Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Aclasta 5 mg solution for infusion
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
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 (as monohydrate).
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Solution for infusion
Clear and colourless solution.
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Treatment of osteoporosis
•in
•in adult men
at increased risk of fracture, including those with a recent
Treatment of osteoporosis associated with
•in
•in adult men
at increased risk of fracture.
Treatment of Paget’s disease of the bone in adults.
4.2Posology and method of administration
Posology
Patients must be appropriately hydrated prior to administration of Aclasta. 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 Aclasta administration.
Osteoporosis
For the treatment of
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be
In patients with a recent
Paget’s disease
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. 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).
Special populations
Patients with renal impairment
Aclasta is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).
No dose adjustment is necessary in patientswith creatinine clearance ≥ 35 ml/min.
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly (≥ 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. No data are available.
Method of administration
Intravenous use.
Aclasta is administered via a vented infusion line and givenslowly at a constant infusion rate. The infusion time must not be less than 15minutes. For information on the infusion of Aclasta, see section 6.6.
Patients treated with Aclasta should be given the package leaflet and the patient reminder card.
4.3Contraindications
-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
4.4Special warnings and precautions for use
Renal function
The use of Aclasta 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 Aclasta (see section4.8), especially in patients with
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
•Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.
•Monitoring of serum creatinine should be considered in
•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 5mg and the duration of infusion should be at least 15 minutes (see section 4.2).
Hypocalcaemia
- Zoledronic acid actavis - zoledronic acid monohydrate
- Zoledronic acid hospira - zoledronic acid monohydrate
- Zometa - zoledronic acid / zoledronic acid monohydrate
- Zoledronic acid teva - zoledronic acid
- Zoledronic acid medac - zoledronic acid monohydrate
- Zoledronic acid teva pharma - zoledronic acid
Prescription drugs listed. Substance: "Zoledronic acid"
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 zoledronic acid (see section 4.8).
Osteonecrosis of the jaw (ONJ)
ONJ has been reported in the
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
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,
-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
The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving
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 incompletefemur fracture.
General
The incidence of
Other products containing zoledronic acid as an active substance are available for oncology indications. Patients being treated with Aclasta should not be treated with such products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial of Aclasta, i.e. essentially “sodium free”.
4.5Interaction 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
and interactions resulting from displacement of highly
Zoledronic acid is eliminated by renal excretion. Caution is indicated whenzoledronic 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.
4.6Fertility, pregnancy and lactation
Women of childbearing potential
Aclasta is not recommended in women of childbearing potential.
Pregnancy
Aclasta 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.
Aclasta is contraindicated during
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.
4.7Effects on ability to drive and use machines
Adverse reactions, such as dizziness, may affect the ability to drive or use machines.
4.8Undesirable 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 individualadverse reactions following the first infusion was: pyrexia (17.1%), myalgia (7.8%),
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 | Uncommon | Influenza, nasopharyngitis |
Blood and lymphatic system disorders | Uncommon | Anaemia |
Immune system disorders | Not known** | Hypersensitivity reactions including |
|
| rare cases of bronchospasm, urticaria |
|
| and angioedema, and very rare cases of |
|
| anaphylactic reaction/shock |
Metabolism and nutrition disorders | Common | Hypocalcaemia* |
| Uncommon | Decreased appetite |
| Rare | Hypophosphataemia |
Psychiatric 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 parophthalmia |
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 | Uncommon | Cough, dyspnoea |
disorders |
|
|
Gastrointestinal disorders | Common | Nausea, vomiting, diarrhoea |
| Uncommon | Dyspepsia, abdominal pain upper, |
|
| abdominal pain, |
|
| reflux disease, constipation, dry mouth, |
|
| oesophagitis, toothache, gastritis# |
Skin and subcutaneous tissue | Uncommon | Rash, hyperhidrosis, pruritus, erythema |
disorders |
|
|
Musculoskeletal and connective tissue | Common | Myalgia, arthralgia, bone pain, back |
disorders |
| pain, pain in extremity |
| Uncommon | Neck pain, musculoskeletal stiffness, |
|
| joint swelling, muscle spasms, |
|
| musculoskeletal chest pain, |
|
| musculoskeletal pain, joint stiffness, |
|
| arthritis, muscular weakness |
| Rare | Atypical subtrochanteric and diaphyseal |
|
| femoral fractures† (bisphosphonate class |
|
| adverse reaction) |
| Very rare | Osteonecrosis of the external auditory |
|
| canal (bisphosphonate class adverse |
|
| reaction) |
| 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 |
|
| 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) |
General disorders and administration | Very common | Pyrexia |
site conditions | Common | |
|
| asthenia, pain, malaise, infusion site |
|
| reaction |
| Uncommon | Peripheral oedema, thirst, acute phase |
|
| reaction, |
| Not known** | Dehydration secondary to |
|
| symptoms such as pyrexia, vomiting and |
|
| diarrhoea |
Investigations | Common | |
| Uncommon | Blood calcium decreased |
#Observed in patients taking concomitant glucocorticosteroids.
*Common in Paget’s disease only.
**Based on
† Identified in
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 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.
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
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
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.
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
All patients received adequate supplementation with vitamin D and calcium in the
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
- Signifor - Novartis Europharm Limited
- Simulect - Novartis Europharm Limited
- Afinitor - Novartis Europharm Limited
- Rasilez - Novartis Europharm Limited
- Mekinist - Novartis Europharm Limited
- Rasilez hct - Novartis Europharm Limited
Prescription drugs listed. Manufacturer: "Novartis Europharm Limited"
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 section4.4). 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. Cases of ONJ have been reported in the

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9Overdose
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
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Mechanism of action
Zoledronic acid belongs to the class of
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.
Aclasta treatment rapidly reduced the rate of bone turnover from elevated
Clinical efficacy in the treatment of
The efficacy and safety of Aclasta 5 mg once a year for 3 consecutive years were demonstrated in

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 36months
Outcome | Aclasta | Placebo | Absolute reduction in | Relative reduction in |
| (%) | (%) | fracture incidence % | fracture incidence % |
|
|
| (CI) | (CI) |
|
|
|
|
|
At least one new vertebral | 1.5 | 3.7 | 2.2 (1.4, 3.1) | 60 (43, 72)** |
fracture |
|
|
|
|
|
|
|
|
|
At least one new vertebral | 2.2 | 7.7 | 5.5 (4.4, 6.6) | 71 (62, 78)** |
fracture |
|
|
|
|
|
|
|
|
|
At least one new vertebral | 3.3 | 10.9 | 7.6 (6.3, 9.0) | 70 (62, 76)** |
fracture |
|
|
|
|
|
|
|
|
|
** 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
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 | Placebo | Absolute | Relative risk |
|
| (N=3,875) | (N=3,861) | reduction in | reduction in |
|
| event rate | event rate | fracture event rate | fracture |
|
| (%) | (%) | % | incidence % |
|
|
|
| (CI) | (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)** |
| 8.0 | 10.7 | 2.7 (1.4, 4.0) | 25 (13, 36)* | |
|
|
|
|
(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
Bone turnover markers
Bone specific alkaline phosphatase (BSAP), serum
Effect on height
In the
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).
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,
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 | Placebo | Absolute | Relative risk |
|
| (N=1,065) | (N=1,062) | reduction in | reduction in |
|
| event rate | event rate | fracture event | fracture incidence |
|
| (%) | (%) | rate % | % (CI) |
|
|
|
| (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)* | |
7.6 | 10.7 | 3.1 (0.3, 5.9) | 27 (2, 45)* | ||
|
|
|
|
(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 rendt was seen towards reduction in new hip fractures.
All cause mortality was 10% (101 patients) in the
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
Clinical efficacy in men
In the
In another study in men (study CZOL446M2308) an annual infusion of Aclasta was
Clinical efficacy in osteoporosis associated with
The efficacy and safety of Aclasta in the treatment and prevention ofosteoporosis associated with
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 5mg 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
Effect on bone mineral density (BMD)
The increases in BMD were significantly greater in the
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
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30mg risedronate for
- Zoledronic acid teva - M05BA08
- Zoledronic acid actavis - M05BA08
- Zoledronic acid teva pharma - M05BA08
- Zometa - M05BA08
- Zoledronic acid accord - M05BA08
- Zoledronic acid teva generics - M05BA08
Prescription drugs listed. ATC Code: "M05BA08"
2 months was demonstrated in two
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
Six patients who achieved therapeutic response 6 months after treatment with Aclasta and later experienced disease relapse during the extended
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 Aclasta in all subsets of the paediatric population in Paget’s disease of the bone, osteoporosis in
5.2Pharmacokinetic properties
Single and multiple 5 and
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 exceeding0.1% of peak levels.
Elimination
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with
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
Pharmacokinetic/pharmacodynamic relationships
No interaction studies with other medicinal products have been performedwith zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a
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
5.3Preclinical safety data
Acute toxicity
The highest
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
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 andcarcinogenicity testing did not provide any evidence of carcinogenic potential.
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Mannitol
Sodium citrate
Water for injections
6.2Incompatibilities
This medicinal product must not be allowed to come into contact with any
6.3Shelf life
Unopened bottle: 3 years
After opening: 24 hours at 2°C - 8°C
From a microbiological point of view, the product should be used immediately. If not used immediately,
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening of the medicinal product, see section 6.3.
6.5Nature and contents of container
100 ml solution in a transparent plastic (cycloolefinic polymer) bottle closed with a
Aclasta is supplied in packs containing one bottle as unit pack, or in multipacks comprising five packs, each containing one bottle.
Not all pack sizes may be marketed.
6.6Special precautions for disposal and other handling
For single use only.
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/05/308/001
EU/1/05/308/002
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 15 April 2005
- Farydak
- Zoledronic acid hospira
- Inomax
- Pramipexole accord
- Duloxetine lilly
- Acomplia
Prescription drugs listed:
Date of latest renewal: 19 April 2015
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
Comments