Brand names: Zometa, Reclast
Drug class: Bone Resorption Inhibitors
VA class: HS900
Chemical name: [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bis-phosphonic acid monohydrate
Molecular formula: C₅H₁₀N₂O₇P₂•H₂O
CAS number: 165800-06-6

Medically reviewed by Drugs.com on Nov 15, 2023. Written by ASHP.

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.^{1 4 5}

Uses for Zoledronic Acid

Hypercalcemia Associated with Malignancy

Used in conjunction with achievement and maintenance of adequate hydration for the treatment of moderate to severe hypercalcemia (albumin-corrected serum calcium concentration ≥12 mg/dL) associated with malignant neoplasms.^{1 2 3 5 6}

For treatment of mild or asymptomatic hypercalcemia, more conservative measures (e.g., hydration alone or combined with loop diuretics) generally used.¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

Used as an adjunct to antineoplastic therapy for the treatment of osteolytic bone metastases of solid tumors and osteolytic lesions of multiple myeloma.^{1 7}

Second-line therapy of bone metastases associated with prostate cancer in patients with disease progression following one or more hormonal therapies.^{1 3}

Osteoporosis

Prevention of osteoporosis in postmenopausal women.^{17 41} Risk factors for postmenopausal osteoporosis and related fractures include early menopause, advanced age, low bone mineral density (BMD), low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).^{44 45}

Treatment of osteoporosis in postmenopausal women.^{17 21}

Used to increase bone mass in men with osteoporosis.¹⁷

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women and men (≥50 years of age) with previous hip or vertebral fractures or low BMD; pharmacologic therapy also may be considered in postmenopausal women and men (≥50 years of age) with low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.^{44 45}

Use of a drug with proven efficacy in reducing fracture risk is recommended; bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate) are recommended as one of several first-line drugs.^{44 45}

Individualize choice of therapy based on potential benefits (with respect to fracture risk reduction) and adverse effects of therapy, patient preferences, comorbidities, and risk factors.^{44 45}

Glucocorticoid-induced Osteoporosis

Treatment and prevention of glucocorticoid-induced osteoporosis.^{17 40} Manufacturer recommends use of zoledronic acid in men and women who are either initiating or receiving long-term (≥12 months) systemic glucocorticoid therapy in a daily dosage ≥7.5 mg of prednisone or equivalent.^{17 40}

American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high risk of fracture.⁶²² Oral bisphosphonates are preferred because of their demonstrated antifracture benefits, safety, and low cost.⁶²²

Paget Disease of Bone

Treatment of Paget disease of bone (osteitis deformans) in patients with serum alkaline phosphatase concentrations ≥ 2 times ULN or who are symptomatic or at risk for future complications.¹⁷

Prevention of Aromatase Inhibitor-associated Bone Loss in Postmenopausal Women

Use of zoledronic acid for the prevention of bone loss in postmenopausal women with early-stage breast cancer receiving aromatase inhibitor therapy^{† [off-label]} is a reasonable choice (accepted, with possible conditions).¹⁰⁰³⁴

Upfront administration of zoledronic acid in postmenopausal women receiving aromatase inhibitor therapy significantly prevented bone loss compared with delayed therapy (i.e., zoledronic acid initiated following a decline in T-score to <-2 standard deviations, nontraumatic fracture, or evidence of asymptomatic fracture).^{10017 10019 10021 10022}

Consider baseline BMD and history of prior fractures when determining the optimal time to initiate therapy.¹⁰⁰³⁴

Prevention of Aromatase Inhibitor-associated Bone Loss in Premenopausal Women

Use of zoledronic acid in premenopausal women with early-stage breast cancer receiving zoledronic acid concurrently with an aromatase inhibitor and gonadotropin-releasing hormone (GnRH) agonist^{† [off-label]} is not fully established because of unclear risk/benefit.¹⁰⁰³⁴

Improvements in BMD have been observed in such patients; however, long-term follow-up needed, especially as women enter menopause, to establish whether zoledronic acid is associated with clinically important fracture reduction.¹⁰⁰³⁴

Breast Cancer

Use of zoledronic acid in combination with adjuvant systemic therapy in postmenopausal women with early or locally advanced breast cancer^{† [off-label]} is a reasonable choice (accepted).¹⁰⁰³⁵

ASCO and Cancer Care Ontario (CCO) state that postmenopausal women who are candidates for adjuvant systemic therapy should consider receiving a bisphosphonate (i.e., zoledronic acid) during the course of adjuvant therapy for up to 5 years.¹⁰⁰³¹ Consider patient and disease characteristics (e.g., risk of recurrence) and adverse effects when deciding whether bisphosphonate therapy should be added to adjuvant systemic therapy.¹⁰⁰³¹

Optimal time for initiating bisphosphonates not established; however, bisphosphonate therapy was generally initiated soon after surgery or chemotherapy in most clinical trials.¹⁰⁰³¹

Optimal duration of adjuvant bisphosphonate therapy not established; however, the duration of adjuvant bisphosphonate therapy should not exceed 5 years, since toxicity of long-term (e.g., beyond 5 years) use of bisphosphonates not determined.¹⁰⁰³¹

Zoledronic Acid Dosage and Administration

General

• Evaluate renal function (S_cr or Cl_cr) prior to administration of each dose.^{1 3 17} (See Renal Effects under Cautions.)

• Carefully monitor standard hypercalcemia-related metabolic parameters (e.g., serum concentrations of calcium, phosphate, magnesium, other electrolytes in patients with hypercalcemia of malignancy) following initiation of therapy.^{1 17}

Osteoporosis

• Supplemental calcium (average daily dose of 1.2 g) and vitamin D (average daily dose of 800–1000 international units [IU, units]) recommended if dietary intake insufficient.¹⁷

• Appropriately hydrate patients prior to initiation of therapy.¹⁷ Withhold therapy if dehydration is evident; may resume once normovolemic status achieved.¹⁷

Paget Disease of Bone

• To reduce risk of hypocalcemia, administer supplemental calcium and vitamin D, especially during first 2 weeks of therapy; recommended daily intake is 1.5 g of elemental calcium in divided doses (750 mg twice daily or 500 mg 3 times daily) and 800 units of vitamin D.¹⁷

• Appropriately hydrate patients prior to initiation of therapy.¹⁷ Withhold therapy if dehydration is evident; may resume once normovolemic status achieved.¹⁷

Hypercalcemia Associated with Malignancy

• Adequately hydrate patients prior to treatment initiation and throughout treatment.^{1 3} Avoid overhydration, especially in patients at risk for the development of heart failure.^{1 3} Attempt to restore urine output to 2 L/day throughout treatment.¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

• Supplemental calcium (500 mg of elemental calcium daily) and a multivitamin containing vitamin D (400 units daily) is recommended in patients with multiple myeloma or bone metastases associated with solid tumors.^{1 7} (See Metabolic Effects under Cautions.)

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.^{1 3 7 17}

Available as a 4 mg/5 mL solution concentrate (Zometa or generic equivalents) and a 4 mg/100 mL ready-to-use infusion (Zometa or generic equivalents) for patients with cancer-related indications.¹ Also available as a ready-to-use 5 mg/100 mL infusion (Reclast or generic equivalents) for use in the prevention or treatment of osteoporosis or treatment of Paget disease of bone.¹⁷

Administer through separate vented IV lines apart from other drugs.^{1 17} Do not allow contact with any calcium or other divalent cation-containing solutions.^{1 17}

Zoledronic Acid for Cancer-related Indications

Must dilute concentrated solution of Zometa (or generic equivalents) prior to administration.¹ (See Dilution under Dosage and Administration.) To avoid inadvertent injection of the concentrated solution, do not store the undiluted concentrate in a syringe.¹

The ready-to-use solution of Zometa (or generic equivalents) may be administered directly without further dilution to provide a dose of 4 mg in patients with normal renal function.¹ To prepare reduced doses for patients with mild to moderate renal impairment, withdraw appropriate volume of solution from the 100-mL ready-to-use bottle and replace with an equal volume of an appropriate diluent (0.9% sodium chloride or 5% dextrose injection).¹ For dose of 3.5 mg, withdraw 12 mL of drug solution and replace with 12 mL of diluent.¹ For dose of 3.3 mg, withdraw 18 mL of drug solution and replace with 18 mL of diluent.¹ For dose of 3 mg, withdraw 25 mL of drug solution and replace with 25 mL of diluent.¹

Zoledronic Acid for Osteoporosis and Paget Disease of Bone

To minimize risk of renal toxicity, appropriately hydrate patient prior to administration of the drug.¹⁷ Withhold therapy in such patients with evidence of dehydration; may resume once normovolemic status has been achieved.¹⁷

Follow each dose with 10 mL of a 0.9% sodium chloride flush.¹⁷

Administration of acetaminophen following zoledronic acid may reduce incidence of acute-phase inflammatory reactions (e.g., fever, myalgia, flu-like symptoms, headache, arthralgia).¹⁷

Dilution

For dilution of the zoledronic acid concentrate (Zometa or generic equivalents), withdraw the appropriate volume of solution needed to provide the prescribed dose (see Table 1) from the 5-mL vial and dilute in 100 mL of 0.9% sodium chloride or 5% dextrose injection.¹ Increased risk of renal impairment or failure associated with smaller infusion volumes (e.g., 50 mL).^{3 4 7}

Rate of Administration

Administer by IV infusion over ≥15 minutes.^{1 3 7 17} Rapid IV infusion rates (5 minutes) are associated with an increased risk of renal impairment and renal failure.^{1 3 4 7}

Dosage

Available as zoledronic acid (as the monohydrate); dosage expressed in terms of the anhydrous drug.¹

Adults

Hypercalcemia Associated with Malignancy

IV

4 mg as a single dose in patients with an albumin-corrected serum calcium concentration of ≥12 mg/dL.^{1 3}

Consider retreatment if serum calcium concentrations do not return to normal or do not remain normal.¹ May repeat initial dose ≥7 days after treatment initiation to allow full response to initial dose.¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

IV

4 mg once every 3–4 weeks in patients with baseline Cl_cr >60 mL/minute.^{1 3} Optimum duration of such therapy is not known.^{1 3 7}

If renal function deteriorates (defined as an increase in S_cr of ≥0.5 mg/dL) in patients with a baseline S_cr of <1.4 mg/dL, withhold therapy until S_cr returns to within 10% of baseline levels.^{1 3 7} Reinitiate therapy at the same dosage used prior to treatment interruption.^{1 3 7}

Osteoporosis

Prevention in Postmenopausal Women

IV

5 mg once every 2 years.¹⁷

Treatment in Postmenopausal Women

IV

5 mg once yearly.¹⁷

Reevaluate need for continued therapy periodically in all patients receiving bisphosphonates.¹⁷

Treatment in Men

IV

5 mg once yearly.¹⁷

Reevaluate need for continued therapy periodically in all patients receiving bisphosphonates.¹⁷

Glucocorticoid-induced Osteoporosis

IV

5 mg once yearly.¹⁷

Paget Disease of Bone

IV

Single dose of 5 mg.¹⁷

May consider retreatment if relapse occurs based on increases in serum alkaline phosphatase, if initial dose fails to normalize serum alkaline phosphatase concentrations, or if patient is symptomatic; however, no specific data available on effects of retreatment.¹⁷

Prevention of Aromatase Inhibitor-associated Bone Loss† [off-label] in Postmenopausal Women

IV

Dosage of 4 mg once every 6 months for 5 years has been used in clinical trials in women with early-stage breast cancer.^{10001 10019 10022}

Adjuvant Treatment of Early or Locally Advanced Breast Cancer† [off-label]

IV

Dosage of 4 mg once every 6 months for 3–5 years has been used in clinical trials in postmenopausal women with early or locally advanced breast cancer.^{10001 10004 10019 10022 10023}

Prescribing Limits

Adults

Hypercalcemia Associated with Malignancy

IV

Maximum 4 mg as a single dose.^{1 3 5 7} Safety and efficacy of >1 course of retreatment not established.^{2 3}

Special Populations

Hepatic Impairment

No dosage recommendations at this time.¹

Renal Impairment

Hypercalcemia Associated with Malignancy

IV

Dosage adjustments are not necessary in patients with mild to moderate renal impairment (S_cr <4.5 mg/dL).¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

IV

In patients with mild to moderate renal impairment (baseline Cl_cr of 30–60 mL/minute), lower initial dosages of zoledronic acid are recommended.¹ (See Table 2.)

If renal function deteriorates (defined as an increase in S_cr of ≥1 mg/dL) in patients with a baseline S_cr of ≥1.4 mg/dL, withhold therapy until S_cr returns to within 10% of baseline levels.^{1 3 7} Reinitiate therapy at the same dosage that was used prior to the treatment interruption.¹ Studies in this patient population included individuals with S_cr <3 mg/dL.^{1 3 7}

Osteoporosis

IV

Dosage adjustments not necessary in patients with Cl_cr ≥35 mL/minute.¹⁷ Do not use in patients with Cl_cr<35 mL/minute.¹⁷

Paget Disease of Bone

IV

Dosage adjustments not necessary in patients with Cl_cr ≥35 mL/minute.¹⁷ Do not use in patients with Cl_cr<35 mL/minute.¹⁷

Geriatric Patients

No dosage recommendations at this time.¹

Cautions for Zoledronic Acid

Contraindications

• Known hypersensitivity to zoledronic acid, other bisphosphonates, or any ingredient in the formulation.^{1 2 17}

• Hypocalcemia (in patients with osteoporosis or Paget disease of bone).¹⁷

• Reclast also contraindicated in patients with Cl_cr <35 mL/minute or evidence of acute renal impairment.¹⁷

Warnings/Precautions

Fetal/Neonatal Morbidity

May cause fetal harm; use not recommended in pregnant women, and women of childbearing potential should avoid conception during therapy.^{1 17} (See Advice to Patients.)

Renal Effects

Risk of renal toxicity.^{1 2 3 4 7 17 38} Acute renal failure requiring dialysis and sometimes resulting in hospitalization and/or death reported during postmarketing experience with Reclast.^{17 38 42} Transient increases in S_cr also observed.⁴² Renal function deterioration progressing to renal failure and dialysis also observed in clinical trials and during postmarketing experience with Zometa; occurred following administration of higher than recommended doses and with usual dosages.¹

Evaluate renal function (S_cr or Cl_cr) prior to administering each dose and more frequently in patients at high risk of acute renal failure (e.g., geriatric patients, those receiving diuretic therapy).^{1 17}

Do not use Reclast in patients with Cl_cr <35 mL/minute or in those with evidence of acute renal impairment; use with caution in those with chronic renal impairment.¹⁷

Risk of renal toxicity appears to be increased in patients with underlying renal disease or other risk factors (e.g., dehydration, advanced age, concomitant use of nephrotoxic agents).^{1 17 38 42} Such risk factors should be identified and managed.^{1 17} To prevent renal impairment, appropriately hydrate patients prior to initiation of therapy.¹⁷ May correct transient increases in S_cr with administration of IV fluids.¹⁷

Weigh the risks versus the potential benefits of subsequent treatment in patients with hypercalcemia of malignancy and severe renal impairment if renal function deteriorates during therapy.¹

Metabolic Effects

Possible hypocalcemia, hypophosphatemia, or hypomagnesemia.^{1 17}

Correct hypocalcemia and manage other factors affecting bone and mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine) before initiating therapy in patients with Paget disease of bone or osteoporosis.¹⁷

Carefully monitor standard hypercalcemia-related metabolic parameters (e.g., serum concentrations of calcium, phosphate, magnesium, and potassium in patients with hypercalcemia of malignancy) following initiation of therapy.^{1 3 17} Short-term supplemental therapy may be necessary if hypocalcemia, hypophosphatemia, or hypomagnesemia occurs.^{1 3}

Osteonecrosis of the Jaw

Osteonecrosis and osteomyelitis of the jaw have been reported in cancer patients receiving bisphosphonates.^{1 12 13 14} Most patients were receiving concurrent chemotherapy and corticosteroids^{1 13 14} and the majority of cases were associated with dental procedures (e.g., tooth extraction).^{1 12 13 14}

A dental examination with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, glucocorticoids, poor oral hygiene).^{1 12 13} Avoid invasive dental procedures if possible during therapy in such patients.^{1 13}

Concomitant use with angiogenesis inhibitors may increase risk.¹

Musculoskeletal Effects

Severe and occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.¹ Time to onset of symptoms varied from 1 day to years (mean onset about 3 months) after treatment initiation.¹ Such pain generally improves following discontinuance of the drug, but may recur upon subsequent rechallenge.¹

Atypical Fracture of the Femur

Atypical (subtrochanteric or diaphyseal) femur fractures reported rarely with long-term use (>3 years) of bisphosphonates, mostly in patients receiving these drugs for osteoporosis.^{17 30 32 33} Often occurs with minimal or no trauma, and may be bilateral.^{17 29 30 32 36} Causality not established; atypical fractures also occur in osteoporotic patients not receiving bisphosphonates.^{17 30 31 32 33} Risk may be increased with concomitant use of glucocorticoid, estrogen, and proton-pump inhibitor therapy.^{17 32 34 35 37}

Evaluate patients who present with new thigh or groin pain for possibility of an atypical femoral fracture; include assessment of the contralateral limb.^{17 29 30 32} Consider interruption of bisphosphonate therapy in patients with manifestations of possible femoral fracture; weigh risks versus benefits of continued treatment.^{17 29} Discontinue if a femoral shaft fracture is confirmed.^{30 31 32}

Atrial Fibrillation

Although data are conflicting, possible increased risk of atrial fibrillation with use of bisphosphonates.^{21 22 23} FDA analysis of data from long-term (6 months to 3 years) controlled trials identified a higher rate of atrial fibrillation in patients receiving bisphosphonates (alendronate, ibandronate, risedronate, or zoledronic acid) versus placebo; however, only a few events reported in each study.²³ FDA is continuing to monitor this safety concern.²³

Hematologic Effects

Possible anemia; monitor hematocrit and hemoglobin regularly throughout treatment.¹

Respiratory Effects

Possible bronchoconstriction in aspirin-sensitive asthmatic patients.¹ Use with caution in such patients.¹

Formulation Considerations

Patients receiving Zometa should not receive Reclast or vice versa since both preparations contain the same active ingredient.^{1 17}

Specific Populations

Pregnancy

Category D.^{1 17} (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Not known if zoledronic acid is distributed into milk; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹ Because of long-term retention in bone, use recommended only if the potential benefit from the drug outweighs the possible risk.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

Possible age-related impaired renal function.¹ Careful renal function monitoring recommended.¹

Renal Impairment

Possible renal toxicity.^{1 17} (See Renal Effects under Cautions.)

Use in patients with hypercalcemia of malignancy and severe renal impairment only after consideration of other treatment options.^{1 3} Carefully weigh the possible benefits and risks of therapy.^{1 3} Use not recommended in patients with bone metastases and severe renal impairment.^{1 3}

Reclast contraindicated in patients with osteoporosis or Paget’s disease of bone who have a Cl_cr <35 mL/minute or in those with evidence of acute renal impairment; use with caution in those with chronic renal impairment.¹⁷

Common Adverse Effects

Patients with hypercalcemia of malignancy: Fever,^{1 2 3 5} nausea,^{1 2 3 5} constipation,^{1 2 3 5} anemia,^{1 2 3 5} dyspnea,^{1 2 3 5} diarrhea,^{1 2 3} progression of cancer,^{1 3} abdominal pain,^{1 2 3} insomnia,^{1 2 3} vomiting,^{1 2 3} urinary tract infection,^{1 3} anxiety,¹ hypophosphatemia,¹ confusion,^{1 2 3 5} agitation,¹ moniliasis,¹ hypokalemia,^{1 2 3 5} skeletal pain,^{1 3} cough,¹ hypotension,¹ hypomagnesemia.¹

Patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma: Nausea,^{1 3 5 7} fatigue,^{1 3 7} anemia,^{1 3 5 7} vomiting,^{1 3 7} fever,^{1 3 5 7} constipation,^{1 3 5 7} dyspnea,^{1 3 5 7} diarrhea,^{1 3 7} myalgia,¹ cough,^{1 7} edema of the lower extremities,^{1 7} arthralgia,^{1 3 7} headache,^{1 3 7} dizziness,^{1 3} weight loss,^{1 3 7} paresthesia,^{1 3} depression,^{1 3} abdominal pain,^{1 3} dehydration,^{1 3} limb pain,¹ decreased appetite,¹ neutropenia,^{1 3} urinary tract infection,^{1 3} hypoesthesia,^{1 3} anxiety,¹ alopecia,^{1 7} dermatitis,^{1 3} rigors,^{1 3} thrombocytopenia,³ dyspepsia,¹ upper respiratory tract infection.¹

Postmenopausal women with osteoporosis: Arthralgia,^{17 21} fever,^{17 21} headache,^{17 21} hypertension,¹⁷ myalgia,^{17 21} extremity pain,¹⁷ flu-like illness,^{17 21} dizziness,¹⁷ shoulder pain,¹⁷ diarrhea,¹⁷ bone pain,¹⁷ fatigue,¹⁷ chills,¹⁷ asthenia.¹⁷

Postmenopausal women with osteopenia: Headache, dizziness, hypoesthesia, hypertension, nausea, diarrhea, vomiting, dyspepsia, abdominal pain, constipation, arthralgia, myalgia, back pain, extremity pain, muscle spasms, musculoskeletal pain, bone pain, neck pain, generalized pain, pyrexia, chills, fatigue, asthenia, peripheral edema, noncardiac chest pain.¹⁷

Patients with corticosteroid-induced osteoporosis: Adverse effects generally similar to those reported in women with postmenopausal osteoporosis.¹⁷ Common adverse effects not reported or reported more frequently than in postmenopausal osteoporosis patients include abdominal pain, musculoskeletal pain, back pain, bone pain, extremity pain, nausea, and dyspepsia.¹⁷

Men with osteoporosis: Myalgia,¹⁷ fatigue,¹⁷ headache,¹⁷ musculoskeletal pain,¹⁷ pain (unspecified),¹⁷ chills,¹⁷ flu-like illness,¹⁷ abdominal pain,¹⁷ malaise,¹⁷ dyspnea.¹⁷

Patients with Paget’s disease of bone: Headache,¹⁷ nausea,¹⁷ dizziness,¹⁷ arthralgia,¹⁷ bone pain,¹⁷ influenza/flu-like illness,¹⁷ fever,¹⁷ fatigue,¹⁷ rigors,¹⁷ myalgia,¹⁷ diarrhea,¹⁷ constipation, lethargy,¹⁷ dypsnea,¹⁷ dyspepsia,¹⁷ pain.¹⁷

Does not inhibit CYP isoenzymes.¹

Drugs Eliminated by Renal Excretion

Potential pharmacokinetic interaction (increased exposure of concomitant drugs eliminated renally).¹⁷ Consider more frequent renal function monitoring in patients at high risk of renal impairment.¹⁷

Nephrotoxic Agents

Potential pharmacologic interaction (increased risk of renal toxicity).¹ Use concomitantly with caution.¹ (See Renal Effects under Cautions.)

Specific Drugs

Zoledronic Acid Pharmacokinetics

Absorption

Onset

Hypercalcemia of malignancy: Normocalcemia usually is apparent within 7–10 days.^{1 2 3}

Duration

Hypercalcemia of malignancy: Median time to recurrence (time to last corrected serum calcium concentration of <11.6 mg/dL) was 30 days.¹

Prostate cancer: Bone-related complications not observed within 10.5 months of therapy.¹

Bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Median time to first bone-related complication was 373 days.¹

Bone metastases of solid tumors other than breast or prostate cancer: Median time to the first bone-related complication was 230 days.¹

Special Populations

In adults with mild or moderate renal impairment, the AUC is increased 15 or 43%, respectively, compared with patients with normal renal function.¹

Distribution

Extent

Distributes rapidly to skeletal tissues.¹ Subsequently, the drug is released systemically via bone turnover.¹ Not known whether distributed into breast milk.¹

Plasma Protein Binding

Approximately 22%.¹

Elimination

Metabolism

No evidence of metabolism.¹

Elimination Route

In patients with cancer and bone metastases, excreted in urine (39% within 24 hours) as unchanged drug.¹

Half-life

Terminal half-life is 146 hours.¹

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment and in pediatric patients.¹

Pharmacokinetics not affected by age or race in patients with cancer and bone metastases.¹

Stability

Storage

Parenteral

Solution for Injection

25°C (may be exposed to 15–30°C).^{1 17}

After opening vials, stable for 24 hours at 2–8°C.¹⁷

If the injection concentrate is not used immediately following dilution, may store at 2–8°C; total time between dilution, storage, and administration should not exceed 24 hours.¹

Compatibility

Do not admix with other agents.¹

Solution Compatibility1

Actions

• Incorporates into bone and selectively inhibits osteoclast-mediated bone resorption.^{1 4 5}

• Inhibits increased osteoclastic activity and skeletal calcium release induced by tumors.¹

• Decreases serum calcium and phosphorus and increases urinary calcium and phosphorus excretion in patients with hypercalcemia of malignancy.¹

Advice to Patients

• Importance of calcium and vitamin D supplementation for maintenance of serum calcium concentrations in patients with Paget disease of bone, multiple myeloma and bone metastasis of solid tumors, or osteoporosis.^{1 17} Importance of contacting a clinician promptly if symptoms of hypocalcemia (e.g., numbness or tingling feeling [especially in or around the mouth], muscle spasms) occur.¹⁷

• Importance of informing a clinician if severe bone pain, joint pain, muscular pain, or jaw disease develops.²⁰

• Importance of informing a clinician if new thigh or groin pain develops.³⁰

• Importance of informing patients that zoledronic acid should not be used in patients with severe renal impairment.¹⁷

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 3} Advise women of childbearing potential to avoid pregnancy.¹ If pregnant, apprise of potential fetal hazard.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant conditions (e.g., kidney disease, aspirin sensitivity).¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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