ZOLEDRONIC ACID INJECTION

ZOLEDRONIC ACID INJECTION

ZOLEDRONIC ACID INJECTION

Zoledronic Acid Injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid monohydrate is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate.

Zoledronic acid monohydrate is a white crystalline powder. Its molecular formula is C5H10N2O7P2•H2O and its molar mass is 290.1g/mol. Zoledronic acid monohydrate is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.0. Zoledronic Acid Injection is available in bags as a sterile liquid solution for intravenous infusion.

Each 100 mL bag contains 4.264 mg of zoledronic acid monohydrate (equivalent to 4 mg zoledronic acid on an anhydrous basis), 900 mg of sodium chloride, USP, 220 mg of mannitol, USP, water for injection q.s. and 24 mg of sodium citrate to adjust pH. The pH of the solution is approximately 5.5 to 6.5.

INDICATIONS AND USAGE

Hypercalcemia of Malignancy: Zoledronic Acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3 mmol/L] using the formula: cCa in mg/dL = Ca in mg/dL + 0.8 (4 g/dL – patient albumin [1g/dL]).

Multiple Myeloma and Bone Metastases of Solid Tumors: Zoledronic Acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Limitations of Use

The safety and efficacy of Zoledronic Acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established.

Mechanism of Action

The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.

DOSAGE AND ADMINISTRATION

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

Hypercalcemia of Malignancy

The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 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.

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. 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.

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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 Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection.

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 to 4 weeks. The optimal duration of therapy is not known.

This product is not intended for use with patients with reduced renal function (CrCl 60 mL/min or less).

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 mg/dL

In the clinical studies, Zoledronic Acid Injection 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.

Preparation of Solution

Zoledronic Acid Injection must not be mixed with calcium or other divalent cationcontaining 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 per 100 mL Single-Dose Ready-to-Use Bag

Bags of Zoledronic Acid Injection ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This solution is ready to use and may be administered directly to the patient without further preparation. For singledose only.

Caution: After removing the overwrap check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard container as sterility may be compromised. Use only if solution is clear and the container is undamaged.

Preparation for Administration:

  1. Close flow control clamp of administration set.
  2. Remove cover from port at bottom of container.
  3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
  4. Suspend container from hanger.
  5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Zoledronic Acid Injection.
  6. Open flow control clamp to expel air from set. Close clamp.
  7. Regulate rate of administration with flow control clamp.

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.

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 Injection dose.

CONTRAINDICATIONS

Hypersensitivity reactions including cases of urticaria and angioedema, and cases of anaphylactic reaction/shock have been reported.

WARNINGS AND PRECAUTIONS

Drugs with Same Active Ingredient or in the Same Drug Class: Zoledronic Acid Injection contains the same active ingredient as found in Reclast®(zoledronic acid). Patients being treated with Zoledronic Acid Injection should not be treated with Reclast orother bisphosphonates.

Hydration and Electrolyte Monitoring: Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zoledronic Acid Injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zoledronic Acid Injection in order to avoid hypocalcemia. Zoledronic Acid Injection should be used with caution with other nephrotoxic drugs.

Renal Impairment: Zoledronic Acid Injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased. Preexisting renal insufficiency and multiple cycles of Zoledronic Acid Injection and other bisphosphonates are risk factors for subsequent renal deterioration with Zoledronic Acid Injection. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zoledronic Acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates.

Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

Musculoskeletal Pain: In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic Acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zoledronic Acid Injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

Patients with Asthma: While not observed in clinical trials with Zoledronic Acid Injection, there have been reports ofbronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.

Hepatic Impairment: Only limited clinical data are available for use of Zoledronic Acid Injection to treat hypercalcemiaof malignancy in patients with hepatic insufficiency, and these data are not adequate to provideguidance on dosage selection or how to safely use Zoledronic Acid Injection in these patients.

Hypocalcemia: Hypocalcemia has been reported in patients treated with Zoledronic Acid Injection. Cardiacarrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reportedsecondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be lifethreatening.

Caution is advised when Zoledronic Acid Injection is administered with drugs known to cause hypocalcemia, as severe hypocalcemia may develop. Serum calcium should be measured and hypocalcemia must be corrected before initiating Zoledronic Acid Injection. Adequately supplement patients with calcium and vitamin D.

DRUG INTERACTIONS

In vitro studies indicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60%-77%. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.

Aminoglycosides and Calcitonin: Caution is advised when bisphosphonates are administered with aminoglycosides or calcitonin, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledronic Acid Injection clinical trials.

Loop Diuretics: Caution should also be exercised when Zoledronic Acid Injection is used in combination with loop diuretics due to an increased risk of hypocalcemia.

Nephrotoxic Drugs: Caution is indicated when Zoledronic Acid Injection is used with other potentially nephrotoxic drugs.

Thalidomide: No dose adjustment for Zoledronic Acid Injection 4 mg is needed when coadministered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic Acid Injection 4 mg given as a 15-minute infusion was administered either alone or with thalidomide (100 mg once daily on Days 1-14 and 200 mg once daily on Days 15-28). Coadministration of thalidomide with Zoledronic Acid Injection did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk.

Lactation: After administration of Zoledronic Acid Injection, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after Zoledronic Acid Injection treatment.

Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiation of Zoledronic Acid Injection.

Contraception: Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.

Infertility: Based on animal studies, zoledronic acid injection may impair fertility in females of reproductive potential.

Pediatric Use: Zoledronic Acid Injection is not indicated for use in children.

OVERDOSAGE

Clinical experience with acute overdosage of Zoledronic Acid Injection is limited. Two patients received Zoledronic Acid Injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.

A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100 unit/L, each value unknown). The outcome of this case is not known.

In controlled clinical trials, administration of Zoledronic Acid Injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zoledronic Acid Injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zoledronic Acid Injection 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy

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