Zoletrust

Approved Indication (Hypercalcemia):

• Treatment of hypercalcemia of malignancy (HCM):
  Indicated for the management of elevated serum calcium levels (corrected for albumin) associated with malignancy, particularly when associated with bone metastases or tumor-secreted parathyroid hormone-related peptide (PTHrP). Especially effective when serum calcium >12 mg/dL or when symptoms are present (e.g., confusion, arrhythmias, polyuria).

Other Approved Uses (Not for HCM focus but listed for clarity):

• Osteolytic bone metastases from solid tumors.
• Multiple myeloma-related bone disease.
• Paget’s disease of bone.
• Osteoporosis (postmenopausal, male, glucocorticoid-induced).

রেজিস্টার্ড চিকিৎসকের পরামর্শ ছাড়া ওষুধ সেবন করবেন না।

Adults with Hypercalcemia of Malignancy:

• Dose: 4 mg as a single intravenous infusion over no less than 15 minutes.
• Hydration: Ensure patients are adequately hydrated prior to administration.
• Re-treatment:
• Consider repeat dose after 7 days if serum calcium levels do not normalize or rebound.
• Assess renal function before retreatment.

Renal Impairment Adjustments (for HCM):

• Use with caution; not recommended in patients with severe renal impairment (CrCl <30 mL/min).
• For mild-to-moderate renal dysfunction, monitor serum creatinine and consider longer intervals between doses.

Special Populations:

• Elderly: No dose adjustment required; monitor renal function closely.
• Pediatrics: Safety and efficacy not established for HCM.
• Hepatic Impairment: No specific dose adjustment recommended; not significantly metabolized by liver.

Administration Notes:

• Use a separate IV line.
• Do not mix with calcium- or divalent cation-containing solutions.
• Ensure calcium and phosphate levels are monitored and corrected if needed.

Zoledronic acid is a potent nitrogen-containing bisphosphonate that targets osteoclast-mediated bone resorption. It binds strongly to hydroxyapatite crystals in bone and is preferentially localized to sites of high bone turnover. Zoledronic acid inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, leading to disruption of prenylation of small GTPase signaling proteins essential for osteoclast function. This inhibition induces osteoclast apoptosis, thereby reducing bone resorption and the subsequent release of calcium into the blood, effectively lowering serum calcium levels in malignancy-associated hypercalcemia.

• Absorption: Not applicable (IV administration).
• Distribution: Rapid uptake into bone; approximately 22% bound to plasma proteins.
• Volume of Distribution: ~0.3 L/kg.
• Metabolism: Not metabolized.
• Excretion: Primarily renal (approximately 39% excreted unchanged in urine within 24 hours).
• Half-life:
• Initial distribution half-life: 0.24 hours
• Terminal elimination half-life: ~146 hours
• Renal Clearance: Proportional to creatinine clearance.
• Cumulative Bone Retention: Drug persists in bone for extended periods; released slowly over time.

• Pregnancy:
• FDA Category D.
• Contraindicated in pregnancy due to potential fetal harm, including skeletal abnormalities and impaired bone growth.
• Zoledronic acid persists in bone for years, posing long-term fetal risk if conception occurs later.
• Lactation:
• Unknown if excreted in human milk.
• Due to potential for serious adverse effects in nursing infants, breastfeeding is not recommended during or shortly after therapy.
• Use with caution if benefits outweigh risks.

• Primary Class: Bisphosphonate
• Subclass: Nitrogen-containing bisphosphonate (third-generation)

• Hypersensitivity to zoledronic acid or any bisphosphonates
• Hypocalcemia (must be corrected before administration)
• Severe renal impairment (CrCl <30 mL/min)
• Pregnancy and lactation
• Concurrent use with other bisphosphonates

• Renal Impairment:
• Dose-dependent risk of renal failure; monitor serum creatinine before each dose.
• Avoid in patients with CrCl <30 mL/min unless benefit outweighs risk.
• Hypocalcemia:
• Common in the early post-infusion period; ensure adequate calcium and vitamin D status prior to therapy.
• Monitor serum calcium levels post-treatment.
• Osteonecrosis of the Jaw (ONJ):
• Rare, particularly in cancer patients receiving multiple infusions.
• Recommend dental evaluation before treatment initiation.
• Acute Phase Reactions:
• Fever, myalgia, arthralgia, and flu-like symptoms common within 3 days post-dose.
• Atypical Femur Fractures:
• Monitor for unexplained thigh or groin pain.
• Visual Disturbances:
• Inflammation of the eye (e.g., uveitis, scleritis) reported.

Common Side Effects (≥1%):

• General: Fever, fatigue, flu-like symptoms
• Musculoskeletal: Bone pain, arthralgia, myalgia
• GI: Nausea, vomiting, constipation
• Renal: Increase in serum creatinine
• Metabolic: Hypocalcemia, hypophosphatemia

Serious/Rare Side Effects:

• Acute renal failure (especially with rapid infusion or dehydration)
• Osteonecrosis of the jaw
• Atypical subtrochanteric or femoral shaft fractures
• Anaphylaxis, bronchospasm
• Uveitis, episcleritis, scleritis
• Severe musculoskeletal pain

Timing and Severity:

• Flu-like symptoms usually occur within 3 days after the first dose.
• Hypocalcemia can be dose-dependent and symptomatic if not monitored.

• Nephrotoxic Agents (e.g., aminoglycosides, NSAIDs, diuretics):
• Increased risk of renal toxicity and electrolyte imbalance.
• Loop Diuretics:
• Additive hypocalcemic effect.
• Thalidomide and Chemotherapy:
• Combined use may increase ONJ risk.
• Other Bisphosphonates:
• Concomitant use not recommended.
• Calcium- or Iron-containing IV Solutions:
• May precipitate with bisphosphonates; use a separate IV line.
• CYP Enzymes:
• Not metabolized by CYP450; minimal impact on hepatic enzyme systems.
• Alcohol:
• May exacerbate dizziness, dehydration, and renal effects.

• FDA and EMA have issued reinforced guidance on renal monitoring and infusion rates.
• Inclusion in international cancer guidelines for first-line management of HCM (especially in solid tumors and hematologic malignancies).
• Warning updates on ONJ, renal failure, and atypical femur fractures in long-term use.
• Recommended use in combination with rehydration and monitoring of electrolytes emphasized in oncology guidelines.

• Temperature: Store at 20–25°C (68–77°F); excursions permitted to 15–30°C (59–86°F).
• Light Protection: Protect from direct sunlight.
• Freezing: Do not freeze.
• Dilution:
• Diluted solution should be used immediately.
• If necessary, can be stored at 2–8°C for up to 24 hours post-dilution.
• Handling: Use dedicated IV line. Do not mix with calcium- or multivalent-cation-containing solutions.