Zoldix^®

Zoldix^® is the preparation of Zoledronic Acid Monohydrate. Zoledronic acid is a bisphosphonate which is an inhibitor of osteoclastic bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

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Zoldix^® is indicated for-

• Treatment of osteoporosis in postmenopausal women
• Prevention of osteoporosis in postmenopausal women
• Treatment to increase bone mass in men with osteoporosis
• Treatment and prevention of glucocorticoid-induced osteoporosis
• Treatment of Paget's disease of bone

The safety and effectiveness of Zoldix^® for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Route of administration: Zoldix^® should be administered as an intravenous infusion.

Treatment of osteoporosis in postmenopausal women

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

Prevention of osteoporosis in postmenopausal women

The recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes.

Treatment to increase bone mass in men with osteoporosis

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

Treatment and prevention of glucocorticoid-induced osteoporosis

The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. Patients being treated for osteoporosis should be instructed to take supplemental calcium and vitamin D if their dietary intake is inadequate. An average of at least 1200 mg elemental calcium and 800-1000 III vitamin D daily, or 2 tablets of Biocal^®-DX daily is recommended.

Treatment of Paget’s disease of bone

The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate. Patients being treated for Paget's disease of bone should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels and on the symptoms of hypocalcaemia. All patients should take 1500 mg elemental calcium daily in divided doses (750 mg two times a day or 500 mg three times a day) and 800 IL! vitamin D daily, or 2 tablets of Biocal^®-DX daily particularly in the 2 weeks following Zoldix^® administration.

Re-treatment of Paget’s disease

After a single treatment with Zoldix® in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with Zoldix^® may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase or in those patients who failed to achieve normalization of their serum alkaline phosphatase or in those patients with symptoms, as dictated by medical practice.

Renal impairment

Prior to administration of each dose of Zoldix®, a serum creatinine should be obtained and creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula. Zoldix^® is contraindicated in patients with creatinine clearance less than 35 ml/min and in those with evidence of acute renal impairment. A 5 mg dose of Zoldix^® administered intravenously is recommended for patients with creatinine clearance greater than or equal to 35 ml/min. There are no safety or efficacy data to support the adjustment of the Zoldix^® dose based on baseline renal function. Therefore, no dose adjustment is required in patients with creatinine clearance greater than or equal to 35 ml/min.

Method of administration

Zoldix^® must be administered as an intravenous infusion over no less than 15 minutes at a constant infusion rate. Patients must be appropriately hydrated prior to administration of Zoldix^®. Intravenous infusion should be followed by a 10 ml normal saline flush of the intravenous line. Administration of acetaminophen following Zoldix® administration may reduce the incidence of acute-phase reaction symptoms. Zoldix^® solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions and should be administered as a single intravenous solution through a separate vented infusion line. If refrigerated, the refrigerated solution should be allowed to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2^OC-8°C.

Pregnancy: Available data on the use of zoledronic acid in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Zoledronic acid should be discontinued when pregnancy is recognized.

Lactation: There are no data on the presence of zoledronic acid in human milk, the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zoledronic acid and any potential adverse effects on the breastfed child from zoledronic acid or from the underlying maternal condition.

Use in children and adolescents

Safety and effectiveness of zoledronic acid in children and adolescents has not been established.

Hypocalcaemia may worsen during treatment. Patients must be adequately supplemented with calcium and vitamin D. In patients with renal impairment, a single dose should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Renal toxicity may be greater in patients with underlying renal impairment or with other risk factors, including advanced age or dehydration. Creatinine clearance should be monitored before each dose. Osteonecrosis of the jaw (ONJ) has been reported. Atypical femur fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture. Severe bone, joint and muscle pain may occur. Future doses of zoledronic acid should be withhold if severe symptoms occur.

The most common side effects are pyrexia, myalgia, headache, arthralgia and pain in extremity. Other important side effects are flu-like illness, nausea, vomiting, diarrhea and eye inflammation.

Zoledronic acid is contraindicated in patients with known hypersensitivity to zoledronic acid or any other components of this product. It is also contraindicated in hypocalcaemia and creatinine clearance less than 35 ml/min and in those with evidence of acute renal impairment due to an increased risk of renal failure.

Drug interaction with medication: Caution is advised when bisphosphonates, including zoledronic acid, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. Caution should also be exercised when zoledronic acid is used in combination with loop diuretics due to an increased risk of hypocalcaemia. Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs. Renal impairment has been observed following the administration of zoledronic acid in patients with pre-existing renal compromise or other risk factors. In patients with renal impairment, the exposure to concomitant medications that are primarily renally excreted (e.g., digoxin) may increase. Monitoring serum creatinine should be considered in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidney.

Drug interaction with food & others: Not applicable.

Clinical experience with acute overdose of zoledronic acid solution for intravenous infusion is limited. Patients who have received doses higher than those recommended should be carefully monitored. Overdose may cause clinically significant renal impairment, hypocalcaemia, hypophosphatemia and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium, phosphorus and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate and magnesium sulfate, respectively.

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Zoldix^® Solution for IV Infusion: Each 100 ml vial contains Zoledronic Acid Monohydrate BP 5.33 mg equivalent to Zoledronic Acid 5 mg.

Storage

Store in a cool (below 30°C) and dry place protected from light. Keep away from the reach of children.

Packing

Zoldix^® Solution for IV Infusion: Each pack contains a single 100 ml vial of Zoledronic Acid 5 mg, one container of Biocal^®-DX (30 coated tablets of Calcium (Algae source) 600 mg & Vitamin Ds 400 III), one infusion set, one alcohol pad and one first aid bandage