Xoleron4 mg/5 ml

Approved Indication

Xoleron is indicated for the treatment of hypercalcemia of malignancy (HCM), defined as an albumin-corrected serum calcium level of ≥12 mg/dL (3 mmol/L). It is used to rapidly lower dangerously elevated calcium levels caused by certain cancers (e.g. squamous cell carcinomas, breast cancer, multiple myeloma, and other tumors producing humoral or local osteolytic hypercalcemia).

Other Zoledronic Acid Uses (Different Dose/Schedule – Not This Indication)

Zoledronic acid, as a molecule, is also used at different doses and dosing schedules for osteoporosis prevention/treatment, Paget's disease of bone, and to reduce skeletal-related events in bone metastases from solid tumors or multiple myeloma. These are separate regimens and are not the hypercalcemia-of-malignancy indication covered by Xoleron; do not substitute one dosing schedule for another.

Each single-use vial/ampoule of Zoledronic Acid [For hypercalcemia] contains zoledronic acid (as zoledronic acid monohydrate) equivalent to 4 mg zoledronic acid, supplied either as a concentrate for solution for infusion or as a ready-to-dilute powder, along with excipients such as mannitol and sodium citrate to be diluted in normal saline or 5% dextrose before intravenous infusion.

Xoleron is a nitrogen-containing bisphosphonate administered by intravenous infusion. It works by binding to bone mineral and inhibiting osteoclast-mediated bone resorption, which lowers the release of calcium from bone into the bloodstream. In the specific indication covered here, Xoleron is used as a single intravenous infusion to treat hypercalcemia of malignancy, a metabolic emergency seen in certain cancer patients.

Xoleron belongs to the nitrogen-containing bisphosphonate class of drugs, functioning here as an antihypercalcemic agent / inhibitor of bone resorption.

Zoledronic Acid [For hypercalcemia] acts primarily on bone. Zoledronic acid binds avidly to bone mineral (hydroxyapatite), particularly at sites of active bone remodeling, and is taken up by osteoclasts. Inside osteoclasts it inhibits the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway, which disrupts protein prenylation required for osteoclast function and survival. This suppresses osteoclast-mediated bone resorption, reducing the release of calcium from bone into the circulation and thereby lowering serum calcium concentrations. The calcium-lowering effect of Zoledronic Acid [For hypercalcemia] typically begins within 1–2 days, with maximal effect around day 4–7 after infusion.

Xoleron must be administered only by intravenous infusion, never as a bolus injection or intramuscular/subcutaneous injection, because rapid administration increases the risk of renal toxicity. The required dose should be diluted (if not already supplied ready-to-use) in 100 mL of calcium-free infusion fluid (0.9% sodium chloride or 5% dextrose) and infused over a single infusion period of no less than 15 minutes. Patients should be well hydrated with intravenous saline before and during the infusion. Do not mix Xoleron with calcium-containing or other divalent cation-containing infusion solutions (e.g. Lactated Ringer's), as precipitation may occur.

Clinically Significant Drug Interactions

• Aminoglycosides and calcitonin: Co-administration with Xoleron may produce an additive hypocalcemic effect, potentially causing prolonged, clinically significant hypocalcemia; calcium levels should be monitored closely.
• Loop diuretics: Combined use with Xoleron may increase the risk of hypocalcemia, especially if the patient is not adequately hydrated beforehand.
• Nephrotoxic drugs (e.g. NSAIDs, other nephrotoxic agents): Concurrent use with Xoleron may increase the risk of renal impairment; renal function should be monitored closely.
• Thalidomide: In multiple myeloma patients, concomitant use of thalidomide with zoledronic acid-containing products such as Xoleron has been associated with an increased risk of renal dysfunction; renal function should be monitored.
• Other bisphosphonates or calcium-modifying agents: Concurrent use with other bisphosphonates is not recommended, as the combined effects on serum calcium have not been studied.

Very Common / Common

• Acute phase reaction: fever, flu-like symptoms, myalgia, arthralgia, and bone pain, typically occurring within 1–3 days of the first infusion of Xoleron and resolving within a few days.
• Nausea, vomiting, constipation, loss of appetite
• Fatigue, weakness, headache
• Anemia
• Hypophosphatemia, hypocalcemia, hypomagnesemia
• Increase in serum creatinine (renal function changes)

Less Common but Serious

• Osteonecrosis of the jaw (ONJ) — see Precautions and Warnings.
• Atypical femur fractures (more associated with long-term/chronic bisphosphonate use) — see Precautions and Warnings.
• Acute renal failure, especially with pre-existing renal impairment, dehydration, or rapid infusion.
• Severe symptomatic hypocalcemia (muscle cramps, tetany, cardiac arrhythmia in severe cases).
• Ocular inflammation (uveitis, scleritis, conjunctivitis) — rare.
• Infusion-site reactions (redness, swelling, pain).

Xoleron may cause fetal harm based on animal reproduction studies and is not recommended for use during pregnancy. Women of childbearing potential should be advised to use effective contraception during, and for an appropriate period after, treatment with Xoleron. It should be used in pregnancy only if the treating physician determines that the potential benefit to the mother (e.g. treating life-threatening hypercalcemia) clearly justifies the potential risk to the fetus, and only after full consultation with a physician.

It is not known whether zoledronic acid is excreted in human breast milk. Because of the potential for serious adverse effects in a nursing infant, a decision should be made whether to discontinue breastfeeding or discontinue Xoleron, taking into account the importance of treatment to the mother; a physician should be consulted before breastfeeding during treatment.

Renal Toxicity

Deterioration of renal function, including acute renal failure, has been reported with Xoleron, particularly with pre-existing renal impairment, dehydration, or use of other nephrotoxic drugs. Ensure adequate hydration, avoid exceeding the recommended dose and infusion time, and monitor serum creatinine before each dose.

Osteonecrosis of the Jaw (ONJ)

ONJ has been reported in patients treated with intravenous bisphosphonates such as Xoleron, generally in association with tooth extraction, dental surgery, or local infection, and is more frequent in cancer patients. A dental examination with appropriate preventive dentistry is recommended before starting treatment when feasible. Invasive dental procedures should be avoided during therapy where possible.

Atypical Femur Fractures

Atypical, low-trauma subtrochanteric and femoral shaft fractures have been reported with bisphosphonate therapy, more typically with long-term chronic dosing schedules (e.g. osteoporosis regimens) rather than single-dose hypercalcemia treatment. Patients presenting with new thigh, hip, or groin pain during or after bisphosphonate therapy should be evaluated for possible incomplete femur fracture.

Acute Phase Reaction

Flu-like symptoms (fever, myalgia, arthralgia, chills) commonly occur after the first infusion of Xoleron and usually resolve without specific treatment within a few days; antipyretics/analgesics may be used for symptomatic relief.

Hypocalcemia and Electrolyte Disturbances

Monitor serum calcium, phosphate, and magnesium during treatment, as Xoleron can cause hypocalcemia, hypophosphatemia, and hypomagnesemia, particularly in patients with impaired parathyroid function or vitamin D deficiency.

Overdose of Xoleron may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia, as well as worsening of renal function. There is no specific antidote. In case of suspected overdose, seek immediate medical attention or contact emergency services/poison control. Management is supportive and should be carried out in a hospital setting, and may include intravenous calcium gluconate for symptomatic hypocalcemia, phosphate or magnesium supplementation as required, close monitoring of renal function, serum electrolytes, and cardiac status (including ECG monitoring), with appropriate supportive care.

Store below 30°C. If refrigerated, allow the vial/solution to reach room temperature before use. Once diluted for infusion, the solution should be used promptly; if not used immediately, refrigerate and use within the time specified on the product label. Do not freeze. Keep out of reach of children. Discard any unused portion; this is a single-use product.

Renal Impairment

See Dosage and Administration and Contraindications for detailed renal guidance for Xoleron. In summary, no adjustment is generally needed for mild-to-moderate impairment; severe impairment requires individualized risk-benefit assessment.

Hepatic Impairment

No dedicated studies have been conducted in patients with hepatic impairment; Xoleron should be used with caution in this population, as zoledronic acid is not metabolized and is eliminated renally, so hepatic dysfunction alone is not expected to require dose adjustment, but overall clinical status should be considered.

Elderly

No overall differences in safety or effectiveness have been observed between elderly and younger patients, but because elderly patients more often have reduced renal function, dose selection and renal monitoring should be approached cautiously when using Xoleron.

Pediatric Population

See Pediatric Uses.

For hypercalcemia of malignancy, Xoleron is typically given as a single intravenous infusion. It is not intended for fixed chronic/indefinite dosing in this indication. If hypercalcemia persists or recurs, retreatment may be considered, but only after a minimum of 7 days and after reassessing renal function and calcium status. The treating physician determines the need for and timing of any further doses based on the patient's calcium response and overall clinical status.

If Xoleron is supplied as a concentrate or lyophilized powder, it must be reconstituted/diluted before use, exactly as directed on the product insert: the required 4 mg dose is diluted in 100 mL of sterile 0.9% sodium chloride or 5% dextrose infusion fluid (calcium-free solutions only). The diluted solution should be administered as a single intravenous infusion over no less than 15 minutes. Do not mix with calcium-containing or other divalent-cation-containing solutions (e.g. Lactated Ringer's solution). Use aseptic technique throughout preparation, and inspect the solution visually for particulate matter and discoloration prior to administration.

Nitrogen-containing bisphosphonate; antihypercalcemic agent; bone resorption inhibitor.

Zoledronic Acid [For hypercalcemia] inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate (cholesterol biosynthesis) pathway within osteoclasts. This blocks the prenylation of small GTP-binding proteins essential for osteoclast cytoskeletal integrity and function, leading to osteoclast inactivation and apoptosis. The resulting suppression of osteoclast-mediated bone resorption reduces the flux of calcium from bone into the blood, lowering elevated serum calcium levels in hypercalcemia of malignancy.

D

Xoleron is not indicated for use in pediatric patients. The safety and effectiveness of zoledronic acid for the treatment of hypercalcemia of malignancy in children have not been established. Use in pediatric patients should only be considered by a specialist in exceptional circumstances where no alternative is available, with close monitoring for renal toxicity and effects on the developing skeleton.