Data Sheet
ACLASTA®
Zoledronic Acid
5 mg/100 mL solution for infusion
Qualitative and quantitative composition
One bottle with 100 mL solution contains 5 mg zoledronic acid (anhydrous), corresponding to 5.330 mg zoledronic acid monohydrate.
For a full list of excipients, see List of excipients.
Pharmaceutical form
Solution for infusion.
The solution is sterile, clear and colourless.
Clinical particulars
Therapeutic indications
- Treatment of osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures and to increase bone mineral density.
- Prevention of clinical fractures in patients after hip fracture.
- Treatment of osteoporosis in men.
- Treatment and prevention of glucocorticoid-induced osteoporosis.
- Prevention of postmenopausal osteoporosis.
- Treatment of Paget's disease of bone.
Dosage and method of administration
General
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 must be appropriately hydrated prior to administration of Aclasta. This is especially important in the elderly and for patients receiving diuretic therapy (see Special warnings and precautions for use).
Treatment of Postmenopausal Osteoporosis
For the treatment of postmenopausal osteoporosis, the recommended dose is a single intravenous infusion of 5 mg infusion of Aclasta administered once a year.
Adequate supplemental calcium and vitamin D intake is important in women with osteoporosis if dietary intake is inadequate (see Special warnings and precautions for use).
Prevention of Clinical Fractures after a Hip Fracture
For the prevention of clinical fractures after a hip fracture, 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 first Aclasta infusion two or more weeks after hip fracture repair.
It is also recommended to have, a loading dose of 50,000 to 125,000 IU of vitamin D given orally or via the intramuscular route prior to the first Aclasta infusion.
Supplemental calcium and vitamin D intake is recommended for patients treated to prevent clinical fractures after a hip fracture (see Special warnings and precautions for use).
Treatment of osteoporosis in men
For the treatment of osteoporosis in men, the recommended dose is a single intravenous infusion of 5 mg Aclasta administered once a year.
Adequate supplemental calcium and vitamin D intake is important in men with osteoporosis if dietary intake is inadequate (see Special warnings and precautions for use).
Treatment and prevention of glucocorticoid-induced osteoporosis
For the treatment and prevention of glucocorticoid-induced osteoporosis, the recommended dose is a single intravenous infusion of 5 mg Aclasta administered once a year.
Adequate supplemental calcium and vitamin D intake is important in patients with osteoporosis if dietary intake is inadequate (see Special warnings and precautions for use).
Prevention of postmenopausal osteoporosis
For the prevention of postmenopausal osteoporosis, the recommended regimen is a single intravenous infusion of 5 mg Aclasta. An annual assessment of the patient's risk of fracture and clinical response to treatment should guide the decision of when re-treatment should occur.
For the prevention of postmenopausal osteoporosis it is important that patients be adequately supplemented with calcium and vitamin D if dietary intake is inadequate (see Special warnings and precautions for use).
Treatment of Paget's disease of bone
For the treatment of Paget's disease, Aclasta should be prescribed only by physicians with experience in 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 (see Pharmacodynamic properties). However, re-treatment with Aclasta may be considered in patients who have relapsed, based on 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 12 months after the initial dose.
In patients with Paget's disease, adequate vitamin D intake is recommended in association with Aclasta administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following Aclasta administration (see Special warnings and precautions for use).
Method of administration
Aclasta (5 mg in 100 mL ready to infuse solution) is administered intravenously via a vented infusion line, given at a constant infusion rate. The infusion time must not be less than 15 minutes.
For information on the infusion of Aclasta, see Instructions for use and handling.
Patients with renal impairment
The use of Aclasta in patients with creatinine clearance <35 mL/min is not recommended due to limited clinical safety data in such patients (see Special warnings and precautions for use).
No dose adjustment is necessary in patients with creatinine clearance ≥35 mL/min.
Patients with hepatic impairment
No dose adjustment is required (see Pharmacokinetic properties).
Elderly (≥65 years)
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.
Children and adolescents
Aclasta is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
Contraindications
Hypersensitivity to the active substance or to any of the excipients or to any bisphosphonates.
Hypocalcaemia (see Special warnings and precautions for use).
Pregnancy and breast feeding women (see Pregnancy and lactation).
Special warnings and precautions for use
General
The dose of 5 mg zoledronic acid must be administered over at least 15 minutes.
Aclasta contains the same active ingredient found in Zometa (zoledronic acid), used for oncology indications, and a patient being treated with Zometa should not be treated with Aclasta.
Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important in the elderly and for patients receiving diuretic therapy.
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (see Contraindications). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve; thyroid surgery, parathyroid surgery, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.
Renal impairment
Aclasta is not recommended for patients with renal impairment (creatinine clearance < 35 mL/min) due to limited clinical safety data in such patients. Patients should have serum creatinine measured before receiving Aclasta.
Calcium and Vitamin D Supplementation
Treatment of Postmenopausal Osteoporosis
Adequate calcium and vitamin D intake is important in women with osteoporosis if dietary intake is inadequate.
Prevention of Clinical Fractures after a Hip Fracture
Supplemental calcium and vitamin D intake is recommended for patients treated to prevent clinical fractures after a hip fracture.
Treatment of male osteoporosis
Adequate supplemental calcium and vitamin D intake is important in men with osteoporosis if dietary intake is inadequate.
Treatment and prevention of glucocorticoid induced osteoporosis
Adequate supplemental calcium and vitamin D intake is important in patients with osteoporosis if dietary intake is inadequate.
Prevention of postmenopausal osteoporosis
Adequate supplemental calcium and vitamin D intake is important in patients treated to prevent postmenopausal osteoporosis if dietary intake is inadequate.
Treatment of Paget's disease of bone
Elevated bone turnover is a characteristic of Paget's disease of 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 Adverse effects). Adequate vitamin D intake is recommended in association with Aclasta administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following Aclasta administration. Patients should be informed about symptoms of hypocalcaemia. Physicians should consider clinical monitoring for patients at risk.
Musculoskeletal pain
Severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Aclasta.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ): Osteonecrosis of the jaw has been reported predominantly in cancer patients treated with 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.
Interaction with other medicinal products and other forms of interaction
Specific drug-drug interaction studies have not been conducted with zoledronic acid. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see Pharmacokinetic properties). Zoledronic acid is not highly bound to plasma proteins (approximately 43 to 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 drugs that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration).
Pregnancy and lactation
There are no data on the use of zoledronic acid in pregnant women. Studies in animals have shown reproductive toxicological effects (see Preclinical safety data). The potential risk for humans is unknown. Aclasta is contraindicated during pregnancy and in breast-feeding women (see Contraindications).
Effects on ability to drive and use machines
There are no data to suggest that Aclasta affects the ability to drive or use machines.
Adverse effects
The presented adverse reactions in this section have been derived from different studies in the clinical program. Aclasta was studied in post menopausal osteoporosis in the pivotal fracture trial, a randomised, double-blind, placebo-controlled, multinational study including 7,736 women and in Paget's disease in two double blind, randomized safety and efficacy trials involving 357 patients; the prevention of clinical fractures in patients who suffered from a recent low-trauma hip fracture was demonstrated in a randomized, double-blind, placebo-controlled, multinational endpoint study of 2,127 men and women. Aclasta was studied in the treatment and prevention of glucocorticoid-induced osteoporosis in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women. Aclasta was studied in men with osteoporosis or significant osteoporosis secondary to hypogonadism in a randomised, multicentre, double-blind, active-controlled study of 302 men. Finally, Aclasta was studied in the prevention of bone loss in postmenopausal women with osteopenia in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women.
Treatment of postmenopausal osteoporosis, osteoporosis in men, prevention of clinical fractures after hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease of the bone
In the studies to support the indications treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease of the bone, there were no significant differences in the overall incidence of serious adverse events compared to placebo or comparator and most adverse events were mild to moderate. Aclasta was administered once a year in all aforementioned studies.
Consistent with the intravenous administration of bisphosphonates, Aclasta has been most commonly associated with the following post-dose symptoms (frequencies derived from the study in treatment of postmenopausal osteoporosis: fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occur within the first 3 days following Aclasta administration. The majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased markedly with subsequent doses of Aclasta.
The incidence of post-dose symptoms occurring within the first 3 days after administration of Aclasta, can be reduced by approximately 50% with the administration of paracetamol or ibuprofen shortly following Aclasta administration.
Table 1 lists the adverse reactions suspected (investigator assessment) to be associated with Aclasta in the pooled studies supporting the indications: treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after hip fracture, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease of the bone by system organ class and by frequency using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000) adverse drug reactions.
Table 1 Adverse drug reactions suspected to be associated with Aclasta treatment
| Infections and infestations | |
|---|---|
| Uncommon: | Influenza, nasopharyngitis |
| Blood and lymphatic system disorders | |
| Uncommon: | Anaemia |
| Metabolism and nutrition disorders | |
| Uncommon: | Anorexia*, decreased appetite |
| Psychatric disorders | |
| Uncommon: | Insomnia |
| Nervous system disorders | |
| Common: | Headache, dizziness |
| Uncommon: | Lethargy*, paraesthesia, somnolence, tremor, syncope |
| Eye disorders | |
| Uncommon: | Conjunctivitis, eye pain |
| Rare: | Uveitis*, episcleritis, iritis |
| Ear and labyrinth disorders | |
| Uncommon: | Vertigo |
| Vascular disorders | |
| Uncommon: | Hypertension, flushing |
| 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* |
| Skin and subcutaneous tissue disorders | |
| Uncommon: | Rash, hyperhydrosis*, pruritus, erythema |
| Musculoskeletal 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 |
| Renal and urinary disorders | |
| Uncommon: | Blood creatinine increased, pollakiuria, proteinuria |
| General disorders and administration site conditions | |
| Very common: | Fever |
| Common: | Flu-like symptoms, chills, fatigue*, asthenia, pain*, malaise, |
| Uncommon: | Peripheral oedema, thirst*, acute phase reaction*. non-cardiac chest pain |
* Adverse reactions reported more frequently in the individual studies are: Very common: myalgia, arthralgia, fatigue, pain Common: lethargy, dyspnoea, dyspepsia, oesophagitis, abdominal pain, hyperhydrosis, musculoskeletal (muscle) stiffness, joint swelling, musculoskeletal chest pain, joint stiffness, anorexia, thirst, acute phase reaction Uncommon: uveitis.
Additional adverse reactions which were reported in the individual studies but are not included in the Table 1 (due to a lower frequency in the Aclasta group compared with that of the placebo group when the data was pooled) include: ocular hyperaemia, C-reactive protein increased, hypocalcaemia, dysgeusia, toothache, gastritis, palpitation, infusion site reaction.
In one 3 year trial in postmenopausal osteoporosis women (Horizon PFT), the overall incidence of all atrial fibrillation adverse events was 2.5% (96 out of 3,862) in the Aclasta group vs. 1.9% (75 out of 3,852) in the placebo group.
The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) in patients receiving Aclasta compared with 0.6% (22 out of 3,852) in patients receiving placebo. The mechanism behind the increased incidence of atrial fibrillation is unknown.
The imbalance observed in this trial has not been observed in other clinical trials with zoledronic acid.
Prevention of postmenopausal osteoporosis
The overall safety and tolerability profile of Aclasta in the prevention of osteoporosis was comparable to the adverse reaction profile reported in the Aclasta postmenopausal osteoporosis treatment trial, however there was a higher incidence of post-dose symptoms in the Aclasta treated osteopenic patients that occurred within 3 days after infusion: pain, fever, chills, myalgia, nausea, headache, fatigue, dizziness, and arthralgia. The majority of these symptoms were mild to moderate and resolved within 3 days of the reaction onset. The incidence of these symptoms decreased with a subsequent dose of Aclasta. Adverse drug reactions suspected (investigator assessment) to be associated with Aclasta treatment in prevention of postmenopausal osteoporosis which occurred more than once and which are either not included in Table 1 or reported with a higher frequency in the prevention of postmenopausal osteoporosis trial are summarised in Table2 using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100).
Table 2 Adverse drug reactions suspected to be associated with Aclasta
treatment in prevention of
postmenopausal osteoporosis. The adverse reactions are either not included in
Table 1 or reported with a higher frequency
| Metabolism and nutrition disorders | |
|---|---|
| Common: | Anorexia |
| Psychiatric disorders | |
| Uncommon: | Anxiety |
| Nervous system disorders | |
| Very Common: | Headache |
| Common: | Tremor, lethargy |
| Uncommon: | Hypoaesthesia, dysgeusia |
| Eye disorders | |
| Common: | Conjunctivitis, eye pain, iritis |
| Uncommon: | Vision blurred |
| Gastrointestinal disorders | |
| Very Common: | Nausea |
| Common: | Abdominal pain, abdominal pain upper, constipation |
| Skin and subcutaneous tissue disorders | |
| Common: | Night sweats |
| Musculoskeletal and connective tissue disorders | |
| Very common: | Myalgia |
| Common: | Musculoskeletal pain, muscle spasms, musculoskeletal chest pain, pain in jaw, neck pain |
| Uncommon: | Flank pain |
| General disorders and administration site conditions | |
| Very common: | Pain, chills |
| Common: | Oedema peripheral, infusion related reaction, non cardiac chest pain |
Class Effects
Renal dysfunction
Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal dysfunction manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal dysfunction has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise or additional risk factors (e.g. oncology patients with chemotherapy, concomitant nephrotoxic medications, severe dehydration), the majority of whom received a 4 mg dose every 3 to 4 weeks, but it has also been observed in patients after a single administration.
In the HORIZON-PFT trial, 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 3 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.
In the studies to support the indications prevention of clinical fractures after hip fracture, treatment of osteoporosis in men, treatment and prevention of glucocorticoid-induced 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 or comparator treatment groups.
In the prevention of postmenopausal osteoporosis trial, the change in creatinine clearance (measured annually prior to dosing and at one month after the first dose) and the incidence of renal failure and impairment were comparable in the Aclasta and placebo groups.
Laboratory findings
In the HORIZON-PFT trial, 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 HORIZON-RFT, treatment of male osteoporosis and treatment and prevention of glucocorticoid-induced osteoporosis trials, there were no patients who had treatment emergent serum calcium levels below 1.87 mmol/L.
In the prevention of postmenopausal osteoporosis trial there were no patients who had treatment emergent serum calcium levels below 1.87 mmol/L.
In the Paget's disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, all of which resolved.
Local reactions
In the HORIZON-PFT trial, local reactions at the infusion site such as redness, swelling and/or pain were reported (0.7%) following the administration of zoledronic acid.
In the HORIZON-RFT trial, the event rate was comparable for both the Aclasta and placebo treatment groups.
In the treatment of male osteoporosis trial, the event rate was 2.6% in the zoledronic acid treatment group and 1.4% in the alendronate treatment group.
In the treatment and prevention of glucocorticoid-induced osteoporosis trial, no local reactions were reported.
In the prevention of postmenopausal osteoporosis trial, the event rate was 1.1% in Aclasta treated patients compared to 2.0% in placebo treated patients.
Osteonecrosis of the jaw
Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates, including zoledronic acid (uncommon). 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 (ONJ) 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 Special warnings and precautions for use).
In the HORIZON-PFT trial in 7736 patients, ONJ has been reported in one patient treated with Aclasta and one patient treated with placebo. Both cases resolved. In the HORIZON-RFT, treatment of male osteoporosis, treatment and prevention of glucocorticoid-induced osteoporosis and prevention of postmenopausal osteoporosis trials there were no cases of osteonecrosis of the jaw.
Post-marketing experience
The following adverse reactions have been reported during post-approval use of zoledronic acid. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported.
Overdose
Clinical experience with acute overdosage 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 infusion of calcium gluconate.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group: Bisphosphonate (ATC code: M05B A08)
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
Osteoporosis
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 stabilized within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
A. Clinical efficacy for the treatment of post-menopausal osteoporosis (HORIZON - Post-menopausal Fracture Trial [PFT])
The efficacy and safety of Aclasta 5mg once a year for 3 consecutive years were demonstrated in post-menopausal women,(7,736 women aged 65 to 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 an 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. All women received daily elemental calcium and vitamin D supplements.
Effect on Vertebral Fracture
Aclasta significantly decreased therisk relative to placebo of at least one new moderate or severe vertebral fractures by 60% (AR 2.2; CI 1.4, 3.1) at 1 year, and by 70% (AR 7.6; CI 6.6, 9.0) at 3 years (all p<0.0001). Specifically for patients aged 75 years and older, Aclasta patients had a 60% reduction in the risk of vertebral fractures compared to placebo patients (p<0.0001).
Effect on Hip Fracture
Aclasta demonstrated a consistent 41% reduction in the risk of hip fractures over 3 years. The hip fracture event rate was 1.45% for Aclasta-treated patients compared to 2.50% for placebo-treated patients. The risk reduction was comparable to bisphosphonate-naïve patients and women allowed to take concomitant osteoporosis therapy.
Effect on All Clinical Fractures
Aclasta treatment for 3 years demonstrated superiority to placebo by reducing the incidence of all clinical fractures by 33% (AR 4.4; p<0.0001), of clinical vertebral fractures 77% (AR 2.1; p<0.0001) and of non-vertebral fractures by 25% (AR 2.7. p<0.001).
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 6.9% increase in BMD at the lumbar spine, 6.0% at the total hip, and 5.0% at the femoral neck, and 3.2% at the distal radius over 3 years as compared to placebo.
Bone Histology
Dynamic bone histomorphometry in 36 postmenopausal patients with osteoporosis treated with 3 annual doses of Aclasta showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralization defects. Microcomputed tomography analysis demonstrated preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.
Bone turnover Markers
Treatment with a 5 mg annual dose of Aclasta reduces bone turnover markers to the pre-menopausal range. Repeat dosing does not lead to further reduction of bone turnover markers.
Effect on Height
In the 3-year osteoporosis study standing height was measured annually using a stadiometer. The Aclasta group revealed less height loss compared to placebo (4.2 mm vs. 6.7 mm, respectively (p<0.0001).
Days of Disability
Aclasta significantly reduced both the days of limited activity and the days of bed rest due to back pain and due to fractures compared to placebo (all p <0.01).
B. Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip fracture (HORIZON - Recurrent Fracture Trial [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 T-score below -2.5 and approximately 45% of the patients had a 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. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.
Effect on All Clinical Fractures
In the HORIZON-RFT trial showed that Aclasta significantly reduced the risk of new clinical fracture by 35%. The risk of new vertebral fractures was reduced by 46% (AR 2.1; p=0.02)
and new non-vertebral fractures (i.e. hip, wrist, arm, leg, rib) by 27% (AR 3.1 ; p=0.03). 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).
Aclasta did not delay hip fracture healing. The incidence of confirmed 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 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.
C. Treatment of male osteoporosis
The efficacy and safety of Aclasta in men with osteoporosis or significant osteoporosis secondary to hypogonadism were assessed in a randomised, multicentre, double-blind, active-controlled study of 302 men aged 25-86 years (mean age of 64 years). The duration of the trial was two years. Patients were randomised to either Aclasta, which was administered once annually as a single 5 mg dose in 100 mL infused over 15 minutes for a total of two doses, or to oral alendronate 70 mg weekly for two years. All participants received 1000 mg elemental calcium plus 800 to 1000 IU vitamin D supplementation per day. Efficacy was demonstrated if non-inferiority to alendronate was shown with respect to the percentage change in lumbar spine BMD at 24 months relative to baseline.
Effect on Bone Mineral Density (BMD)
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 (Aclasta 6.1% compared to alendronate 6.2%). The percentage increases in lumbar spine BMD at month 12 were also similar between treatment groups.
D. Treatment and prevention of glucocorticoid-induced osteoporosis
The efficacy and safety of Aclasta in the treatment and prevention of glucocorticoid-induced osteoporosis were assessed in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women aged 18-85 years (mean age of 54.4 years) treated with ≥ 7.5 mg/day oral prednisone (or equivalent). Patients in the prevention subpopulation were treated with glucocorticoids ≤ 3 months prior to randomisation, and the treatment subpopulation was treated with glucocorticoids ≥ 3 months prior to randomisation. The duration of the trial was one year. Patients were randomised to either Aclasta, which was administered once as a single 5 mg dose in 100 mL infused over 15 minutes, or to oral risedronate 5 mg daily for one year. All participants received 1000 mg elemental calcium plus 400 to 1000 IU vitamin D supplementation per day. The study was designed to show non-inferiority of a single infusion of Aclasta relative to risedronate in these two subpopulations. 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.
Effect on Bone Mineral Density (BMD)
The increases in BMD were significantly greater in the Aclasta treated group at all sites, which included the lumbar spine, femoral neck, total hip, trochanter, and distal radius at 12 months compared to risedronate (all p < 0.03). A summary of the key results appear in Table 3.
Table 3 Effects of Aclasta and risedronate on bone mineral density of the
lumbar spine,
total hip and femoral neck (modified ITT population)
| Aclasta | Risedronate | LS Mean difference | ||
|---|---|---|---|---|
| Population | Location | n LS Mean (SE) | n LS Mean (SE) | (95% CI) 1 |
| Treatment | Lumbar spine | 249 4.06 (0.28) | 245 2.71 (0.28) | 1.36 (0.67, 2.05)** |
| Total hip | 247 1.65 (0.21) | 239 0.45 (0.20) | 1.21 (0.71, 1.79)** | |
| Femoral neck | 247 1.45 (0.31) | 239 0.39 (0.30) | 1.06 (0.32, 1.79)* | |
| Prevention | Lumbar spine | 129 2.60 (0.45) | 136 0.64 (0.46) | 1.96 (1.04, 2.88)** |
| Total hip | 126 1.54 (0.36) | 135 0.03 (0.36) | 1.51 (0.78, 2.23)** | |
| Femoral neck | 126 1.30 (0.45) | 135 -0.03 (0.46) | 1.33 (0.41, 2.25)* |
* p < 0.01, ** p < 0.001
Bone Histology
Bone biopsy specimens were obtained at month 12 from 23 patients treated with either an annual dose of Aclasta or daily oral risedronate (12 in the Aclasta treatment group and 11 in the risedronate treatment group). All biopsies were adequate for qualitative histomorphometry assessment. Qualitative, quantitative assessments showed bone of normal architecture and quality without mineralization defects.
E. Prevention of postmenopausal osteoporosis
The efficacy and safety of Aclasta in the prevention of osteoporosis in postmenopausal women was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged ≥45 years, who were stratified by years since menopause: Stratum I women <5 years from menopause (n = 224); Stratum II women ≥5 years from menopause (n= 357). Patients within Stratum I and II were randomized to one of three treatment groups: Aclasta was given annually: at randomization and Month 12 (n= 77) in Stratum I and (n=121) in Stratum II. Aclasta given at randomization and placebo at Month 12 (n=70) in Stratum I and (n=111) in Stratum II. Placebo was given at randomization and Month 12 (n=202). Aclasta was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1,200 mg elemental calcium plus 400 to 800 IU vitamin D supplementation per day. The primary efficacy variable was the percent change of BMD at 24 Months relative to baseline.
Effect on Bone Mineral Density
Aclasta significantly increased lumbar spine BMD relative to placebo at Month 24. Treatment with Aclasta given annually resulted in 6.9% increase in BMD in Stratum I patients and 6.2% in Stratum II patients (both p<0.0001). Also, Aclasta given at randomization resulted in 6.3% increase in BMD in Stratum I patients and 5.4% in Stratum II patients (both p<0.0001).
Aclasta administered annually and as a single dose significantly increased total hip BMD relative to placebo at Month 24 across both strata (all p <0.0001). Treatment with Aclasta given annually resulted in 4.8% increase in BMD in Stratum I patients and 4.1% in Stratum II patients relative to placebo. Treatment with a single dose of Aclasta resulted in 4.7% increase in BMD in Stratum I patients and 3.2% in Stratum II patients relative to placebo.
Bone Turnover Markers
The effect of Aclasta treatment on markers of bone resorption b-CTx and bone formation BSAP, P1NP was evaluated in 571 patients stratified by duration from menopause at periodic intervals. Treatment with Aclasta results in a significantly greater reduction in bone turnover markers compared to placebo, and with the two annual Aclasta doses there was a significantly greater reduction compared to the single Aclasta dose. The two annual doses of Aclasta and the single Aclasta dose were associated with reductions in bone turnover markers to the pre-menopausal range with an approximate 55% and 44% reductions in b-CTx in post-menopausal women within 5 years of menopause, respectively, and approximately 59% and 46% reduction in b-CTx in post-menopausal women 5 years or more from menopause, respectively, over 24 months. The two annual doses of Aclasta and the single Aclasta dose were both associated with approximately 55% and 40% reductions in P1NP, in post-menopausal women within 5 years and 5 years or more from menopause, over 24 months.
F. Clinical efficacy for the treatment of Paget's disease of the bone
Aclasta was studied in male and female patients aged above 30 years with primary mild to moderate Paget's disease of the bone (median serum alkaline phosphatase level 2.6 to 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 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 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.
The cumulative rate of maintaining therapeutic response in the extended follow-up period is displayed in Figure 1.
Figure 1 Cumulative rate of maintaining therapeutic response over time in Paget's disease
* Time to first loss of therapeutic response: the occurrence of an SAP level that no longer meets the criteria of a therapeutic response (less than 75% reduction in SAP excess and/or SAP above the upper limit of the normal range).
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.
Bone safety studies
Dose-response and duration of action of a single intravenous injection of zoledronic acid (0.8 to 500 micrograms/kg) were investigated in ovariectomised adult rats for 8 months after dosing, which corresponds to approximately 8 remodelling cycles over 2.7 years in humans. A single dose of zoledronic acid protected against ovariectomy-induced bone loss; both the magnitude and duration of the effect were dose-dependent. The two highest doses of 100 and 500 micrograms/kg significantly increased total bone mineral density, trabecular bone volume, trabecular number and connectivity density to levels above those of the sham-operated controls. Lower doses produced a weaker and less prolonged effect. Mechanical testing at study termination showed a dose-dependent increase in bone strength to values above those of the sham-operated controls at the higher dose. Histomorphometric analysis and measurement of plasma osteocalcin levels confirmed that bone formation was present at 32 weeks post-injection even at the highest dose of 500 micrograms/kg. This dose in rats is approximately 3.4 fold higher than the 5 mg dose administered to a 50 kg patient. Similar results showing a dose-dependent improvement in bone mass and strength were obtained when weekly subcutaneous injections of zoledronic acid were given to ovariectomised rats (0.3 to 7.5 micrograms/kg for 52 weeks) and ovariectomised monkeys (0.5 to 12.5 micrograms/kg for 69 weeks). Overall, the results provide preclinical evidence for the efficacy and bone safety of zoledronic acid at clinically-relevant doses.
In addition, two studies were performed in ovariectomised (OVX) rats (12-month treatment with 0.3, 1.5 and 7.5 micrograms/kg) and OVX rhesus monkeys (16-month treatment with 0.5, 2.5 and 12.5 micrograms/kg) using once-a-week subcutaneous injections. Zoledronic acid treatment dose-dependently prevented all the OVX-induced changes in bone mineral density, bone mechanics and biochemical markers of bone metabolism in serum and urine. Often full efficacy was achieved with the intermediate dose, whereas the low dose had either no or only a slight effect. Drug treatment was well tolerated and there were no clinically meaningful adverse events in either species. Static and dynamic histomorphometric analysis of bones from both of these experiments indicated that zoledronic acid dose-dependently prevented the changes induced by OVX in both trabecular and Haversian bone. Moreover, there was no indication of any abnormality in bone or marrow tissue, no evidence of a mineralising defect, no accumulation of osteoid, and no woven bone. Except for its high anti-resorptive potency, the effect of zoledronic acid on bone was qualitatively similar to that published for other bisphosphonates. These results demonstrate bone safety in a laboratory rodent and a non-human primate species with a more frequent dosing regimen, and a 5- to 8-fold higher total yearly dose (based on 5 mg human dose), than the planned once-a-year dosing in humans.
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 t½alpha 0.24 and t½beta 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½gamma 146 hours. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (alpha and beta, with t½ values above) presumably represent rapid uptake into bone and excretion via the kidneys.
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. 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 specific drug-drug interaction studies have been conducted 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 to 55% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.
Special populations (see Dosage and method of administration)
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 mL/min (range 22 to 143 mL/min) in the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50 to 80 mL/min) and moderate (Clcr = 30 to 50 mL/min) renal impairment are not necessary. The use of Aclasta in patients with creatinine clearance <35 mL/min is not recommended due to limited clinical safety data in such patients (see Special warnings and precautions for use). No dose adjustment is necessary in patients with creatinine clearance ≥35 mL/min.
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 bolus parenteral studies, zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to dogs at doses of up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously in rats and 0.005 mg/kg intravenously once every 2 to 3 days in dogs for up to 52 weeks was also well tolerated. In intravenous infusion studies, renal tolerability occurred in rats at doses of up to 0.6 mg/kg given as six infusions at 3-day intervals (6-fold the clinical dose), while five infusions of 0.25 mg/kg administered at 2 to 3-week intervals (7-fold the clinical dose) were well tolerated in dogs.
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 the rat 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 the rabbit, 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.
Pharmaceutical particulars
List of excipients
Mannitol, sodium citrate, water for injections.
Incompatibilities
Aclasta solution for infusion must not be allowed to come into contact with any calcium- or other divalent cation-containing solutions.
Shelf life
3 years.
Special precautions for storage
Store below 30°C prior to opening
After opening, the solution is chemically and physically stable for at least 24 hours at 2 to 8°C.
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 to 8°C.
Aclasta must be kept out of the reach and sight of children.
Nature and contents of container
Aclasta 5 mg/100 mL solution for infusion is supplied in a 100 mL transparent plastic bottle closed with a fluoro-polymer-coated bromobutyl rubber stopper and an aluminium/polypropylene cap with a flip component.
Aclasta is supplied as packs containing one bottle.
Instructions for use and handling
Aclasta must not be mixed or given intravenously with any other medication and must be given through a separate vented infusion line at a constant infusion rate. If refrigerated, allow the refrigerated solution to reach room temperature before administration. Aseptic techniques must be followed during the preparation of the infusion.
For single use only. Any unused solution should be discarded. Only clear solution free from particles and discoloration should be used.
Medicine classification
Prescription Medicine
Name and address
Novartis New Zealand Limited
Private Bag 65904
Mairangi Bay
Auckland 0754
Building G, 5 Orbit Drive
Rosedale
Auckland 0632
Telephone: 09 361 8100
Date of preparation
8 June 2009
(Ref: BPI 30 Sept 2008 + correction 6 Nov 08 + Fracture amendments approved 8
Jan 2009