Drug Description

Presentation

Indications

'Aclasta' is indicated for the treatment of osteoporosis in post-menopausal women and osteoporosis treatment in men both 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 and in men at increased risk of fracture.

Treatment of Paget's disease of the bone.

Adult Dosage

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.

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. Retreatment of Paget's disease: specific retreatment data are not available. After a single treatment with Aclasta in Paget's disease, an extended remission period is observed in responding patients.

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.

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.

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

Use of Aclasta in patients with creatinine clearance < 35 ml/min is not recommended due to limited clinical experience in this population.

No dose adjustment is necessary in patients with creatinine clearance 35 ml/min.

Patients with hepatic impairment

No dose adjustment is required

Elderly patients ( 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 lack of data on safety and efficacy.

Contra Indications

Hypersensitivity to the active substance or to any of the excipients or to any bisphosphonates.

Aclasta is contraindicated for patients with hypocalcaemia.

Aclasta is contraindicated during pregnancy and in breast-feeding women.

Special Precautions

The dose of 5 mg zoledronic acid must be administered over at least 15 minutes.

Aclasta is not recommended in patients with severe renal impairment (creatinine clearance < 35 ml/min) due to limited clinical experience in this population. Patients should have their serum creatinine level measured before receiving Aclasta.

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important in the elderly and for patients receiving diuretic therapy. 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).

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta. 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.

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. 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.

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.

Interactions

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. Zoledronic acid is not highly bound to plasma proteins (approximately 4355% 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).

Adverse Reactions

The overall percentage of patients who experienced post-dose symptoms were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual symptoms 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 symptoms decreased markedly with subsequent doses of Aclasta.

The majority of these symptoms occur within the first three days following Aclasta administration. The majority of these symptoms were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced post-dose symptoms was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against post-dose symptoms was used as described below.

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.

In the HORIZON – Pivotal Fracture Trial [PFT], 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 dysfunction

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 3–4 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.

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. 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.

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. 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.

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