Each 5 mL contains: Zoledronic acid monohydrate eq. to Zoledronic acid anhydrous 4 mg.
Water for injections Ph. Eur. Q.S. to 5 mL.
Pharmacology: Pharmacodynamics: Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption. The selective action of bisphosphonates on bone is based on their affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorptio withour adversely affecting the formation, mineralisation or mechanical prorpertie of bone.
In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anti-tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies:
In vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment , making it less conducive to tumour cell growth, anti-angiogenic activity and anti-pain activity.
In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic on tumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti-adhesion/invasion activity.
Pharmacokinetics: Single and multiple 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients with bone metastases yielded the following pharmacokinetic data, which were found to be dose independent. After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, 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 prior to the second infusion of zoledronic acid on day 28. Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic diasppeaance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hours, followed by a long elimintation phase with a terminal elimination half-life of t½γ 146 hours. There was no accumulation of zoledronic acid in plasma after multiple doses given every 28 days. Zoledronic acid is not metabolised and 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 and body weight. 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. The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen with other bisphosphonates. No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro, shows no biotransformation and in animal studies <3% of the administered dose was recovered in the faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid. 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 cancer patients studied. Population analysis showed that for a patient with creatinine clearance of 20 ml/min (severe renal impairment), or 50 ml/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, of that of a patient showing clearance of 84 ml/min. Only limited pharmacokinetic data are available in patients with severe renal insufficiency (creatinine clearance <30 ml/min). Zoledronic acid shows no affinity for the cellular components of blood and plasma protein binding is low (approximately 56%) and independent of the concentration of zoledronic acid.
Special populations: Paediatric patients: Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.
Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcemia) in adult patients with advanced malignancies involving bone.
Treatment of adult patients with tumour-induced hypercalcaemia (TIH).
Zoledronic Acid must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.
Posology: Prevention of skeletal related events in patient with advanced malignancies involving bone: Adults and older people: The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid every 3 to 4 weeks.
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months.
Treatment of TIH: Adults and older people: The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥ 12.0 mg/dl or 3.0 mmol/l) is a single dose of 4 mg zoledronic acid.
General: Patients must be assessed prior to administration of Zoledronic Acid to ensure that they are adequately hydrated. Overhydration should be avoided in patients at risk of cardiac failure. Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful function monitoring should be considered. Zoledronic Acid should not be treated with any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Pregnancy: There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity. The potential risk for humans is unknown. Zoledronic Acid should not be used during pregnancy.
Breast-feeding: It is not known whether zoledronic acid is excreted into human milk. Zoledronic Acid is contraindicated in breast-feeding women.
Summary of the safety profile: Within three days after Zoledronic Acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, mayalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days.
The following are the important identified risks with Zoledronic Acid in the approved indications:
Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, ocular adverse events, atrial fibrillation, anaphylaxis.
In clinical studies, Zoledronic Acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro, but no formal clinical interaction studies have been performed.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents may have been additive effects, resulting in a lower serum calcium level for longer periods than required.
Caution is indicated when Zoledronic Acid is used with other potentially nephrotoxic medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.
In multiple myeloma patients, the risk of renal dysfunction may be increased when Zoledronic Acid is used in combination with thalidomide.
Caution is advised when Zoledronic Acid is administered with anti-angiogenic medicinal products as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.
Store at temperature not exceeding 30°C.
For storage conditions of the reconstituted solution for infusion, see Shelf-life.
Shelf-life: 3 years.
M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Accord Zoledronic 4 conc for infusion 4 mg/5 mL
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