Zoledronic Acid is indicated in:

• Hypercalcaemia of malignancy
• Bone metastases associated with solid tumours
• Osteolytic lesions associated with multiple myeloma
• Corticosteroid-induced osteoporosis
• Increase of bone mass in men with osteoporosis
• Osteoporosis in postmenopausal women
• Paget’s disease of bone
• Prophylaxis of postmenopausal osteoporosis

Zoledronic acid is a nitrogen-containing bisphosphonate that acts primarily on bone. It inhibits osteoclast-mediated bone resorption. Bisphosphonates have a high affinity for mineralized bone, allowing rapid distribution of intravenously administered zoledronic acid to bone tissue.The main molecular target in osteoclasts is farnesyl pyrophosphate synthase, although other mechanisms may also be involved. Clinical studies in tumour-induced hypercalcaemia show that zoledronic acid reduces serum calcium and urinary calcium excretion. In addition to anti-resorptive activity, zoledronic acid also exhibits anti-tumour, anti-angiogenic, anti-pain, cytostatic, and pro-apoptotic effects on tumour cells, and shows synergistic cytostatic activity with other anticancer drugs. There is no accumulation of the drug after repeated dosing every 28 days. Zoledronic acid is not metabolized and is excreted unchanged via the kidneys.

Hypercalcemia of malignancy: The maximum recommended dose of Zoledronic Acid in hypercalcemia of malignancy (serum calcium 12 mg/dl or 3.0 mmol/l) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion. Dose adjustment of Zoledronic Acid is not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment. Re-treatment with Zoledronic Acid may be considered if serum calcium does not return to normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose.

Multiple myeloma and bone metastases of solid tumors: The recommended dose of Zoledronic Acid in patients with multiple myeloma and metastatic bone lesions from solid tumors is 4 mg infused every 3-4 weeks. Patients should also be administered an oral calcium supplement of 500 mg and 400 IU of Vitamin-D daily.

Prior to administration, the required amount of concentrate from one vial must be further diluted with 100 ml of calcium-free infusion solution (0.9% w/v sodium chloride solution or 5% w/v glucose solution). The duration of infusion must not be less than 15 minutes. After addition of the solution to the infusion media, the infusion solution should be used as soon as possible. If storage of the infusion solution is necessary, hold at 2-8º C for not more than 24 hours. If refrigerated, the solution must be allowed to reach room temperature before administration.

Zoledronic Acid must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

In clinical studies, Zoledronic Acid has been administered with commonly used anticancer agents, diuretics, antibiotics, and analgesics without clinically significant interactions. Caution is advised when used with aminoglycosides, as both may have additive effects in lowering serum calcium for a prolonged period. In multiple myeloma patients, the risk of renal dysfunction may increase when Zoledronic Acid is used with thalidomide. Concomitant use with loop diuretics increases the risk of hypocalcaemia. Caution is also required when used with other potentially nephrotoxic drugs.

Zoledronic Acid is contraindicated in patients with:, Hypersensitivity to zoledronic acid, other bisphosphonates, or any excipients, Severe renal impairment (creatinine clearance <30 mL/min), Pregnancy and lactation.

Post-dose adverse reactions include headache, nausea, anorexia, fatigue, osteonecrosis of the jaw, anemia, bone pain, constipation, fever, vomiting, flu-like syndrome, hypocalcaemia, myalgia, arthralgia, and hypophosphataemia.

Zoledronic Acid is contraindicated during pregnancy and breastfeeding. It is also not recommended for use in children and adolescents under 18 years.

Patients should be adequately hydrated before administration. This is especially important in elderly patients and those receiving diuretics. Hydration may be ensured by drinking two glasses of fluid before and after infusion. Serum calcium, phosphate, magnesium, potassium, and creatinine should be closely monitored after starting therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplementation may be required. Renal function should be carefully monitored during treatment.

Patients with renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min). No dose adjustment is needed if CrCl >60 mL/min.

Dose adjustment based on creatinine clearance:

• CrCl >60 mL/min: 4 mg (5 mL)
• CrCl 50–60 mL/min: 3.5 mg (4.4 mL)
• CrCl 40–49 mL/min: 3.3 mg (4.1 mL)
• CrCl 30–39 mL/min: 3 mg (3.8 mL)

Clinical experience is limited. Overdose may cause hypocalcaemia, hypophosphataemia, and hypomagnesaemia. Treatment includes intravenous replacement of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate as required.

Bisphosphonate preparations

Store below 30°C before opening. Protect from moisture and light. Keep out of reach and sight of children.