffset': 343, 'Score': 0.42018619179725647, 'Text': 'primary site', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 5, 'BeginOffset': 351, 'EndOffset': 355, 'Score': 0.9591646194458008, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 11, 'BeginOffset': 382, 'EndOffset': 389, 'Score': 0.7113378047943115, 'Text': 'calcium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a tumour', 'Type': 'PROBLEM', 'BeginOffset': 465, 'EndOffset': 473}, {'Text': 'tumours', 'Type': 'PROBLEM', 'BeginOffset': 475, 'EndOffset': 482}, {'Id': 6, 'BeginOffset': 505, 'EndOffset': 509, 'Score': 0.8686074614524841, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 12, 'BeginOffset': 551, 'EndOffset': 558, 'Score': 0.9139317274093628, 'Text': 'calcium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 564, 'EndOffset': 568, 'Score': 0.8861179947853088, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'tumour-induced hypercalcaemia', 'Type': 'PROBLEM', 'BeginOffset': 610, 'EndOffset': 639}]}
{'Title': '2. what you need to know before you are given zometa', 'Section_Content': 'follow carefully all instructions given to you by your doctor. your doctor will carry out blood tests before you start treatment with zometa and will check your response to treatment at regular intervals. you should not be given zometa: if you are breast-feeding. if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which zometa 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 zometa: 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 zometa. if you are having dental treatment or are due to undergo dental surgery, tell your dentist that you are being treated with zometa and inform your doctor about your dental treatment. while being treated with zometa, 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 zometa. 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 zometa. you will be given adequate calcium and vitamin d supplements. patients aged 65 years and over zometa 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 zometa is not recommended for use in adolescents and children below the age of 18 years. other medicines and zometa 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. aclasta (a medicine that also contains zoledronic acid and is 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 zometa are unknown. anti-angiogenic medicines (used to treat cancer), since the combination of these with zometa has been associated with an increased risk of osteonecrosis of the jaw (onj). pregnancy and breast-feeding you should not be given zometa if you are pregnant. tell your doctor if you are or think that you may be pregnant. you must not be given zometa 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 zometa. you should therefore be careful when driving, using machinery or performing other tasks that need full attention.', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 51, 'BeginOffset': 90, 'EndOffset': 101, 'Score': 0.6934443712234497, 'Text': 'blood tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 119, 'EndOffset': 128}, {'Id': 15, 'BeginOffset': 134, 'EndOffset': 140, 'Score': 0.9933179616928101, 'Text': 'zometa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 173, 'EndOffset': 182}, {'Id': 16, 'BeginOffset': 229, 'EndOffset': 235, 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{'Title': '3. how zometa is used', 'Section_Content': ' zometa 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 zometa 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 zometa is given if you are being treated for the prevention of bone complications due to bone metastases, you will be given one infusion of zometa 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 zometa. how zometa is given zometa 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 zometa 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.', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 8, 'BeginOffset': 1, 'EndOffset': 7, 'Score': 0.9862052798271179, 'Text': 'zometa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'bisphosphonates intravenously', 'Type': 'TREATMENT', 'BeginOffset': 80, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. 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 you experience such symptoms while being treated with zometa 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 zometa 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. 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.', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 30, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9635578989982605, 'Text': 'side 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{'Title': '5. how to store zometa', 'Section_Content': 'your doctor, pharmacist or nurse knows how to store zometa properly (see section 6).', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 52, 'EndOffset': 58, 'Score': 0.9407297968864441, 'Text': 'zometa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what zometa contains the active substance of zometa is zoledronic acid. one vial contains 4 mg zoledronic acid, corresponding to 4.264 mg zoledronic acid monohydrate. the other ingredients are mannitol, sodium citrate. what zometa looks like and contents of the pack zometa is supplied as a powder in a vial. one vial contains 4 mg of zoledronic acid. each pack contains the vial with powder, together with an ampoule of 5 ml water for injections, which is used to dissolve the powder. zometa is supplied as unit packs containing 1 or 4 vials and 1 or 4 ampoules, respectively, and as multi-packs containing 10 (10x 1+1) vials and ampoules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'zometa', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 11, 'Score': 0.9753406047821045, 'Text': 'zometa', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 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