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ZOLEDRONIC ACID INJECTION - PREMIXED SOLUTION FOR INTRAVENOUS INFUSION (FOR SINGLE DOSE) (zoledronic acid for injection - PREMIXED SOLUTION FOR INTRAVENOUS INFUSION (FOR SINGLE DOSE)) Dosage and Administration

2 DOSAGE AND ADMINISTRATION

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.1 Hypercalcemia of Malignancy

The maximum recommended dose of zoledronic acid in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 µmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [see Warnings and Precautions (5.2)].

2.2 Multiple Myeloma and Bone Metastases of Solid Tumors

The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 – 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended Zoledronic Acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/min
Baseline Creatinine Clearance
(mL/min)
Zoledronic Acid Injection
Recommended Dose*
*
Doses calculated assuming target AUC of 0.66 (mg∙hr/L) (CrCl = 75 mL/min)
greater than 604 mg
50 to 603.5 mg
40 to 493.3 mg
30 to 393 mg

During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

 
For patients with normal baseline creatinine, increase of 0.5 mg/dL
 
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

In the clinical studies, zoledronic acid treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

2.3 Preparation of Solution

Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg/100 mL (0.04 mg/mL) Single-Dose Premixed Bag

Each Zoledronic Acid Injection bag contains 100 mL of solution equivalent to 4 mg zoledronic acid. This solution is premixed and for single-dose only.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL /min, withdraw the specified volume of Zoledronic Acid Injection solution from the premixed bag (see Table 2) using an intravenous bag transfer device (follow the transfer device manufacturer instructions).

  • Insert the transfer device into the premixed bag administration port.
  • Withdraw the specified volume of Zoledronic Acid Injection per Table 2.
  • Discard the withdrawn volume – do not store or reuse.
  • Label the premixed bag with appropriate final drug content and final volume.
  • Administer the newly-prepared dose-adjusted solution immediately to the patient by intravenous infusion.
Table 2: Preparation of Reduced Doses – Zoledronic Acid Injection Premixed Bag
DoseRemove and discard the following volume of zoledronic acid injection premixed solution
3.5 mg12 mL
3.3 mg18 mL
3 mg25 mL

2.4 Method of Administration

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid dose.

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