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ZOLEDRONIC ACID 5MG/100 ML SOLUTION FOR INFUSION

Active substance(s): ZOLEDRONIC ACID MONOHYDRATE / ZOLEDRONIC ACID MONOHYDRATE / ZOLEDRONIC ACID MONOHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Zoledronic Acid 5 mg/ 100 ml solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each bag of solution contains zoledronic acid monohydrate corresponding to 5 mg
zoledronic acid This medicinal product contains 2.2 – 3.1 mg of sodium.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for infusion
Clear and colourless solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of osteoporosis
in post-menopausal women
in adult men
at increased risk of fracture, including those with a recent low-trauma hip fracture.
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy
in post-menopausal women
in adult men
at increased risk of fracture.
Treatment of Paget’s disease of the bone in adults.

4.2

Posology and method of administration
Posology
Patients must be appropriately hydrated prior to administration of Zoledronic Acid .
This is especially important for the elderly (≥ 65 years) and for patients receiving
diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with
Zoledronic Acid administration.
Osteoporosis
For the treatment of post-menopausal osteoporosis, osteoporosis in men and the
treatment of osteoporosis associated with long-term systemic glucocorticoid therapy,
the recommended dose is a single intravenous infusion of 5 mg Zoledronic Acid
administered once a year.
The optimal duration of bisphosphonate treatment for osteoporosis has not been
established. The need for continued treatment should be re-evaluated periodically
based on the benefits and potential risks of Zoledronic Acid on an individual patient
basis, particularly after 5 or more years of use.
In patients with a recent low-trauma hip fracture, it is recommended to give the
Zoledronic Acid infusion two or more weeks after hip fracture repair (see section
5.1). In patients with a recent low-trauma hip fracture, a loading dose of 50,000 to
125,000 IU of vitamin D given orally or via the intramuscular route is recommended
prior to the first Zoledronic Acid infusion.
Paget’s disease
For the treatment of Paget’s disease, Zoledronic Acid should be prescribed only by
physicians with experience in the treatment of Paget’s disease of the bone. The
recommended dose is a single intravenous infusion of 5 mg Zoledronic Acid .
In patients with Paget’s disease, it is strongly advised that adequate supplemental
calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for
at least 10 days following Zoledronic Acid administration (see section 4.4).
Re-treatment of Paget’s disease: After initial treatment with Zoledronic Acid in
Paget’s disease, an extended remission period is observed in responding patients. Retreatment consists of an additional intravenous infusion of 5 mg Zoledronic Acid after
an interval of one year or longer from initial treatment in patients who have relapsed.
Limited data on re-treatment of Paget’s disease are available (see section 5.1).
Special populations
Patients with renal impairment
Zoledronic Acid is contraindicated in patients with creatinine clearance < 35 ml/min
(see sections 4.3 and 4.4).
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min.
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Older people (≥ 65 years)
No dose adjustment is necessary since bioavailability, distribution and elimination
were similar in elderly patients and younger subjects.

Paediatric population
The safety and efficacy of Zoledronic Acid in children and adolescents below 18
years of age have not been established. No data are available.
Method of administration
Intravenous use.
Zoledronic Acid (5 mg in 100 ml ready-to-infuse solution) is administered via a
vented infusion line and given at a constant infusion rate. The infusion time must not
be less than 15 minutes. For information on the infusion of Zoledronic Acid , see
section 6.6.
'Patients treated with zolendronic acid should be given the package leaflet and the
patient reminder card.

4.3

Contraindications





4.4

Hypersensitivity to the active substance, to any bisphosphonates or to any of the
excipients listed in section 6.1.
Patients with hypocalcaemia (see section 4.4).
Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).
Pregnancy and breast-feeding (see section 4.6).

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





Zoledronic Acid should be used with caution when concomitantly used with other
medicinal products that could impact renal function (see section 4.5).
Patients, especially elderly patients and those receiving diuretic therapy, should
be appropriately hydrated prior to administration of Zoledronic Acid .
A single dose of Zoledronic Acid should not exceed 5 mg and the duration of
infusion should be at least 15 minutes (see section 4.2).

Hypocalcaemia
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and
vitamin D before initiating therapy with Zoledronic Acid (see section 4.3). Other
disturbances of mineral metabolism must also be effectively treated (e.g. diminished
parathyroid reserve, intestinal calcium malabsorption). Physicians should consider
clinical monitoring for these patients.
Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the
rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia,
sometimes symptomatic, may develop and is usually maximal within the first 10 days
after infusion of Zoledronic Acid (see section 4.8).
Adequate calcium and vitamin D intake are recommended in association with
Zoledronic Acid administration. In addition, in patients with Paget's disease, it is
strongly advised that adequate supplemental calcium corresponding to at least 500 mg
elemental calcium twice daily is ensured for at least 10 days following Zoledronic
Acid administration (see section 4.2).
Patients should be informed about symptoms of hypocalcaemia and receive adequate
clinical monitoring during the period of risk. Measurement of serum calcium before
infusion of Zoledronic Acid is recommended for patients with Paget´s disease.
Severe and occasionally incapacitating bone, joint and/or muscle pain have been
infrequently reported in patients taking bisphosphonates, including Zoledronic Acid
(see section 4.8).
Osteonecrosis of the jaw (ONJ)
ONJ has been reported in the post-marketing setting in patients receiving Zoledronic
Acid for osteoporosis (see section 4.8).
The start of treatment or of a new course of treatment should be delayed in patients
with unhealed open soft tissue lesions in the mouth. A dental examination with
preventive dentistry and an individual benefit-risk assessment is recommended prior
to treatment with Zoledronic Acid in patients with concomitant risk factors.
The following should be considered when evaluating a patient’s risk of developing
ONJ:
- Potency of the medicinal product that inhibits bone resorption (higher risk for highly
potent compounds), route of administration (higher risk for parenteral administration)
and cumulative dose of bone resorption therapy.
- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors,
radiotherapy to head and neck.

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental
disease, invasive dental procedures, e.g. tooth extractions.
All patients should be encouraged to maintain good oral hygiene, undergo routine
dental check-ups, and immediately report any oral symptoms such as dental mobility,
pain or swelling, non-healing of sores or discharge during treatment with zoledronic
acid. While on treatment, invasive dental procedures should be performed with
caution and avoided in close proximity to zoledronic acid treatment.
The management plan for patients who develop ONJ should be set up in close
collaboration between the treating physician and a dentist or oral surgeon with
expertise in ONJ. Temporary interruption of zoledronic acid treatment should be
considered until the condition resolves and contributing risk factors are mitigated
where possible.
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 bisphosphonatetreated patients who have sustained a femoral shaft fracture. Poor healing of these
fractures has also been reported. Discontinuation of bisphosphonate therapy in
patients suspected to have an atypical femur fracture should be considered pending
evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip
or groin pain and any patient presenting with such symptoms should be evaluated for
an incomplete femur fracture.
General
The incidence of post-dose symptoms occurring within the first three days after
administration of Zoledronic Acid can be reduced with the administration of
paracetamol or ibuprofen shortly following Zoledronic Acid administration.

Patients being treated with Zoledronic Acid should not be treated with any other
medicines containing zoledronic acid or any other bisphosphonate concomitantly,
since the combined effects of these agents are unknown.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates,
mainly in association with long-term therapy. Possible risk factors for osteonecrosis
of the external auditory canal include steroid use and chemotherapy and/or local risk
factors such as infection or trauma. The possibility of osteonecrosis of the external
auditory canal should be considered in patients receiving bisphosphonates who
present with ear symptoms including chronic ear infections.

Warning regarding excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e.
essentially “sodium-free”.

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies with other medicinal products have been performed.
Zoledronic acid is not systemically metabolised and does not affect human
cytochrome P450 enzymes in vitro (see section 5.2). Zoledronic acid is not highly
bound to plasma proteins (approximately 43-55% bound) and interactions resulting
from displacement of highly protein-bound drugs are therefore unlikely.
Zoledronic acid is eliminated by renal excretion. Caution is indicated when
Zoledronic Acid is administered in conjunction with medicinal products that can
significantly impact renal function (e.g. aminoglycosides or diuretics that may cause
dehydration) (see section 4.4).
In patients with renal impairment, the systemic exposure to concomitant medicinal
products that are primarily excreted via the kidney may increase.

4.6

Fertility, pregnancy and lactation
Women of childbearing potential
Zoledronic acid is not recommended in women of childbearing potential.
Pregnancy
Zoledronic Acid is contraindicated during pregnancy (see section 4.3). There are no
adequate data on the use of zoledronic acid in pregnant women. Studies in animals
with zoledronic acid have shown reproductive toxicological effects including
malformations (see section 5.3). The potential risk for humans is unknown.
Breast-feeding
Zoledronic Acid is contraindicated during breast-feeding (see section 4.3). It is
unknown whether zoledronic acid is excreted into human milk.
Women of childbearing potential
Zoledronic Acid is not recommended in women of childbearing potential.
Fertility
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the
parental and F1 generation. This resulted in exaggerated pharmacological effects
considered related to the compound’s inhibition of skeletal calcium mobilisation,
resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and
early termination of the study. Thus these results precluded determining a definitive
effect of zoledronic acid on fertility in humans.

4.7

Effects on ability to drive and use machines
Adverse reactions, such as dizziness, may affect the ability to drive or use machines.

4.8

Undesirable effects
Summary of the safety profile
The overall percentage of patients who experienced adverse reactions were 44.7%,
16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of
individual adverse reactions following the first infusion was: fever (17.1%), myalgia
(7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The
incidence of these reactions decreased markedly with subsequent annual doses of
zoledronic acid. The majority of these reactions occur within the first three days
following zoledronic acid administration. The majority of these reactions were mild
to moderate and resolved within three days of the event onset. The percentage of
patients who experienced adverse reactions was lower in a smaller study (19.5%,
10.4%, 10.7% after the first, second and third infusion, respectively), where
prophylaxis against adverse reactions was used.

Tabulated list of adverse reactions
Adverse reactions in Table 1 are listed according to MedDRA system organ class and
frequency category. Frequency categories are defined using the following convention:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100);
rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated
from the available data). Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
Table 1
Infections and infestations
Blood and lymphatic system
disorders
Immune system disorders

Uncommon
Uncommon

Influenza, nasopharyngitis
Anaemia

Not known**

Metabolism and nutrition disorders

Common
Uncommon
Uncommon
Common
Uncommon

Hypersensitivity reactions
including rare cases of
bronchoconstriction, urticaria
and angioedema, and very rare
cases of anaphylactic
reaction/shock
Hypocalcaemia*
, decreased appetite
Insomnia
Headache, dizziness
Lethargy, paraesthesia,
somnolence, tremor, syncope,
dysgeusia

Psychiatric disorders
Nervous system disorders

Common
Uncommon
Rare
Not known**
Uncommon

Ocular hyperaemia
Conjunctivitis, eye pain
Uveitis, episcleritis, iritis
Scleritis and parophthalmia
Vertigo

Cardiac disorders

Common
Uncommon

Atrial fibrillation
Palpitations

Vascular disorders

Uncommon
Not known**

Respiratory, thoracic and
mediastinal disorders

Uncommon

Hypertension, flushing
Hypotension (some of the
patients had underlying risk
factors)
Cough, dyspnoea

Gastrointestinal disorders

Common
Uncommon

Skin and subcutaneous tissue
disorders

Uncommon

Musculoskeletal and connective
tissue disorders

Common

Eye disorders

Ear and labyrinth disorders

Uncommon

Rare

Very rare:

Renal and urinary disorders

Not known**
Uncommon

Nausea, vomiting, diarrhoea
Dyspepsia, abdominal pain
upper, abdominal pain,
gastroesophageal reflux disease,
constipation, dry mouth,
oesophagitis, toothache,
gastritis#
Rash, hyperhydrosis, pruritus,
erythema
Myalgia, arthralgia, bone pain,
back pain, pain in extremity
Neck pain, musculoskeletal
stiffness, joint swelling, muscle
spasms, shoulder pain,
musculoskeletal chest pain,
musculoskeletal pain, joint
stiffness, arthritis, muscular
weakness
Atypical subtrochanteric and
diaphyseal femoral fractures†
(bisphosphonate class adverse
reaction)
Osteonecrosis of the external
auditory canal (bisphosphonate
class adverse reaction)
Osteonecrosis of the jaw (see
sections 4.4 and 4.8 Class
effects)

Blood creatinine increased,
pollakiuria, proteinuria

Not known**

General disorders and
administration site conditions

Very Common
Common

Uncommon

Not known**

Renal impairment. Rare cases of
renal failure requiring dialysis
and rare cases with a fatal
outcome have been reported in
patients with pre-existing renal
dysfunction or other risk factors
such as advanced age,
concomitant nephrotoxic
medicinal products, concomitant
diuretic therapy, or dehydration
in the post infusion period (see
sections 4.4 and 4.8 Class
effects)
Pyrexia
Influenza-like symptoms, chills,
fatigue, asthenia, pain, malaise,
infusion site reaction
Peripheral oedema, thirst, acute
phase reaction, non-cardiac
chest pain
Dehydration secondary to postdose symptoms such as fever,
vomiting and diarrhoea
C-reactive protein increased
Blood calcium decreased

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

Investigations

Description of selected adverse reactions
Atrial fibrillation
In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall
incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852)
in patients receiving zoledronic acid and placebo, respectively. The rate of atrial
fibrillation serious adverse events was increased in patients receiving zoledronic acid
(1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of
3,852). The mechanism behind the increased incidence of atrial fibrillation is
unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial
[RFT]) the pooled atrial fibrillation incidences were comparable between zoledronic
acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the
pooled incidences were 1.3% for zoledronic acid and 0.8% for placebo.
Class effects:
Renal impairment
Zoledronic acid has been associated with renal impairment manifested as
deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute

renal failure. Renal impairment has been observed following the administration of
zoledronic acid, especially in patients with pre-existing renal dysfunction or
additional risk factors (e.g advanced age, oncology patients with chemotherapy,
concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe
dehydration), with the majority of them receiving a 4 mg dose every 3–4 weeks, but it
has been observed in patients after a single administration.
In clinical trials in osteoporosis, the change in creatinine clearance (measured
annually prior to dosing) and the incidence of renal failure and impairment was
comparable for both the zoledronic acid and placebo treatment groups over three
years. There was a transient increase in serum creatinine observed within 10 days in
1.8% of zoledronic acid treated patients versus 0.8% of placebo-treated patients.
Hypocalcaemia
In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines
of serum calcium levels (less than 1.87 mmol/l) following zoledronic acid
administration. No symptomatic cases of hypocalcaemia were observed.
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in
approximately 1% of patients, in all of whom it resolved.
Based on laboratory assessment, transient asymptomatic calcium levels below the
normal reference range (less than 2.10 mmol/l) occurred in 2.3% of zoledronic acid
treated patients in a large clinical trial compared to 21% of zoledronic acid treated
patients in the Paget’s disease trials. The frequency of hypocalcaemia was much
lower following subsequent infusions.
All patients received adequate supplementation with vitamin D and calcium in the
post-menopausal osteoporosis trial, the prevention of clinical fractures after hip
fracture trial, and the Paget’s disease trials (see also section 4.2). In the trial for the
prevention of clinical fractures following a recent hip fracture, vitamin D levels were
not routinely measured but the majority of patients received a loading dose of vitamin
D prior to zoledronic acid administration (see section 4.2).
Local reactions
In a large clinical trial, local reactions at the infusion site, such as redness, swelling
and/or pain, were reported (0.7%) following the administration of zoledronic acid.
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer
patients treated with medicinal products that inhibit bone resorption, including
zoledronic acid (see section 4.4). In a large clinical trial in 7,736 patients,
osteonecrosis of the jaw has been reported in one patient treated with Zoledronic acid
and one patient treated with placebo. Cases of ONJ have been reported in the postmarketing setting for Zoledronic acid.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
Clinical experience with acute overdose is limited. Patients who have received doses
higher than those recommended should be carefully monitored. In the event of
overdose leading to clinically significant hypocalcaemia, reversal may be achieved
with supplemental oral calcium and/or an intravenous infusion of calcium gluconate.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates,
ATC code: M05BA08
Mechanism of action
Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts
primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.
Pharmacodynamic effects
The selective action of bisphosphonates on bone is based on their high affinity for
mineralised bone.
The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl
pyrophosphate synthase. The long duration of action of zoledronic acid is attributable
to its high binding affinity for the active site of farnesyl pyrophosphate (FPP)
synthase and its strong binding affinity to bone mineral.
Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated
post-menopausal levels with the nadir for resorption markers observed at 7 days, and
for formation markers at 12 weeks. Thereafter bone markers stabilised within the premenopausal range. There was no progressive reduction of bone turnover markers with
repeated annual dosing.
Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)
The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years
were demonstrated in post-menopausal women (7,736 women aged 65–89 years) with
either: a femoral neck bone mineral density (BMD) with a T-score ≤ –1.5 and at least
two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD Tscore ≤ –2.5 with or without evidence of existing vertebral fracture(s). 85% of
patients were bisphosphonate-naïve. Women who were evaluated for the incidence of
vertebral fractures did not receive concomitant osteoporosis therapy, which was
allowed for women contributing to the hip and all clinical fracture evaluations.
Concomitant osteoporosis therapy included: calcitonin, raloxifene, tamoxifen,
hormone replacement therapy, tibolone; but excluded other bisphosphonates. All

women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU of vitamin
D supplements daily.
Effect on morphometric vertebral fractures
Zoledronic acid significantly decreased the incidence of one or more new vertebral
fractures over three years and as early as the one year timepoint (see Table 2).
Table 2 Summary of vertebral fracture efficacy at 12, 24 and 36 months
Outcome
zoledronic acid
Placebo (%)
Absolute
Relative reduction
(%)
reduction in
in
fracture
fracture incidence incidence % (CI)
% (CI)
At least one new
1.5
3.7
2.2 (1.4, 3.1)
60 (43, 72)**
vertebral fracture
(0–1 year)
At least one new
2.2
7.7
5.5 (4.4, 6.6)
71 (62, 78)**
vertebral fracture
(0–2 year)
At least one new
3.3
10.9
7.6 (6.3, 9.0)
70 (62, 76)**
vertebral fracture
(0–3 year)
** p <0.0001
Zoledronic acid treated patients aged 75 years and older exhibited a 60% reduction in
the risk of vertebral fractures compared to placebo patients (p<0.0001).
Effect on hip fractures
Zoledronic acid demonstrated a consistent effect over 3 years, resulting in a 41%
reduction in the risk of hip fractures (95% CI, 17% to 58%). The hip fracture event
rate was 1.44% for zoledronic acid-treated patients compared to 2.49% for placebotreated patients. The risk reduction was 51% in bisphosphonate-naïve patients and
42% in patients allowed to take concomitant osteoporosis therapy.
Effect on all clinical fractures
All clinical fractures were verified based on the radiographic and/or clinical evidence.
A summary of results is presented in Table 3.
Table 3 Between treatment comparisons of the incidence of key clinical fracture
variables over 3 years
Outcome
zoledronic acid
Placebo
Absolute
Relative
risk
(N=3,875) event
(N=3,861) event
reduction
in reduction
in
rate (%)
rate (%)
fracture event rate fracture incidence
%
% (CI)
(CI)
Any clinical
8.4
12.8
4.4 (3.0, 5.8)
33 (23, 42)**
fracture (1)
Clinical vertebral
0.5
2.6
2.1 (1.5, 2.7)
77 (63, 86)**
fracture (2)

Non-vertebral
8.0
10.7
2.7 (1.4, 4.0)
fracture (1)
*p-value <0.001, **p-value <0.0001
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures

25 (13, 36)*

Effect on bone mineral density (BMD)
Zoledronic acid significantly increased BMD at the lumbar spine, hip, and distal
radius relative to treatment with placebo at all timepoints (6, 12, 24 and 36 months).
Treatment with zoledronic acid resulted in a 6.7% increase in BMD at the lumbar
spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal radius
over 3 years as compared to placebo.
Bone histology
Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in
152 post-menopausal patients with osteoporosis treated with zoledronic acid (N=82)
or placebo (N=70). Histomorphometric analysis showed a 63% reduction in bone
turnover. In patients treated with zoledronic acid, no osteomalacia, marrow fibrosis or
woven bone formation was detected. Tetracycline label was detectable in all but one
of 82 biopsies obtained from patients on zoledronic acid. Microcomputed tomography
(μCT) analysis demonstrated increased trabecular bone volume and preservation of
trabecular bone architecture in patients treated with zoledronic acid compared to
placebo.
Bone turnover markers
Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I
collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets
ranging from 517 to 1,246 patients at periodic intervals throughout the study.
Treatment with a 5 mg annual dose of zoledronic acid significantly reduced BSAP by
30% relative to baseline at 12 months which was sustained at 28% below baseline
levels at 36 months. P1NP was significantly reduced by 61% below baseline levels at
12 months and was sustained at 52% below baseline levels at 36 months. B-CTx was
significantly reduced by 61% below baseline levels at 12 months and was sustained at
55% below baseline levels at 36 months. During this entire time period bone turnover
markers were within the pre-menopausal range at the end of each year. Repeat dosing
did not lead to further reduction of bone turnover markers.
Effect on height
In the three-year osteoporosis study standing height was measured annually using a
stadiometer. The zoledronic acid group revealed approximately 2.5 mm less height
loss compared to placebo (95% CI: 1.6 mm, 3.5 mm) [p<0.0001].
Days of disability
Zoledronic acid significantly reduced the mean days of limited activity and the days
of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to
placebo and significantly reduced the mean days of limited activity and the days of
bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo
(all p<0.01).

Clinical efficacy in the treatment of osteoporosis in patients at increased risk of
fracture after a recent hip fracture (RFT)
The incidence of clinical fractures, including vertebral, non-vertebral and hip
fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5
years) with a recent (within 90 days) low-trauma hip fracture who were followed for
an average of 2 years on study medication. Approximately 42% of patients had a
femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a
femoral neck BMD T-score above -2.5. Zoledronic acid was administered once a
year, until at least 211 patients in the study population had confirmed clinical
fractures. Vitamin D levels were not routinely measured but a loading dose of vitamin
D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the
majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500
mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day.
Ninety-five percent of the patients received their infusion two or more weeks after the
hip fracture repair and the median timing of infusion was approximately six weeks
after the hip fracture repair. The primary efficacy variable was the incidence of
clinical fractures over the duration of the study.
Effect on all clinical fractures
The incidence rates of key clinical fracture variables are presented in Table 4.
Table 4 Between treatment comparisons of the incidence of key clinical fracture
variables
Outcome
zoledronic
Placebo
Absolute
Relative risk
acid
(N=1,062)
reduction in
reduction in
event
rate
fracture
event
fracture
(N=1,065)
(%)
rate % (CI)
incidence %
event rate
(CI)
(%)
Any clinical fracture (1)

8.6

13.9

5.3 (2.3, 8.3)

Clinical vertebral fracture (2)
1.7
3.8
2.1 (0.5, 3.7)
Non-vertebral fracture (1)
7.6
10.7
3.1 (0.3, 5.9)
*p-value <0.05, **p-value <0.01
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures

35 (16, 50)**
46 (8, 68)*
27 (2, 45)*

The study was not designed to measure significant differences in hip fracture, but a
trend was seen towards reduction in new hip fractures.
All cause mortality was 10% (101 patients) in the zoledronic acid treated group
compared to 13% (141 patients) in the placebo group. This corresponds to a 28%
reduction in the risk of all cause mortality (p=0.01).
The incidence of delayed hip fracture healing was comparable between zoledronic
acid (34 [3.2%]) and placebo (29 [2.7%]).
Effect on bone mineral density (BMD)
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD
at the total hip and femoral neck relative to treatment with placebo at all timepoints.

Treatment with zoledronic acid resulted in an increase in BMD of 5.4% at the total
hip and 4.3% at the femoral neck over 24 months as compared to placebo.
Clinical efficacy in men
In the HORIZON-RFT study 508 men were randomised into the study and 185
patients had BMD assessed at 24 months. At 24 months a similar significant increase
of 3.6% in total hip BMD was observed for patients treated with zoledronic acid as
compared to the effects observed in post-menopausal women in the HORIZON-PFT
study. The study was not powered to show a reduction in clinical fractures in men; the
incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus
8.7% for placebo.
In another study in men (study CZOL446M2308) an annual infusion of zoledronic
acid was non-inferior to weekly alendronate for the percentage change in lumbar
spine BMD at month 24 relative to baseline.
Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid
therapy
The efficacy and safety of zoledronic acid in the treatment and prevention of
osteoporosis associated with long-term systemic glucocorticoid therapy were assessed
in a randomised, multicentre, double-blind, stratified, active-controlled study of 833
men and women aged 18-85 years (mean age for men 56.4 years; for women 53.5
years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were
stratified with respect to duration of glucocorticoid use prior to randomisation (≤ 3
months versus > 3 months). The duration of the trial was one year. Patients were
randomised to either zoledronic acid 5 mg single infusion or to oral risedronate 5 mg
daily for one year. All participants received 1,000 mg elemental calcium plus 400 to
1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if noninferiority to risedronate was shown sequentially with respect to the percentage
change in lumbar spine BMD at 12 months relative to baseline in the treatment and
prevention subpopulations, respectively. The majority of patients continued to receive
glucocorticoids for the one year duration of the trial.
Effect on bone mineral density (BMD)
The increases in BMD were significantly greater in the zoledronic acid treated group
at the lumbar spine and femoral neck at 12 months compared to risedronate (all
p<0.03). In the subpopulation of patients receiving glucocorticoids for more than 3
months prior to randomisation, zoledronic acid increased lumbar spine BMD by
4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the
subpopulation of patients that had received glucocorticoids for 3 months or less prior
to randomisation, zoledronic acid increased lumbar spine BMD by 2.60% versus
0.64% for risedronate (mean difference: 1.96% ; p<0.001). The study was not
powered to show a reduction in clinical fractures compared to risedronate. The
incidence of fractures was 8 for zoledronic acid treated patients versus 7 for
risedronate-treated patients (p=0.8055).
Clinical efficacy in the treatment of Paget’s disease of the bone
Zoledronic acid was studied in male and female patients aged above 30 years with
primarily mild to moderate Paget’s disease of the bone (median serum alkaline
phosphatase level 2.6–3.0 times the upper limit of the age-specific normal reference
range at the time of study entry) confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg
risedronate for 2 months was demonstrated in two 6-month comparative trials. After 6
months, zoledronic acid showed 96% (169/176) and 89% (156/176) response and
serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/171)
and 58% (99/171) for risedronate (all p<0.001).
In the pooled results, a similar decrease in pain severity and pain interference scores
relative to baseline were observed over 6 months for zoledronic acid and risedronate.
Patients who were classified as responders at the end of the 6 month core study were
eligible to enter an extended follow-up period. Of the 153 zoledronic acid treated
patients and 115 risedronate-treated patients who entered an extended observation
study, after a mean duration of follow-up of 3.8 years from time of dosing, the
proportion of patients ending the Extended Observation Period due to the need for retreatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%)
compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the
Extended Observation Period due to the need for Paget’s re-treatment from the initial
dose was longer for zoledronic acid (7.7 years) than for risedronate (5.1 years).
Six patients who achieved therapeutic response 6 months after treatment with
zoledronic acid and later experienced disease relapse during the extended follow-up
period were re-treated with zoledronic acid after a mean time of 6.5 years from initial
treatment to re-treatment. Five of the 6 patients had SAP within the normal range at
month 6 (Last Observation Carried Forward, LOCF).
Bone histology was evaluated in 7 patients with Paget’s disease 6 months after
treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal
quality with no evidence of impaired bone remodelling and no evidence of
mineralisation defects. These results were consistent with biochemical marker
evidence of normalisation of bone turnover.
The European Medicines Agency has waived the obligation to submit the results of
studies with the reference medicinal products containing zoledronic acid in all subsets
of the paediatric population in Paget’s disease of the bone, osteoporosis in postmenopausal women at an increased risk of fracture, osteoporosis in men at increased
risk of fracture and prevention of clinical fractures after a hip fracture in men and
women (see section 4.2 for information on paediatric use).

5.2

Pharmacokinetic properties
Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in
64 patients yielded the following pharmacokinetic data, which were found to be dose
independent.
Distribution
After initiation of the zoledronic acid infusion, plasma concentrations of the active
substance increased rapidly, achieving their peak at the end of the infusion period,
followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24
hours, with a subsequent prolonged period of very low concentrations not exceeding
0.1% of peak levels.
Elimination

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid
biphasic disappearance from the systemic circulation, with half-lives of t½α 0.24 and
t½β 1.87 hours, followed by a long elimination phase with a terminal elimination halflife of t½γ 146 hours. There was no accumulation of the active substance in plasma
after multiple doses given every 28 days. The early disposition phases (α and β, with
t½ values above) presumably represent rapid uptake into bone and excretion via the
kidneys.
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over
the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while
the remainder is principally bound to bone tissue. This uptake into bone is common
for all bisphosphonates and is presumably a consequence of the structural analogy to
pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid
in bones is very long. From the bone tissue it is released very slowly back into the
systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ±
2.5 l/h, independent of dose, and unaffected by gender, age, race or body weight. The
inter- and intra-subject variation for plasma clearance of zoledronic acid was shown
to be 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes
caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but
had no effect on the area under the plasma concentration versus time curve.
Pharmacokinetic/pharmacodynamic relationships
No interaction studies with other medicinal products have been performed with
zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance
was found to have little or no capacity as a direct-acting and/or irreversible
metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to
reduce the metabolic clearance of substances which are metabolised via the
cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma
proteins (approximately 43-55% bound) and binding is concentration independent.
Therefore, interactions resulting from displacement of highly protein-bound drugs are
unlikely.
Special populations (see section 4.2)
Renal impairment
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal
clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of
84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 patients studied. Small observed
increases in AUC(0-24hr), by about 30% to 40% in mild to moderate renal impairment,
compared to a patient with normal renal function, and lack of accumulation of drug
with multiple doses irrespective of renal function, suggest that dose adjustments of
zoledronic acid in mild (Clcr = 50–80 ml/min) and moderate renal impairment down
to a creatinine clearance of 35 ml/min are not necessary. The use of zoledronic acid in
patients with severe renal impairment (creatinine clearance < 35 ml/min) is
contraindicated due to an increased risk of renal failure in this population.

5.3

Preclinical safety data
Acute toxicity

The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice
and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the
recommended human therapeutic exposure based on AUC) administered over 15
minutes was well tolerated with no renal effects.
Subchronic and chronic toxicity
In the intravenous infusion studies, renal tolerability of zoledronic acid was
established in rats when given 0.6 mg/kg as 15-minute infusions at 3-day intervals,
six times in total (for a cumulative dose that corresponded to AUC levels about 6
times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/kg
administered at 2–3-week intervals (a cumulative dose that corresponded to 7 times
the human therapeutic exposure) were well tolerated in dogs. In the intravenous bolus
studies, the doses that were well-tolerated decreased with increasing study duration:
0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks in rats and dogs, respectively
but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when given for
52 weeks.
Longer-term repeat administration at cumulative exposures sufficiently exceeding the
maximum intended human exposure produced toxicological effects in other organs,
including the gastrointestinal tract and liver, and at the site of intravenous
administration. The clinical relevance of these findings is unknown. The most
frequent finding in the repeat-dose studies consisted of increased primary spongiosa
in the metaphyses of long bones in growing animals at nearly all doses, a finding that
reflected the compound’s pharmacological antiresorptive activity.
Reproduction toxicity
Teratology studies were performed in two species, both via subcutaneous
administration. Teratogenicity was observed in rats at doses ≥ 0.2 mg/kg and was
manifested by external, visceral and skeletal malformations. Dystocia was observed at
the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or
embryo/foetal effects were observed in rabbits, although maternal toxicity was
marked at 0.1 mg/kg due to decreased serum calcium levels.
Mutagenicity and carcinogenic potential
Zoledronic acid was not mutagenic in the mutagenicity tests performed and
carcinogenicity testing did not provide any evidence of carcinogenic potential.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol (E-421)
Sodium citrate (E-331)
Water for injections

6.2

Incompatibilities
This medicinal product must not be allowed to come into contact with any calciumcontaining solutions. Zoledronic Acid must not be mixed or given intravenously with
any other medicinal products.

6.3

Shelf life
Unopened bag: 3 years
After opening the bag, the product should be used immediately in order to avoid
microbial contamination. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be longer than
24 hours at 2°C – 8°C. Allow the refrigerated solution to reach room temperature
before administration.

6.4

Special precautions for storage
The unopened bag does not require any special temperature storage conditions.
For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container
Zoledronic Acid 5 mg/100 ml comes in 100 ml polyolefin bags as a ready-to-use
solution for infusion. It is supplied in packs containing one bag as unit pack.

6.6

Special precautions for disposal
For single use only.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements. Only clear solution free from particles and discoloration
should be used.
If refrigerated, allow the refrigerated solution to reach room temperature before
administration.
Aseptic techniques must be followed during the preparation of the infusion.

7

MARKETING AUTHORISATION HOLDER
Amneal Pharma Europe Limited
70 Sir John Rogerson’s Quay
Dublin 2, Ireland

8

MARKETING AUTHORISATION NUMBER(S)
PL 42357/0176

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/07/2016

10

DATE OF REVISION OF THE TEXT
21/07/2016

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Source: Medicines and Healthcare Products Regulatory Agency

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