Zolepex

Sterile clear colorless solution, concentrate for solution for infusion.
One vial with 5 ml contains 4.264 mg Zoledronic acid monohydrate equivalent to 4 mg Zoledronic acid anhydrous.
Excipients/Inactive Ingredients: Mannitol, Sodium citrate, Water for injection.

Pharmacology: Pharmacodynamics: Zoledronic acid, a bisphosphonates, which act primarily on bone. Zoledronic acid inhibits bone resorption via actions on osteoclasts and induces osteoclast apoptosis resulting in inhibition of bone degeneration. Zoledronic acid also reduces skeletal calcium release induced by tumors.
Pharmacokinetics: Distribution: After initiating the infusion of zoledronic acid, the plasma concentrations of drug rapidly increased.
Plasma protein binding is low (approximately 23-53%).
Metabolism and elimination: Zoledronate is not metabolized within 24 hours and 39 ±16% of dose is excreted unchanged via the kidney, recovered in the urine and <3% in the feces. 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.

Bone metastases from solid tumors as osteolytic and/or osteoblastic.
Treatment of osteolytic lesions of multiple myeloma in combination with antineoplastic therapy.
Reduction of bone damage in patients with advanced malignancies involving bone.
Hypercalcemia of malignancy (HCM).

Prior to IV infusion of Zoledronic acid to patients the concentrated solution must be diluted as directed.
Preparation of the solution for intravenous infusion and administration: ZOLEPEX 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.
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 microbiology integrity, the total time between dilution, storage in refrigerator, and end of administration must not exceed 24 hours.
An adjunct to antineoplastic therapy for the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma, and reduction of bone damage in patients with advanced malignancies involving bone: Recommended dosage of diluted solution is 4 mg of Zoledronic acid as a single dose.
ZOLEPEX 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.
Dosage in Hypercalcemia of malignancy (HCM): 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.
ZOLEPEX 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.
Patient should be appropriately hydrated prior to administration and throughout the treatment.
Zoledronic acid is not recommended for the treatment of hypercalcemia of malignancy in patients with severe renal function impairment (The treatment should be considered 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 renal impairment: 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

ZOLEPEX 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.
ZOLEPEX is not recommended in patients with severe renal impairment (Creatinine clearance less than 30 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).
Dosage in pregnancy and lactation: There is no adequate safety information on Zoledronic acid usage in pregnant woman.
It is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child, advise a lactating woman not to breastfeed during and after treatment.
Dosage in pediatric patients: Due to inadequate safety and efficacy information of drug used in pediatric patients, ZOLEPEX is not indicated for use in children.

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.

Do not mixed or diluted with calcium or other divalent containing solution (e.g., lactated Ringer's solution).
Known hypersensitivity to Zoledronic acid or any component of products and other bisphosphonates.
Do not use in patients with hypocalcemia condition.
Do not use in pregnant and nursing woman.

Zoledronic acid must not be mixed or diluted with calcium-containing solution or other calcium-containing drug or product. Zoledronic acid should be administered through separate vented infusion lines apart from other drugs.
Patient should be appropriately hydrated prior to treatment with Zoledronic acid.
Overhydration should be avoided in patients at risk of 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 maybe 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.
Bisphosphonates has been associated with renal deterioration. The risk of adverse renal effect 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 and should have a dental examination with preventive prior to 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. There are 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.

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

Click on icon to see table/diagram/image

Concomitant administration of bisphosphonates including Zoledronic acid with aminoglycosides may result in lowering serum calcium concentration for prolonged period. Caution is advised.
Concomitant administration of Zoledronic acid with loop diuretics may increase risk of hypocalcemia. Caution is advised.
Concomitant administration of Zoledronic acid with nephrotoxic agents may cause hypomagnesemia and may increase risk of renal dysfunction. The drugs should be used concomitantly with caution.
Concomitant administration of Zoledronic acid with thalidomide in patients with multiple myeloma may potentiate risk of renal dysfunction.

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.

D