Zoledronic acid

Zoledronic acid
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

Zoledronic acid is a bisphosphonate that is FDA approved for the treatment of hypercalcemia of malignancy, multiple myeloma,, bone metastases of solid tumors, osteoporosis, paget's disease, postmenopausal osteoporosis. Common adverse reactions include nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, dyspnea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

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 [3.0 mmol/L] using the formula: cCa in mg/dL =Ca in mg/dL + 0.8 ( 4.0 g/dL – patient albumin [g/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.

Important Limitation of Use

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

Dosage

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 [3.0 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 mcmol/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.

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 Metastatic Bone Lesions 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.

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. CrCl is calculated using the Cockcroft-Gault formula .

This image is provided by the National Library of Medicine.

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 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 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 / 5 mL Single-Use Vial

Vials of Zoledronic acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic acid Injection concentrate from the vial for the dose required (see Table 2)

This image is provided by the National Library of Medicine.

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

Dosage Forms and Strengths

4 mg/5 mL single-use vial of concentrate

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Zoledronic acid in adult patients.

Non–Guideline-Supported Use

Indications

• Monoclonal gammopathy of uncertain significance, with osteopenia or osteoporosis.
• Osteopenia, secondary to androgen-deprivation therapy in prostate cancer patients;

.* Osteopenia, secondary to hormone therapy in breast cancer patients;

• Osteopenia, secondary to ovarian dysfunction induced by adjuvant chemotherapy in premenopausal women with early-stage breast cancer;

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Zoledronic acid in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Zoledronic acid in pediatric patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Zoledronic acid in pediatric patients.

Contraindications

Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic acid Injection

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

Warnings

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 or other 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.

• Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zoledronic acid Injection. If hypocalcemia hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.

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.

• Zoledronic acid Injection treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 mcmol/L or greater than 4.5 mg/dL were excluded.

• Zoledronic acid Injection treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 mcmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid Injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min.

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. 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.

• While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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.

• Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zoledronic acid Injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

Patients with Asthma

• While not observed in clinical trials with Zoledronic acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.

Hepatic Impairment

• Only limited clinical data are available for use of Zoledronic acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic acid Injection in these patients.

Use in Pregnancy

• Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.

Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus .

Hypocalcemia

• Hypocalcemia has been reported in patients treated with Zoledronic acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Hypocalcemia must be corrected before initiating Zoledronic acid Injection. Adequately supplement patients with calcium and vitamin D.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia of Malignancy

The safety of Zoledronic acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicity

Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes.

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3).

Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zoledronic acid Injection 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Zoledronic acid in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zoledronic acid in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Zoledronic acid during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Zoledronic acid with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Zoledronic acid with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Zoledronic acid with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Zoledronic acid with respect to specific gender populations.

Race

There is no FDA guidance on the use of Zoledronic acid with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Zoledronic acid in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Zoledronic acid in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Zoledronic acid in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Zoledronic acid in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

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.

Monitoring

There is limited information regarding Monitoring of Zoledronic acid in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Zoledronic acid in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Zoledronic acid in the drug label.

Pharmacology

There is limited information regarding Zoledronic acid Pharmacology in the drug label.

Mechanism of Action

Structure

File:Zoledronic acid01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Zoledronic acid in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Zoledronic acid in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Zoledronic acid in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Zoledronic acid in the drug label.

How Supplied

Storage

There is limited information regarding Zoledronic acid Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Zoledronic acid in the drug label.

Precautions with Alcohol

• Alcohol-Zoledronic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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