ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Aclasta 5 mg solution for infusion
2.
Each bottle with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate).
Each ml of the solution contains 0.05 mg zoledronic acid anhydrous, corresponding to 0.0533 mg
zoledronic acid monohydrate.
For a full list of excipients, see section 6.1.
3.
Solution for infusion
Clear and colourless solution.
4.
Treatment of osteoporosis
in post-menopausal women
in 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 men
at increased risk of fracture.
Treatment of Paget’s disease of the bone in adults.
Posology
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 Aclasta administered once a year.
In patients with a recent low-trauma hip fracture, it is recommended to give the Aclasta infusion two
or more weeks after hip fracture repair (see section 5.1).
For the treatment of Paget’s disease, Aclasta 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 Aclasta.
Re-treatment of Paget’s disease: specific re-treatment data are not available. After a single treatment
with Aclasta in Paget’s disease an extended remission period is observed in responding patients.
However, re-treatment with Aclasta may be considered in patients who have relapsed, based on
2
increases in serum alkaline phosphatase, in patients who failed to achieve normalisation of serum
alkaline phosphatase, or in patients with symptoms, as dictated by medical practice (see section 5.1).
Patients must be appropriately hydrated prior to administration of Aclasta. This is especially
important for the elderly and for patients receiving diuretic therapy.
Adequate calcium and vitamin D intake are recommended in association with Aclasta 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 Aclasta administration (see section 4.4).
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 Aclasta infusion.
The incidence of post-dose symptoms occurring within the first three days after administration of
Aclasta can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta
administration.
Patients with renal impairment
Aclasta should not be used in patients with creatinine clearance < 35 ml/min
(s
ee section 4.4).
No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min.
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly patients (≥ 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 Aclasta in children and adolescents below 18 years of age have not been
established.
Method of administration
Intravenous use.
Aclasta (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 Aclasta, see section 6.6.
-
Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients.
-
Patients with hypocalcaemia (see section 4.4).
-
Pregnancy and breast-feeding (see section 4.6).
Renal impairment has been observed following the administration of Aclasta (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 Aclasta 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.
3
The following precautions should be taken into account to minimise the risk of renal adverse
reactions:
Creatinine clearance should be measured before each Aclasta dose.
Aclasta should not be used in patients with creatinine clearance < 35 ml/min (see section 5.2).
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.
Aclasta 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 Aclasta.
A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least
15 minutes (see section 4.2).
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before
initiating therapy with Aclasta (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 Aclasta (see section 4.8).
Adequate calcium and vitamin D intake are recommended in association with Aclasta 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 Aclasta 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 Aclasta 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 Aclasta (see section 4.8).
Aclasta contains the same active substance found in Zometa (zoledronic acid), used for oncology
indications, and a patient being treated with Zometa should not be treated with Aclasta.
Osteonecrosis of the jaw (ONJ)
Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment
regimens including bisphosphonates, including zoledronic acid. Many of these patients were also
receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with
dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior to treatment
with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy,
corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental
procedures if possible. 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 clinical judgement of the treating physician should guide the
management plan of each patient based on individual benefit/risk assessment.
4
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 Aclasta 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.
Pregnancy
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
It is not known whether zoledronic acid is excreted into human breast milk. Aclasta is contraindicated
during pregnancy and in breast-feeding women (see section 4.3).
Women of childbearing potential
Aclasta 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 Aclasta on fertility in humans.
Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no
studies on this effect with Aclasta have been performed.
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 Aclasta. The majority of these reactions occur within the first three days following
Aclasta 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 as described below.
The incidence of adverse reactions occurring within the first three days after administration of Aclasta
can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta
administration as needed (see section 4.2).
5
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 Aclasta and
placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients
receiving Aclasta (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 Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation
serious adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency
category. Frequency categories are defined using the following convention: very common (≥1/10);
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare
(<1/10,000); not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
Infections and infestations
Uncommon
Influenza, nasopharyngitis
Blood and lymphatic system disorders
Uncommon
Anaemia
Immune system disorders
Not known**
Hypersensitivity reactions including rare
cases of bronchoconstriction, urticaria
and angioedema, and very rare cases of
anaphylactic reaction/shock
Metabolism and nutrition disorders
Common
Hypocalcaemia*
Uncommon
Anorexia, decreased appetite
Psychatric disorders
Uncommon
Insomnia
Nervous system disorders
Common
Headache, dizziness
Uncommon
Lethargy, paraesthesia, somnolence,
tremor, syncope, dysgeusia
Eye disorders
Common
Ocular hyperaemia
Uncommon
Conjunctivitis, eye pain
Rare
Uveitis, episcleritis, iritis
Not known**
Scleritis and orbital inflammation
Ear and labyrinth disorders
Uncommon
Vertigo
Cardiac disorders
Common
Atrial fibrillation
Uncommon
Palpitations
Vascular disorders
Uncommon
Hypertension, flushing
Not known**
Hypotension (some of the patients had
underlying risk factors)
Respiratory, thoracic and mediastinal
disorders
Uncommon
Cough, dyspnoea
Gastrointestinal disorders
Common
Nausea, vomiting, diarrhoea
Uncommon
Dyspepsia, abdominal pain upper,
abdominal pain, gastroesophageal reflux
disease, constipation, dry mouth,
oesophagitis, toothache, gastritis
#
Skin and subcutaneous tissue disorders
Uncommon
Rash, hyperhydrosis, pruritus, erythema
6
Musculoskeletal and connective tissue
disorders
Common
Myalgia, arthralgia, bone pain, back pain,
pain in extremity
Uncommon
Neck pain, musculoskeletal stiffness, joint
swelling, muscle spasms, shoulder pain,
musculoskeletal chest pain,
musculoskeletal pain, joint stiffness,
arthritis, muscular weakness
Not known**
Osteonecrosis of the jaw (see sections 4.4
and 4.8 Class effects)
Renal and urinary disorders
Uncommon
Blood creatinine increased, pollakiuria,
proteinuria
Not known**
Renal impairment. Rare cases of renal
failure requiring dialysis and rare cases
with a fatal outcome have been reported
in patients with pre-existing renal
dysfunction or other risk factors such as
advanced age, concomitant nephrotoxic
medicinal products, concomitant diuretic
therapy, or dehydration in the post
infusion period (see sections 4.4 and 4.8
Class effects)
Very common
Fever
Common
Flu-like symptoms, chills, fatigue,
asthenia, pain, malaise, infusion site
reaction
Uncommon
Peripheral oedema, thirst, acute phase
reaction, non-cardiac chest pain
Not known**
Dehydration secondary to post-dose
symptoms such as fever, vomiting and
diarrhoea
Investigations
Common
C-reactive protein increased
Uncommon
Blood calcium decreased
#
Observed in patients taking concomitant glucocorticosteroids.
* Common in Paget’s disease only.
** Based on post-marketing reports. Frequency cannot be estimated from available data.
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), the
majority of whom received 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 Aclasta and
placebo treatment groups over three years. There was a transient increase in serum creatinine
observed within 10 days in 1.8% of Aclasta-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 Aclasta administration. No symptomatic cases of
hypocalcaemia were observed.
7
General disorders and administration
site conditions
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 Aclasta-treated patients in a large clinical trial
compared to 21% of Aclasta-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 Aclasta 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
Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in
cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients had
signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients
following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well
documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy,
radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-
existing dental disease). Although causality has not been determined, it is prudent to avoid dental
surgery as recovery may be prolonged (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 Aclasta and one patient treated
with placebo. Both cases resolved.
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.
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.
8
Aclasta treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels
with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks.
Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive
reduction of bone turnover markers with repeated annual dosing.
Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)
The efficacy and safety of Aclasta 5 mg once a year for 3 consecutive years were demonstrated in
post-menopausal women (7,736 women aged 65–89 years) with either: a femoral neck bone mineral
density (BMD) with a T-score ≤ –1.5 and at least two mild or one moderate existing vertebral
fracture(s); or a femoral neck BMD T-score ≤ –2.5 with or without evidence of existing vertebral
fracture(s). 85% of patients were bisphosphonate-naïve. Women who were evaluated for the incidence
of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for
women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy
included: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded
other bisphosphonates. All women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU
of vitamin D supplements daily.
Effect on morphometric vertebral fractures
Aclasta 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
Aclasta
(%)
Placebo
(%)
Absolute reduction in
fracture incidence %
(CI)
Relative reduction in
fracture incidence %
(CI)
At least one new vertebral
fracture (0–1 year)
1.5
3.7
2.2 (1.4, 3.1)
60 (43, 72)**
At least one new vertebral
fracture (0–2 year)
2.2
7.7
5.5 (4.4, 6.6)
71 (62, 78)**
At least one new vertebral
fracture (0–3 year)
3.3
10.9
7.6 (6.3, 9.0)
70 (62, 76)**
** p <0.0001
Aclasta-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
Aclasta 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 Aclasta-treated patients
compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-naïve
patients and 42% in patients allowed to take concomitant osteoporosis therapy.
9
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
Aclasta
(N=3,875)
event rate
(%)
Placebo
(N=3,861)
event rate
(%)
Absolute reduction
in fracture event
rate %
(CI)
Relative risk
reduction in
fracture incidence
% (CI)
Any clinical fracture (1)
8.4
12.8
4.4 (3.0, 5.8)
33 (23, 42)**
Clinical vertebral fracture (2)
0.5
2.6
2.1 (1.5, 2.7)
77 (63, 86)**
Non-vertebral fracture (1)
8.0
10.7
2.7 (1.4, 4.0)
25 (13, 36)*
*p-value <0.001, **p-value <0.0001
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures
Effect on bone mineral density (BMD)
Aclasta 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 Aclasta 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 Aclasta (N=82) or placebo (N=70).
Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with
Aclasta, 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 Aclasta. Microcomputed
tomography (μCT) analysis demonstrated increased trabecular bone volume and preservation of
trabecular bone architecture in patients treated with Aclasta 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 Aclasta 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
Aclasta 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
Aclasta 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).
10
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. Aclasta 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
Aclasta
(N=1,065)
event rate
(%)
Placebo
(N=1,062)
event rate
(%)
Absolute reduction
in fracture event
rate %
(CI)
Relative risk
reduction in
fracture incidence
% (CI)
Any clinical fracture (1)
8.6
13.9
5.3 (2.3, 8.3)
35 (16, 50)**
Clinical vertebral fracture (2)
1.7
3.8
2.1 (0.5, 3.7)
46 (8, 68)*
Non-vertebral fracture (1)
7.6
10.7
3.1 (0.3, 5.9)
27 (2, 45)*
*p-value <0.05, **p-value <0.01
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures
The study was not designed to measure significant differences in hip fracture, but a trend was seen
towards reduction in new hip fractures.
All cause mortality was 10% (101 patients) in the Aclasta-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 Aclasta (34 [3.2%]) and
placebo (29 [2.7%]).
Effect on bone mineral density (BMD)
In the HORIZON-RFT study Aclasta treatment significantly increased BMD at the total hip and
femoral neck relative to treatment with placebo at all timepoints. Treatment with Aclasta 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 Aclasta 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
11
fractures in men; the incidence of clinical fractures was 7.5% in men treated with Aclasta versus 8.7%
for placebo.
In another study in men (study CZOL446M2308) an annual infusion of Aclasta 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 Aclasta 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 Aclasta
5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mg
elemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy was
demonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentage
change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention
subpopulations, respectively. The majority of patients continued to receive glucocorticoids for the one
year duration of the trial.
Effect on bone mineral density (BMD)
The increases in BMD were significantly greater in the Aclasta-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, Aclasta 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, Aclasta 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 Aclasta-treated patients versus 7 for
risedronate-treated patients (p=0.8055).
Clinical efficacy in the treatment of Paget’s disease of the bone
Aclasta 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, Aclasta 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 Aclasta 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 143 Aclasta-treated patients and 107 risedronate-treated patients
who entered an extended observation study, after a median duration of follow-up of 18 months from
time of dosing, 141 Aclasta-treated patients maintained their therapeutic response compared to
71 risedronate-treated patients. This corresponds to a 96% reduction of risk of relapse in Aclasta
versus risedronate-treated patients.
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.
12
The European Medicines Agency has waived the obligation to submit the results of studies with
Aclasta in all subsets of the paediatric population in Paget’s disease of the bone, osteoporosis in post-
menopausal women at an increased risk of fracture, osteoporosis in men at increased risk of fracture
and prevention of clinical fractures after a hip fracture in men and women (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients
yielded the following pharmacokinetic data, which were found to be dose independent.
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.
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic
disappearance from the systemic circulation, with half-lives of t
½
0.24 and t
½
1.87 hours, followed
by a long elimination phase with a terminal elimination half-life of t
½
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 t
½
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.
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)
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 (Cl
cr
= 50–80 ml/min) and moderate renal impairment down to
a creatinine clearance of 35 ml/min are not necessary. As only limited data are available in severe
renal impairment (creatinine clearance < 30 ml/min), no dosing recommendations are possible for this
population.
13
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.
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. Aclasta must not be mixed or given intravenously with any other medicinal products.
6.3 Shelf life
Unopened bottle: 3 years
After opening: 24 hours at 2°C - 8°C
14
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2°C - 8°C.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. For storage condition of the
medicinal product after opening, please see section 6.3.
6.5 Nature and contents of container
100 ml solution in a transparent plastic (cycloolefinic polymer) bottle closed with a fluoro-polymer
coated bromobutyl rubber stopper and an aluminium/polypropylene cap with a flip component.
Aclasta is supplied in packs containing one bottle as unit pack or in multi-packs comprising 5 packs,
each containing 1 bottle.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
For single use only.
Any unused 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.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/05/308/001
EU/1/05/308/002
9.
Date of first authorisation: 15 April 2005
Date of latest renewal: 15 April 2010
Detailed information on this product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
15
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
16
A. MANUFACTURING AUTHORISATION HOLDER 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 OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall ensure that the educational programme
implemented for the authorised indication of treatment of osteoporosis in post-menopausal women
and men at increased risk of fracture, including those with a recent low-trauma hip fracture, is
extended to the potential prescribers concerned by the new indication: treatment of osteoporosis
associated with long-term systemic glucocorticoid therapy in post-menopausal women and in men at
increased risk of fracture. The educational programme contains the following:
Physician educational material
Patient information pack
The physician educational material should contain the following key elements:
The Summary of Product Characteristics
Reminder card with the following key messages:
o
Need to measure serum creatinine before treatment with Aclasta
o
Recommendation not to use Aclasta in patients with creatinine clearance < 35 ml/min
o
Contraindication in pregnancy and in breast-feeding women due to potential
teratogenicity
o
Need to ensure appropriate hydration of the patient
o
Need to infuse Aclasta slowly over a period of no less than 15 minutes
o
One-yearly dosing regime
o
Adequate calcium and vitamin D intake are recommended in association with Aclasta
administration
o
Need for appropriate physical activity, non-smoking and healthy diet
Patient information pack
The patient information pack should be provided and contain the following key messages:
Package leaflet
Contraindication in pregnancy and in breast-feeding women
Need for adequate calcium and vitamin D supplementation, appropriate physical activity, non-
smoking and healthy diet
Key signs and symptoms of serious adverse events
When to seek attention from the health care provider
17
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 006 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
18
ANNEX III
LABELLING AND PACKAGE LEAFLET
19
A. LABELLING
20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX (WITH BLUE BOX) FOR UNIT PACK
1.
Aclasta 5 mg solution for infusion
Zoledronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each bottle of 100 ml contains 5 mg zoledronic acid (as monohydrate).
3.
LIST OF EXCIPIENTS
Mannitol, sodium citrate and water for injections.
4.
Solution for infusion
1 bottle of 100 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: 24 hours at 2°C - 8°C.
9.
SPECIAL STORAGE CONDITIONS
21
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/308/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including braille accepted.
22
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL FOR UNIT PACK
1.
Aclasta 5 mg solution for infusion
Zoledronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 bottle contains 5 mg zoledronic acid (as monohydrate).
3.
LIST OF EXCIPIENTS
Mannitol, sodium citrate and water for injections.
4.
Solution for infusion
1 bottle – 100 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: 24 hours at 2°C - 8°C.
9.
SPECIAL STORAGE CONDITIONS
23
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/308/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including braille accepted.
24
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
FOLDING BOX FOR INTERMEDIATE PACK
1.
Aclasta 5 mg solution for infusion
Zoledronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each bottle of 100 ml contains 5 mg zoledronic acid (as monohydrate).
3.
LIST OF EXCIPIENTS
Mannitol, sodium citrate and water for injections.
4.
Solution for infusion
1 bottle of 100 ml
Component of a multi-pack comprising 5 bottles, each bottle of 100 ml.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: 24 hours at 2°C - 8°C.
9.
SPECIAL STORAGE CONDITIONS
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/308/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including braille accepted.
26
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
BOTTLE LABEL FOR INTERMEDIATE PACK
1.
Aclasta 5 mg solution for infusion
Zoledronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 bottle contains 5 mg zoledronic acid (as monohydrate).
3.
LIST OF EXCIPIENTS
Mannitol, sodium citrate and water for injections.
4.
Solution for infusion
1 bottle - 100 ml
Component of a multi-pack comprising 5 bottles, each bottle of 100 ml.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: 24 hours at 2°C - 8°C.
9.
SPECIAL STORAGE CONDITIONS
27
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/308/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including braille accepted.
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PARTICULARS TO APPEAR ON THE OUTER CARTON OF MULTI-PACK (INCLUDING
BLUE BOX)
1.
Aclasta 5 mg solution for infusion
Zoledronic acid
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each bottle of 100 ml contains 5 mg zoledronic acid (as monohydrate).
3.
LIST OF EXCIPIENTS
Mannitol, sodium citrate and water for injections.
4.
Solution for infusion
Multi-pack comprising 5 bottles, each bottle of 100 ml.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: 24 hours at 2°C - 8°C.
9.
SPECIAL STORAGE CONDITIONS
29
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/308/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including braille accepted.
30
B. PACKAGE LEAFLET
31
PACKAGE LEAFLET: INFORMATION FOR THE USER
Aclasta 5 mg solution for infusion
Zoledronic acid
Read all of this leaflet carefully before you are given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor, pharmacist or nurse.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor, pharmacist or nurse.
In this leaflet:
1.
What Aclasta is and what it is used for
2.
Before you are given Aclasta
3.
How Aclasta is given
4.
Possible side effects
5.
How to store Aclasta
6.
Further information
1.
WHAT ACLASTA IS AND WHAT IT IS USED FOR
Aclasta contains the active substance zoledronic acid. It belongs to a group of medicines called
bisphosphonates and is used to treat post-menopausal women and men with osteoporosis or
osteoporosis caused by treatment with steroids, and Paget’s disease of the bone.
Osteoporosis
Osteoporosis is a disease that involves the thinning and weakening of the bones and is common in
women after the menopause, but can also occur in men. At the menopause, a woman’s ovaries stop
producing the female hormone oestrogen, which helps keep bones healthy. Following the menopause
bone loss occurs, bones become weaker and break more easily. Osteoporosis could also occur in men
and women because of the long term use of steroids, which can affect the strength of bones. Many
patients with osteoporosis have no symptoms but they are still at risk of breaking bones because
osteoporosis has made their bones weaker. Decreased circulating levels of sex hormones, mainly
oestrogens converted from androgens, also play a role in the more gradual bone loss observed in men.
In both women and men, Aclasta strengthens the bone and therefore makes it less likely to break.
Aclasta is also used in patients who have recently broken their hip in a minor trauma such as a fall and
therefore are at risk of subsequent bone breaks.
Paget’s disease of the bone
It is normal that old bone is removed and is replaced with new bone material. This process is called
remodelling. In Paget’s disease, bone remodelling is too rapid and new bone is formed in a disordered
fashion, which makes it weaker than normal. If the disease is not treated, bones may become
deformed and painful, and may break. Aclasta works by returning the bone remodelling process to
normal, securing formation of normal bone, thus restoring strength to the bone.
32
2.
BEFORE YOU ARE GIVEN ACLASTA
Follow all instructions given to you by your doctor carefully before you are given Aclasta.
You should not be given Aclasta
-
if you are allergic (hypersensitive) to zoledronic acid, other bisphosphonates or any of the other
ingredients of Aclasta.
-
if you have hypocalcaemia (this means that the levels of calcium in your blood are too low).
-
if you are pregnant.
-
if you are breast-feeding.
Take special care with Aclasta
Tell your doctor before you are given Aclasta:
-
if you are being treated with Zometa, which contains the same active substance as Aclasta.
-
if you have a kidney problem, or used to have one.
-
if you are unable to take daily calcium supplements.
-
if you have had some or all of the parathyroid glands in your neck surgically removed.
-
if you have had sections of your intestine removed.
Before you receive treatment with Aclasta, tell your doctor if you have (or have had) pain, swelling or
numbness in your gums, jaw or both, if your jaw feels heavy, or if you have lost a tooth. Before you
receive dental treatment or undergo dental surgery, tell your dentist you are receiving treatment with
Aclasta.
Use in children
Aclasta is not recommended for anyone under 18 years of age. The use of Aclasta in children and
adolescents has not been studied.
Taking other medicines
Please tell your doctor, pharmacist or nurse if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
It is especially important for your doctor to know all the medicines you are taking, especially if you
are taking any medicines known to be harmful to your kidneys (e.g. aminoglycosides) or diuretics
(“waterpills”) that may cause dehydration.
Using Aclasta with food and drink
Make sure you drink enough fluids (at least one or two glasses) before and after the treatment with
Aclasta, as directed by your doctor. This will help to prevent dehydration. You may eat normally on
the day you are treated with Aclasta. This is especially important in patients who take diuretics
(“water pills”) and in elderly patients.
Pregnancy and breast-feeding
There is no adequate information on the use of zoledronic acid in pregnant women. Studies in animals
have shown reproductive toxicological effects. Additionally, there is no information on the use of
Aclasta in breast-feeding women. You must not be given Aclasta if you are pregnant or plan to
become pregnant.
You must not be given Aclasta if you are breast-feeding.
Ask your doctor, pharmacist or nurse for advice before taking any medicine.
Driving and using machines
If you feel dizzy while taking Aclasta, do not drive or use machines until you feel better.
33
3.
HOW ACLASTA IS GIVEN
Follow carefully all instructions given to you by your doctor or nurse. You should check with your
doctor or nurse if you are not sure.
Your doctor should do a blood test to check your kidney functions (levels of creatinine) before each
dose of Aclasta. It is important for you to drink at least one or two glasses of fluid (such as water),
within a few hours before receiving Aclasta, as directed by your doctor or nurse.
Osteoporosis
The usual dose is 5 mg given as one infusion per year into a vein by your doctor or nurse. The
infusion will take at least 15 minutes.
In case you recently broke your hip, it is recommended that Aclasta is administered two or more
weeks after your hip repair surgery.
It is important to take calcium and vitamin D supplements (for example tablets) as directed by your
doctor.
For osteoporosis, Aclasta works for one year. Your doctor will let you know when to return for your
next dose.
Paget’s disease
The usual dose is 5 mg, given to you as one single infusion into a vein by your doctor or nurse. The
infusion will take at least 15 minutes. Aclasta may work for longer than one year, and your doctor will
let you know if you need to be treated again.
Your doctor may advise you to take calcium and vitamin D supplements (e.g. tablets) for at least the
first ten days after being given Aclasta. It is important that you follow this advice carefully so that the
level of calcium in your blood does not become too low in the period after the infusion. Your doctor
will inform you regarding the symptoms associated with hypocalcaemia.
If a dose of Aclasta is missed
Contact your doctor or hospital as soon as possible to re-schedule your appointment.
Before stopping Aclasta therapy
If you are considering stopping Aclasta treatment, please go to your next appointment and discuss this
with your doctor. Your doctor will advise you and decide how long you should be treated with
Aclasta.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
34
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Aclasta can cause side effects, although not everybody gets them. In most cases,
no specific treatment is required.
Side effects may occur with certain frequencies, which are defined as follows:
Very common:
affects more than 1 user in 10
Common:
affects 1 to 10 users in 100
Uncommon:
affects 1 to 10 users in 1,000
Rare:
affects 1 to 10 users in 10,000
Very rare:
affects less than 1 user in 10,000
Not known:
frequency cannot be estimated from the available data.
Side effects related to the first infusion are very common (occurring in more than 30% of patients) but
are less common following subsequent infusions. The majority of the side effects, such as fever and
chills, pain in the muscles or joints, and headache, occur within the first three days following the dose
of Aclasta. The symptoms are usually mild to moderate and go away within three days. Your doctor
can recommend a mild pain reliever such as ibuprofen or paracetamol to reduce these side effects. The
chance of experiencing these side effects decreases with subsequent doses of Aclasta.
Very common side effects
Fever
Common side effects
Headache, dizziness, sickness, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or
joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain),
chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, skin reactions such as
redness, swelling and/or pain at the infusion site.
In patients with Paget’s disease: symptoms due to low blood calcium, such as muscle spasms, or
numbness, or a tingling sensation especially in the area around the mouth.
Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving Aclasta for post-
menopausal osteoporosis. It is currently unclear whether Aclasta causes this irregular heart rhythm but
you should report it to your doctor if you experience such symptoms after you have received Aclasta.
Uncommon side effects
Flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness,
sleepiness which may include reduced alertness and awareness, tingling sensation or numbness,
extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or
inflammation with pain and redness, eye sensitivity to light, spinning sensation, increased blood
pressure, flushing, cough, shortness of breath, upset stomach, abdominal pain, constipation, dry
mouth, heartburn, skin rash, excessive sweating, itching, skin reddening, neck pain, stiffness in
muscles, bones and/or joints, joint swelling, muscle spasms, shoulder pain, pain in your chest muscles
and rib cage, joint inflammation, muscular weakness, abnormal kidney test results, abnormal frequent
urination, swelling of hands, ankles or feet, thirst, toothache, taste disturbances.
Additional side effects which have been reported (frequency not known): severe allergic reactions
including dizziness and difficulty breathing, swelling mainly of the face and throat, decreased blood
pressure, pain in the mouth, teeth and jaw, swelling or sores inside the mouth, numbness or a feeling
of heaviness in the jaw, or loosening of a tooth, kidney disorder (e.g. decreased urine output),
dehydration secondary to post-dose symptoms such as fever, vomiting and diarrhoea.
35
If you notice any of these side effects, tell your doctor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor, pharmacist or nurse.
5.
HOW TO STORE ACLASTA
Your doctor, pharmacist or nurse knows how to store Aclasta properly.
-
Keep out of the reach and sight of children.
-
Do not use Aclasta after the expiry date which is stated on the carton and bottle after EXP.
-
The unopened bottle does not require any special storage conditions.
-
After opening the bottle, the product should be used immediately in order to avoid microbial
contamination. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C. Allow
the refrigerated solution to reach room temperature before administration.
6.
FURTHER INFORMATION
What Aclasta contains
-
The active substance is zoledronic acid. Each bottle with 100 ml of solution contains 5 mg
zoledronic acid anhydrous (as monohydrate).
One ml solution contains 0.05 mg zoledronic acid (as monohydrate).
-
The other ingredients are mannitol, sodium citrate and water for injections.
What Aclasta looks like and contents of the pack
Aclasta is a clear and colourless solution. It comes in 100 ml plastic bottles as a ready-to-use solution
for infusion. It is supplied in packs containing one bottle as unit pack or in multi-packs comprising
5 packs, each containing 1 bottle. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
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
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
36
България
Novartis Pharma Services Inc.
Тел: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
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
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
37
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
38
INFORMATION FOR THE HEALTHCARE PROFESSIONAL
The following information is intended for medical or healthcare professionals only (see section 3):
How to prepare and administer Aclasta
-
Aclasta 5 mg solution for infusion is ready for use.
For single use only. Any unused solution should be discarded. Only clear solution free from particles
and discoloration should be used. Aclasta must not be mixed or given intravenously with any other
medicinal product and must be given through a separate vented infusion line at a constant infusion
rate. The infusion time must not be less than 15 minutes. Aclasta must not be allowed to come into
contact with any calcium-containing solutions. If refrigerated, allow the refrigerated solution to reach
room temperature before administration. Aseptic techniques must be followed during preparation of
the infusion. The infusion must be conducted according to standard medical practice.
How to store Aclasta
-
Keep out of the reach and sight of children.
-
Do not use Aclasta after the expiry date which is stated on the carton and bottle.
-
The unopened bottle does not require any special storage conditions.
-
After opening the bottle, the product should be used immediately in order to avoid microbial
contamination. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C. Allow
the refrigerated solution to reach room temperature before administration.
39
Source: European Medicines Agency
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