Zolennic

Each vial (5 mL) contains Zoledronic acid monohydrate equivalent to Zoledronic acid anhydrous 4 mg.
Excipients/Inactive Ingredients: D-mannitol, sodium citrate dihydrate, water for injection.

Pharmacology: Pharmacodynamics: Zoledronic acid, a bisphosphonate, is a bone resorption inhibitor that acts primarily on bone (due to its high affinity to bone). Zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis resulting in inhibition of bone degeneration. Zoledronic acid also reduces skeletal calcium release induced by various stimulatory factors released by tumors.
Pharmacokinetics: Plasma concentrations of Zoledronate rise rapidly, following an intravenous infusion. Plasma protein binding is low (approximately 22-56%). Zoledronate is not metabolized, and about 23-55% of dose is excreted in urine as unchanged drug. Renal clearance is lower in patients with severe renal impairment. Nonrenal clearance is mainly sequestered to bone. The drug is released systemically via bone turnover.

An adjunct to antineoplastic therapy for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma; Paget's disease of bone; Hypercalcemia of malignancy (HCM).

Prior to IV infusion of Zoledronic acid in patients the concentrated solution must be diluted as directed.
Preparation of the solution for intravenous infusion and administration: Prior to IV infusion ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION must be diluted in 100 mL of appropriate infusion solution such as 0.9% sodium chloride injection or 5% dextrose injection before being administered by IV infusion over not less than 15 minutes.
Note: Do not reconstitute or dilute ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION with calcium-containing or other divalent cation-containing infusion solution such as Ringer's solution.
If diluted solution is not used immediately and stored in refrigerator (at 2-8°C), it is necessary to equilibrate the refrigerated solution to room temperature prior to administration.
For preparation of the diluted solution for intravenous infusion the risk of pathogens contamination should be taken into account. Hence, diluted solution should be used immediately and the rest of the diluted solution should not be stored for further use. Before IV infusion physical appearance such as precipitation or color change should be considered.
Dosage: An adjunct to antineoplastic therapy for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma and Paget's disease of bone: Dosage in adult and elderly patients: Recommended dosage of diluted solution is 4 mg of Zoledronic acid as a single dose. Prior to IV infusion ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION must be diluted in 100 mL of appropriate infusion solution such as 0.9% sodium chloride injection or 5% dextrose injection before being administered by IV infusion over not less than 15 minutes and given IV once every 3-4 weeks.
Patients should be received supplemental therapy with 500 mg of calcium and 400 units of vitamin D daily.
Hypercalcemia of malignancy (HCM): Dosage in adult and elderly patients: Recommended dosage of diluted solution in hypercalcemia of malignancy (albumin-corrected serum calcium is at least 12.0 mg/dL or 3.0 mmol/L) is 4 mg of Zoledronic acid as a single dose. Prior to IV infusion ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION must be diluted in 100 mL of appropriate infusion solution such as 0.9% sodium chloride injection or 5% dextrose injection before administered by IV infusion over not less than 15 minutes.
Patient should be appropriately hydrated prior to administration and throughout the treatment.
Dosage in renal impairment: An adjunct to antineoplastic therapy for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma and Paget's disease of bone: In patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma and mild to moderate renal function impairment dosage adjustments should be adjusted based on renal function listed in the table as follows. (See Table 1.)

Click on icon to see table/diagram/image

Note: Recommendations for preparation of the diluted Zoledronic acid solution for intravenous infusion in patient with renal function impairment, considering the volume of ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION from vial to be diluted are as follows: To obtain a dosage of 3.5 mg, withdraw 4.4 mL of ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION from vial.
To obtain a dosage of 3.3 mg, withdraw 4.1 mL of ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION from vial.
To obtain a dosage of 3.0 mg, withdraw 3.8 mL of ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION from vial.
Prior to IV infusion, ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION must be diluted in 100 mL of appropriate infusion solution such as 0.9% sodium chloride injection or 5% dextrose injection before being administered by IV infusion over not less than 15 minutes.
Zoledronic acid is not recommended for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma in patients with severe renal function impairment (Creatinine clearance less than 35 mL/min).
During treatment, special care should be taken to monitor renal function and measure serum creatinine before each zoledronic acid dose and withhold treatment for renal deterioration.
Renal deterioration is defined as follows: Increase in serum creatinine more than or equal to 44 µmol/L or 0.5 mg/dL for patients with normal baseline serum creatinine (less than 1.4 mg/dL), before treatment.
Increase in serum creatinine more than or equal to 88 µmol/L or 1 mg/dL for patients with an abnormal baseline serum creatinine (greater than 1.4 mg/dL), before treatment.
Zoledronic acid treatment is resumed only when the serum creatinine returned to within 10% of the baseline value (or serum creatinine up to 3.0 mg/dL). Reinitiate Zoledronic acid at the same dose as that prior to treatment interruption.
Hypercalcemia of malignancy (HCM): Zoledronic acid is not recommended for the treatment of hypercalcemia of malignancy in patients with severe renal function impairment. (Consider Zoledronic acid treatment in patient with HCM only after evaluating the risks and benefits of treatment.)
No dose adjustment is needed in patients with hypercalcemia of malignancy and mild to moderate renal impairment (Serum creatinine less than 400 µmol/L or 4.5 mg/dL).
Dosage in pediatric patients: Due to inadequate safety and efficacy information of drug used in pediatric patients it is not recommended to use this drug in pediatric patients.

Overdosage may cause hypocalcemia, hypophosphatemia, and hypomagnesemia.
Treatment: Depends on the overdosage symptoms. IV administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate may be administered to treat hypocalcemia, hypophosphatemia and hypomagnesemia, respectively.

Known hypersensitivity to Zoledronic acid or any component of products.
Do not use in patients with hypocalcemia condition.
Known hypersensitivity to other bisphosphonates.
Do not use in pregnant and nursing women.

Zoledronic acid must not be mixed with calcium-containing infusion solution or other calcium-containing drug or product. However, if concomitant use cannot be avoided, Zoledronic acid should be administered as a single IV solution in a line separated from other drugs.
Patient should be appropriately hydrated prior to administration and throughout the treatment with Zoledronic acid.
Overhydration should be avoided especially in those patients who have cardiac failure. A urinary output should be maintained at 2 L per day throughout therapy with Zoledronic acid.
Patient should be monitored for hypercalcemia-related metabolic parameters including serum concentrations of calcium, phosphate, magnesium, and serum creatinine prior to each administration and throughout the treatment with Zoledronic acid. Hypercalcemia condition may be associated with abnormal renal function. Hence, renal function should be monitored in such patients.
Patients having hypercalcemia associated with malignancy after a post-treatment evaluation should be investigated at least 7 days after drug initiation. A second course of Zoledronic acid at the same dosage may be considered in case that the desired results are not achieved. If patients with hypercalcemia of malignancy experience a deterioration of renal function during therapy with Zoledronic acid, the possible risk of renal failure with subsequent doses of the drug must be carefully weighed against the potential benefits of treatment. No data is available to date on the safety and efficacy of more than one course of retreatment with Zoledronic acid in patients with hypercalcemia of malignancy.
If hypocalcemia, hypophosphatemia or hypomagnesemia occur, short-term supplemental therapy may be necessary.
The onset of treatment with Zoledronic acid in patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma may occur 2-3 months after the initiation of therapy.
Bisphosphonate has been associated with renal deterioration. The risk of adverse renal effects during parenteral therapy with bisphosphonates including Zoledronic acid depends on coexisting conditions associated with renal impairment such as dehydration, preexisting renal disease, concomitant therapy with other drugs such as other bisphosphonates or nephrotoxic drugs, or duration of IV infusion shorter than recommended.
Patients should consult the physician if severe pain of the jaw, muscle or joint pain occurs.
Patients should maintain good oral hygiene. Preventive dental examinations should be performed prior to treatment with Zoledronic acid. Invasive dental procedures should be avoided during treatment with this drug because of reported Osteonecrosis found in patients treated with bisphosphonates including Zoledronic acid. Frequency of osteonecrosis of the jaw depends on pathological cancer (e.g. breast cancer, multiple myeloma) and pre-existing oral disease (e.g. tooth extractions, periodontitis, oral injuries, non-fixed denture). For patients who develop osteonecrosis of the jaw while on Zoledronic acid therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there is no data available to suggest whether discontinuation of Zoledronic acid treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement by physician should be evaluated to determine patients risk and benefit so that treatment for each patient could be planned accordingly.

There is no adequate safety information on Zoledronic acid usage in pregnant women. Studies in pregnant rat show abnormality of fetal organ development. Hence, use Zoledronic acid during pregnancy only if the potential benefit justifies the risk to the mother and fetus.
It is not known whether the drug is excreted in breast milk. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drugs to the nursing women and possible risks to infants nursing.

Patients experiences a flu-like syndrome consisting of bone pain, fever, fatigue and rigors, arthralgia, myalgias, decreased urinary calcium excretion, hypophosphatemia, asymptomatic hypocalcemia, nausea, vomiting, injection site reaction such as swelling, redness and pain, anorexia, rash, urticaria, conjunctivitis, renal deterioration, severe anemia. Long term drug use may cause the following adverse reactions. (See Table 2.)

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Concomitant administration of bisphosphonates including Zoledronic acid with aminoglycosides may result in lowering serum calcium concentration for prolonged period. Use concomitantly with caution.
Concomitant administration of Zoledronic acid with loop diuretics may increase risk of hypocalcemia. Use concomitantly with caution.
Concomitant administration of Zoledronic acid with nephrotoxic agents may cause hypomagnesemia and may increase risk of renal dysfunction. Interim monitoring of renal function should be considered between the initial and subsequent doses of Zoledronic acid.
Concomitant administration of Zoledronic acid with thalidomide in patients with multiple myeloma may potentiate risk of renal dysfunction.

Stability: Diluted ZOLENNIC CONCENTRATE FOR SOLUTION FOR IV INFUSION in 100 mL of appropriate infusion solution such as 0.9% sodium chloride injection or 5% dextrose injection is stable up to 24 hours when stored in refrigerator (at 2-8°C).

Store below 30°C.
Diluted Zoledronic acid solution is stable up to 24 hours when stored in refrigerator (at 2-8°C).

Agents Affecting Bone Metabolism

M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.

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