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Zoledronic Acid

Medically reviewed by Drugs.com. Last updated on Sep 24, 2020.

Pronunciation

(zoe le DRON ik AS id)

Index Terms

  • CGP-42446
  • Zol 446
  • Zoledronate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Concentrate, Intravenous:

Generic: 4 mg/5 mL (5 mL)

Concentrate, Intravenous [preservative free]:

Zometa: 4 mg/5 mL (5 mL [DSC])

Generic: 4 mg/5 mL (5 mL)

Solution, Intravenous:

Zometa: 4 mg/100 mL (100 mL [DSC])

Generic: 4 mg/100 mL (100 mL)

Solution, Intravenous [preservative free]:

Reclast: 5 mg/100 mL (100 mL)

Generic: 4 mg/100 mL (100 mL); 5 mg/100 mL (100 mL)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 4 mg (1 ea [DSC])

Brand Names: U.S.

  • Reclast
  • Zometa [DSC]

Pharmacologic Category

  • Bisphosphonate Derivative

Pharmacology

Zoledronic acid is a bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; it inhibits osteoclastic activity and skeletal calcium release induced by tumors. Decreases serum calcium and phosphorus, and increases their elimination. In osteoporosis, zoledronic acid inhibits osteoclast-mediated resorption, therefore reducing bone turnover.

Distribution

Binds to bone

Metabolism

Primarily eliminated intact via the kidney; metabolism not likely

Excretion

Urine (39% ± 16% as unchanged drug) within 24 hours; feces (<3%)

Half-Life Elimination

Triphasic; Terminal: 146 hours

Protein Binding

23% to 53%

Special Populations: Renal Function Impairment

Mild renal impairment (CrCl 50 to 80 mL/minute) increased AUC by an average of 15%. Moderate renal impairment (CrCl 30 to 50 mL/minute) increased AUC by an average of 43%. The risk of renal deterioration appears to increase with AUC, which doubled at a CrCl of 10 mL/minute.

Use: Labeled Indications

Bone metastases, solid tumors: Zometa: Treatment of documented bone metastases from solid tumors (in conjunction with standard antineoplastic therapy). Prostate cancer should have progressed following treatment with at least one hormonal therapy.

Hypercalcemia of malignancy: Zometa: Treatment of hypercalcemia (albumin-corrected serum calcium ≥12 mg/dL) of malignancy.

Limitations of use: Safety and efficacy for treatment of hypercalcemia associated with hyperparathyroidism or with other non–tumor-related conditions have not been established.

Multiple myeloma: Zometa: Treatment of multiple myeloma.

Osteoporosis: Reclast, Aclasta [Canadian product]: Treatment and prevention of osteoporosis in postmenopausal females; treatment to increase bone mass in males with osteoporosis; treatment and prevention of glucocorticoid-induced osteoporosis in males and females.

Paget disease: Reclast, Aclasta [Canadian product]: Treatment of Paget disease of bone in males and females. Note: Zoledronic acid is considered the most efficacious bisphosphonate with respect to treating bone pain as well as suppressing metabolic bone activity. In patients without contraindications, Endocrine Society guidelines as well as some international guidelines recommend zoledronic acid as the treatment of choice (ES [Singer 2014]; Ralston 2019).

Off Label Uses

Breast cancer, bone loss associated with aromatase inhibitor therapy in postmenopausal females

Data from a randomized, 5-year, open-label, multicenter trial support the use of zoledronic acid in the prevention of bone loss associated with aromatase inhibitor therapy in postmenopausal females with breast cancer [Brufsky 2012].

Based on the American Society of Clinical Oncology (ASCO) guidelines for the management of osteoporosis in survivors of adult cancers with nonmetastatic disease, zoledronic acid should be considered to reduce the risk of fracture in postmenopausal women who are receiving aromatase inhibitor therapy and are at elevated risk of bone loss and/or fracture [ASCO [Shapiro 2019]].

Breast cancer, early stage, adjuvant therapy in postmenopausal females

A systematic review, which included studies in women with early breast cancer, demonstrated an advantage (reduced risk of bone metastases) with adjuvant use of bisphosphonate therapy (including zoledronic acid) in postmenopausal females [O'Carrigan 2017].

Based on the ASCO and Cancer Care Ontario (CCO) guidelines for the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer, zoledronic acid should be considered as adjuvant therapy for postmenopausal women (including females with natural menopause or induced by ovarian ablation/suppression) with nonmetastatic breast cancer who are candidates for adjuvant therapy [ASCO [Dhesy-Thind 2017]].

According to ASCO guidelines for management of male breast cancer, men with early breast cancer should not be treated with bone-modifying agents to prevent recurrence, although they may receive bone-modifying agents for prevention or treatment of osteoporosis [ASCO [Hassett 2020]].

Prostate cancer, bone loss associated with androgen deprivation therapy

Data from 2 randomized, placebo-controlled studies support the use of zoledronic acid (in conjunction with calcium and vitamin D supplementation) for the prevention of bone loss associated with androgen deprivation therapy in nonmetastatic prostate cancer [Michaelson 2007], [Smith 2003].

Based on the ASCO guidelines for the management of osteoporosis in survivors of adult cancers with nonmetastatic disease, zoledronic acid should be considered to reduce the risk of fracture in men who have received or are receiving androgen deprivation therapy and are at elevated risk of bone loss and/or fracture [ASCO [Shapiro 2019]].

According to the CCO guidelines for bone health and bone-targeted therapies for prostate cancer and the ASCO endorsement of the CCO guidelines, zoledronic acid may be considered as an alternative to denosumab to reduce the risk of fracture in men who are receiving androgen deprivation therapy and are at high risk of fracture when denosumab is not available or is contraindicated [ASCO [Saylor 2020]], [CCO [Alibhai 2017]].

Contraindications

US labeling:

Hypersensitivity to zoledronic acid or any component of the formulation; hypocalcemia (Reclast only); CrCl <35 mL/minute and in those with evidence of acute renal impairment (Reclast only).

Canadian labeling:

All indications: Hypersensitivity to zoledronic acid or other bisphosphonates, or any component of the formulation; uncorrected hypocalcemia at the time of infusion; pregnancy, breast-feeding

Nononcology uses: Additional contraindications: Use in patients with CrCl <35 mL/minute and use in patients with evidence of acute renal impairment due to an increased risk of renal failure

Documentation of allergenic cross-reactivity for bisphosphonates is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Acetaminophen administration after the infusion may reduce symptoms of acute-phase (influenza-like) reactions. Establish adequate calcium and vitamin D intake (diet and/or supplement) prior to infusion when appropriate. Consider delaying therapy initiation until dental health is optimized to reduce the risk of osteonecrosis of the jaw (AAOMS [Ruggiero 2014]).

Oncology uses:

Bone metastases, solid tumors (Zometa):

IV: 4 mg once every 3 to 4 weeks.

Breast cancer or castration-resistant prostate cancer, extended dosing interval (off-label dosing): IV: 4 mg once every 12 weeks; dosing once every 12 weeks (versus every 4 weeks) did not result in an increased risk of skeletal events within 2 years in patients with at least 1 site of bone involvement (Himelstein 2017; Hortobagyi 2017). May consider 4 mg once every 4 weeks until bone disease is stabilized, then transition to 4 mg once every 12 weeks (Van Poznak 2020b).

Duration of therapy: May continue indefinitely in patients with breast cancer, although the optimal duration of therapy has not been established in breast cancer or prostate cancer (ASCO [Saylor 2020]; ASCO/CCO [Van Poznak 2017]).

Breast cancer, bone loss associated with aromatase inhibitor therapy in postmenopausal females (off-label use):

Note: May be used in females at elevated risk of bone loss and/or fracture (eg, T-score −2.5 or lower, prior fragility fracture, or T-score between −1 and −2.5 at high fracture risk according to a risk assessment tool (ASCO [Shapiro 2019]).

IV: 4 mg once every 6 months (ASCO [Shapiro 2019]; Brufsky 2012) or 5 mg once every 12 months (ASCO [Shapiro 2019]). The optimal duration of therapy has not been established; therapy is typically continued for 3 to 5 years (Brufsky 2012; Gnant 2008).

Breast cancer, early stage, adjuvant therapy in postmenopausal females (off-label use):

Note: May be considered in females with a moderate to high risk of distant recurrence (≥10%) receiving adjuvant systemic therapy (ASCO [Dhesy-Thind 2017]; Hadji 2016; Van Poznak 2020a).

IV: 4 mg once every 6 months for 3 to 5 years (ASCO [Dhesy-Thind 2017]).

Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL) (Zometa):

Note: Asymptomatic or mildly symptomatic patients with chronic hypercalcemia may not require immediate treatment unless albumin-corrected serum calcium level is >14 mg/dL (Shane 2020).

IV: 4 mg (maximum) given as a single dose. May repeat dose after 7 days if hypercalcemia persists.

Multiple myeloma (Zometa):

Note: For use in conjunction with standard multiple myeloma therapy (ASCO [Anderson 2018]; Mhaskar 2017). May consider zoledronic acid for any patient with active multiple myeloma requiring treatment (ASCO [Anderson 2018]), although some reserve zoledronic acid for only those with osteolytic lesions, osteoporosis, or osteopenia (Berenson 2020; Lacy 2006).

IV: 4 mg once every 3 to 4 weeks (ASCO [Anderson 2018]; Rosen 2001; Rosen 2003).

Extended dosing interval (off-label dosing): IV: 4 mg once every 12 weeks may be considered in patients with stable/responsive disease (ASCO [Anderson 2018]; Himelstein 2017).

Duration of therapy: Continue for up to 2 years, then reassess risks and benefits; resume therapy upon relapse (ASCO [Anderson 2018]).

Prostate cancer, bone loss associated with androgen deprivation therapy (alternative agent) (off-label use):

Note: For use in males without bone metastases treated long-term with androgen deprivation therapy who are at elevated risk of osteoporotic fractures (eg, T-score −2.5 or lower, prior fragility fracture, or T-score between −1 and −2.5 at high fracture risk according to a risk assessment tool) (ASCO [Saylor 2020]; ASCO [Shapiro 2019]).

IV: 5 mg once every 12 months (ASCO [Shapiro 2019]; CCO [Alibhai 2017]) or 4 mg once every 6 to 12 months (ASCO [Shapiro 2019]; Michaelson 2007). The optimal duration of therapy has not been established; current studies provide results for up to 36 months of therapy (ASCO [Saylor 2020]; CCO [Alibhai 2017).

Nononcology uses:

Osteoporosis, prevention of fractures (alternative agent): Note: Prior to use, evaluate and treat any potential causes of secondary osteoporosis (eg, hypogonadism in males) (ES [Watts 2012]).

Males and postmenopausal females:

High fracture risk patients, including those with a history of fragility fracture or males ≥50 years of age and postmenopausal females with a T-score −2.5 or lower or a T-score between −1 and −2.5 at high fracture risk according to a risk assessment tool (ES [Watts 2012]; Finkelstein 2020; NOF [Cosman 2014]):

Treatment: IV: 5 mg once every 12 months (Reclast, Aclasta [Canadian product]).

Patients with T-scores between −1 and −2.5 and not at high fracture risk according to a risk assessment tool but who desire pharmacologic therapy for prevention of bone loss and/or fracture (Lewiecki 2020; NOF [Cosman 2014]):

Prevention: IV: 5 mg once every 2 years (Reclast) or 5 mg as a single (one-time) dose (Aclasta [Canadian product]).

Duration of therapy: The optimal duration of treatment has not been established. Consider discontinuing after 3 years if bone mineral density (BMD) is stable, there have been no previous fragility fractures, and short-term fracture risk is low. If fracture risk remains high (eg, fragility fracture before or during therapy), consider extending treatment for up to 6 years or switching to alternative therapy. If discontinued, the decision to resume treatment is based on multiple factors, including decline in BMD, duration of discontinuation, and risk factors for fracture (Adler 2016; ES [Eastell 2019]; Watts 2010).

Glucocorticoid-induced:

Note: For use in males ≥50 years of age and postmenopausal females with low bone mineral density (T-scores between 1 and 2.5 in either group) and expected to receive systemic glucocorticoid therapy for at least 3 months at a prednisone dose of ≥7.5 mg/day (or its equivalent) or in any patient whose baseline risk of fracture is high and who is receiving a glucocorticoid at any dose or duration (ACR [Buckley 2017]). In younger males and premenopausal females, patient selection must be individualized (Rosen 2020). Avoid use in females who are pregnant, who plan on becoming pregnant, or who are not using effective birth control (ACR [Buckley 2017]).

IV: 5 mg once every 12 months (Reclast, Aclasta [Canadian product]).

Duration of therapy: The optimal duration of treatment has not been established; duration should be individualized based on continuation of glucocorticoid therapy and fracture risk (ACR [Buckley 2017]; NOGG [Compston 2017]).

Paget disease (Reclast, Aclasta [Canadian product]):

Note: For symptomatic patients with active disease and select patients with asymptomatic disease at risk of future complications, or 1 to 3 months prior to planned surgery at an active pagetic site (Charles 2020; ES [Singer 2014]).

Initial: IV: 5 mg as a single dose.

Re-treatment: IV: A repeat 5 mg dose may be considered after 12 months in patients with biochemical relapse (eg, increase in alkaline phosphatase), radiographic progression of disease, or recurrent pain. Intensive re-treatment based on increased biochemical markers alone is not routinely recommended (Ralston 2019; Tan 2017).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Osteoporosis, primary or secondary: Limited data available: Note: Acetaminophen or ibuprofen 30 minutes prior to infusion and 6 hours after is recommended to reduce acute phase reactions (eg, flu-like symptoms including low-grade fever, nausea, myalgias, and fatigue).

Children <2 years (Bowden 2017):

First dose: IV: 0.0125 mg/kg/dose.

Maintenance (to begin 3 months after first dose): IV: 0.025 mg/kg/dose every 3 months.

Children ≥2 years and Adolescents (Bowden 2017; Munns 2007; Trejo 2016):

First dose: IV: 0.0125 mg/kg/dose.

Second dose (3 months after first dose): IV: 0.025 mg/kg/dose.

Maintenance (to begin 6 months after first dose): IV: 0.05 mg/kg/dose every 6 months; maximum dose: 4 mg/dose.

Dose adjustment based on lumbar spine bone mineral density (BMD) Z score: Children ≥2 years and Adolescents:

BMD Z score >−2: Decrease dose to 0.025 mg/kg/dose every 6 months.

BMD Z score >0: Decrease dose to 0.025 mg/kg/dose every 12 months.

Reconstitution

Solution for injection:

Concentrate vials (4 mg/5 mL): Further dilute in 100 mL NS or D5W prior to administration.

Premixed bag (4 mg/100 mL): No further preparation is necessary. If reduced doses are required for patients with renal impairment, withdraw the specified volume of solution using an IV bag transfer device and discard withdrawn volume; label premixed bag with appropriate final drug content and final volume.

Ready-to-use bottles (4 mg/100 mL and 5 mg/100 mL): No further preparation is necessary. If reduced doses are required for patients with renal impairment, withdraw the appropriate volume of solution and replace with an equal amount of NS or D5W.

Administration

IV: If refrigerated, allow solution to reach room temperature before administration. Infuse over at least 15 minutes. Flush IV line with 10 mL NS flush following infusion. Infuse in a line separate from other medications. Patients must be appropriately hydrated prior to treatment. Acetaminophen after administration may reduce the incidence of acute reaction (eg, arthralgia, fever, flu-like symptoms, myalgia).

Multiple myeloma: If treatment is withheld for unexplained albuminuria, consider increasing the infusion time to at least 30 minutes upon reinitiation (ASCO [Anderson 2018]).

Dietary Considerations

Multiple myeloma or metastatic bone lesions from solid tumors: Take daily calcium supplement (500 mg) and daily multivitamin (with 400 units vitamin D).

Osteoporosis: Ensure adequate calcium and vitamin D intake; if dietary intake is inadequate, dietary supplementation is recommended. Males and females should consume:

Calcium: 1,000 mg/day (males: 50 to 70 years) or 1,200 mg/day (females ≥51 years and males ≥71 years) (IOM 2011; NOF [Cosman 2014]).

Vitamin D: 800 to 1,000 int. units/day (males and females ≥50 years) (NOF 2014). Recommended Dietary Allowance (RDA): 600 int. units/day (males and females ≤70 years) or 800 int. units/day (males and females ≥71 years) (IOM 2011).

Paget disease: Take elemental calcium 1,500 mg/day (750 mg twice daily or 500 mg 3 times/day) and vitamin D 800 units/day, particularly during the first 2 weeks after administration.

Storage

Solution for injection:

Aclasta [Canadian product]: Store at room temperature of 15°C to 30°C (59°F to 86°F). Keep sealed in original package until administration.

Reclast: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). After opening, stable for 24 hours at 2°C to 8°C (36°F to 46°F). If refrigerated, allow the refrigerated solution to reach room temperature before administration.

Zoledronic acid 4 mg/100 mL premixed bag: Store at a temperature of ≤30°C (86°F); protect from freezing.

Zometa: Store concentrate vials and ready-to-use bottles at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Diluted solutions for infusion in D5W or NS which are not used immediately after preparation should be refrigerated at 2°C to 8°C (36°F to 46°F). Infusion of solution must be completed within 24 hours of preparation. The ready-to-use bottles are for single use only; if any preparation is necessary (preparing reduced dosage for patients with renal impairment), the prepared, diluted solution may be refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately. Infusion of solution must be completed within 24 hours of preparation. The previously withdrawn volume from the ready-to-use solution should be discarded; do not store or reuse.

Drug Interactions

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Angiogenesis Inhibitors (Systemic): May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Calcitonin: May enhance the hypocalcemic effect of Zoledronic Acid. Monitor therapy

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Thalidomide: May enhance the adverse/toxic effect of Zoledronic Acid. Monitor therapy

Test Interactions

Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Oncology indications:

>10%:

Cardiovascular: Lower extremity edema (5% to 21%), hypotension (11%)

Central nervous system: Fatigue (39%), headache (5% to 19%), dizziness (18%), insomnia (15% to 16%), depression (14%), anxiety (11% to 14%), agitation (13%), confusion (7% to 13%), hypoesthesia (12%), rigors (11%)

Dermatologic: Alopecia (12%), dermatitis (11%)

Endocrine & metabolic: Dehydration (5% to 14%), hypophosphatemia (13%), hypokalemia (12%), hypomagnesemia (11%)

Gastrointestinal: Nausea (29% to 46%), vomiting (14% to 32%), constipation (27% to 31%), diarrhea (17% to 24%), anorexia (9% to 22%), weight loss (16%), abdominal pain (14% to 16%), decreased appetite (13%)

Genitourinary: Urinary tract infection (12% to 14%)

Hematologic & oncologic: Anemia (22% to 33%), progression of cancer (16% to 20%), neutropenia (12%)

Infection: Candidiasis (12%)

Neuromuscular & skeletal: Ostealgia (55%), weakness (5% to 24%), myalgia (23%), arthralgia (5% to 21%), back pain (15%), paresthesia (15%), limb pain (14%), skeletal pain (12%)

Renal: Renal insufficiency (8% to 17%; up to 40% in patients with abnormal baseline creatinine)

Respiratory: Dyspnea (22% to 27%), cough (12% to 22%)

Miscellaneous: Fever (32% to 44%; most common symptom of acute phase reaction)

1% to 10%:

Cardiovascular: Chest pain (5% to 10%)

Central nervous system: Somnolence (5% to 10%)

Endocrine & metabolic: Hypocalcemia (5% to 10%; grades 3/4: ≤1%), hypermagnesemia (grade 3: 2%)

Gastrointestinal: Dyspepsia (10%), dysphagia (5% to 10%), mucositis (5% to 10%), sore throat (8%), stomatitis (8%)

Hematologic & oncologic: Granulocytopenia (5% to 10%), pancytopenia (5% to 10%), thrombocytopenia (5% to 10%)

Infection: Infection (nonspecific; 5% to 10%)

Renal: Increased serum creatinine (grades 3/4: ≤2%)

Respiratory: Upper respiratory tract infection (10%)

Nononcology indications:

>10%:

Cardiovascular: Hypertension (5% to 13%)

Central nervous system: Pain (2% to 24%), fever (9% to 22%), headache (4% to 20%), chills (2% to 18%), fatigue (2% to 18%), flank pain (≤2%)

Endocrine & metabolic: Hypocalcemia (≤3%; Paget disease 21%), dehydration (3%)

Gastrointestinal: Nausea (5% to 18%), upper abdominal pain (5%), abdominal distension (≤2%)

Immunologic: Infusion-related reaction (4% to 25%)

Neuromuscular & skeletal: Arthralgia (9% to 27%), myalgia (5% to 23%), back pain (4% to 18%), limb pain (3% to 16%), musculoskeletal pain (≤12%), osteoarthritis (6%)

Respiratory: Flu-like symptoms (1% to 11%)

1% to 10%:

Cardiovascular: Chest pain (1% to 8%), peripheral edema (3% to 6%), atrial fibrillation (1% to 3%), palpitations (≤3%)

Central nervous system: Dizziness (2% to 9%), rigors (8%), malaise (1% to 7%), hypoesthesia (≤6%), lethargy (3% to 5%), vertigo (1% to 4%), paresthesia (2%), hyperthermia (≤2%)

Dermatologic: Skin rash (2% to 3%), hyperhidrosis (≤3%)

Gastrointestinal: Abdominal pain (1% to 9%), diarrhea (5% to 8%), vomiting (2% to 8%), constipation (6% to 7%), dyspepsia (2% to 7%), abdominal discomfort (1% to 2%), anorexia (1% to 2%)

Hematologic & oncologic: Change in serum protein (C-reactive protein increased; ≤5%)

Neuromuscular & skeletal: Ostealgia (3% to 9%), arthritis (2% to 9%), neck pain (1% to 7%), shoulder pain (≤7%), muscle spasm (2% to 6%), weakness (2% to 6%), stiffness (1% to 5%), jaw pain (2% to 4%), joint swelling (≤3%)

Ophthalmic: Eye pain (≤2%)

Renal: Increased serum creatinine (2%)

Respiratory: Dyspnea (5% to 7%)

All indications: <1%, postmarketing, and/or case reports: Acute phase reaction-like symptoms (including pyrexia, fatigue, bone pain, arthralgia, myalgia, chills, influenza-like illness; usually resolves within 3 to 4 days of onset, although may take up to 14 days to resolve), acute renal failure (requiring hospitalization/dialysis), acute renal tubular necrosis (toxic), anaphylactic shock, anaphylaxis, angioedema, arthralgia (sometimes severe and/or incapacitating), blurred vision, bradycardia, bronchoconstriction, bronchospasm, cardiac arrhythmia, cerebrovascular accident, conjunctivitis, diaphoresis, drowsiness, dysgeusia, episcleritis, exacerbation of asthma, Fanconi syndrome (acquired), femur fracture (diaphyseal or subtrochanteric), hematuria, hyperesthesia, hyperkalemia, hypernatremia, hyperparathyroidism, hypersensitivity reaction, hypertension, injection site reaction (eg, itching, pain, redness), interstitial pulmonary disease, iridocyclitis, iritis, muscle cramps, myalgia (sometimes severe and/or incapacitating), numbness, osteonecrosis (including external auditory canal, femur, and hip), osteonecrosis of the jaw, periorbital edema, periorbital swelling, prolonged QT interval on ECG, proteinuria, pruritus, renal insufficiency, scleritis, seizure, skin rash, Stevens-Johnson syndrome, tetany, toxic epidermal necrolysis, tremor, urticaria, uveitis, weight gain, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures (AFF) have been reported in patients receiving bisphosphonates. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures; AFFs have also been reported in patients not taking bisphosphonates, and in patients receiving glucocorticoids. Patients receiving long-term (>3 years) IV bisphosphonate therapy may be at an increased risk (Adler 2016; NOF [Cosman 2014]); however, benefits of therapy (when used for osteoporosis) generally outweigh absolute risk of AFF within the first 3 years of treatment, especially in patients with high fracture risk (Adler 2016; ES [Eastell 2019]). Patients presenting with thigh or groin pain with a history of receiving bisphosphonates should be evaluated for femur fracture. Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.

• Hypersensitivity reactions: Rare cases of urticaria and angioedema and very rare cases of anaphylactic reactions/shock have been reported.

• Hypocalcemia: Hypocalcemia (including severe and life-threatening cases) has been reported with use; patients with Paget disease may be at significant risk for hypocalcemia after treatment with zoledronic acid (because pretreatment rate of bone turnover may be elevated); severe and life-threatening hypocalcemia has also been reported with oncology-related uses. Measure serum calcium prior to treatment initiation. Correct preexisting hypocalcemia before initiation of therapy in patients with Paget disease, osteoporosis, or oncology indications. Use with caution with other medications known to cause hypocalcemia (severe hypocalcemia may develop). Ensure adequate calcium and vitamin D supplementation during therapy. Use caution in patients with disturbances of calcium and mineral metabolism (eg, hypoparathyroidism, thyroid/parathyroid surgery, malabsorption syndromes, excision of small intestine). QTc prolongation, cardiac arrhythmias, and neurologic events (eg, tetany, tonic-clonic seizures, numbness) secondary to severe hypocalcemia have been reported 1 day to several months after initiation of therapy.

• Influenza-like illness/acute phase reaction: A transient acute phase reaction (eg, fever, chills, pain/myalgia, other influenza-like symptoms) may occur, typically within 3 days following the initial infusion; resolution is usually observed ~3 days after symptom onset but can take up to 14 days. Prophylactic use of acetaminophen may reduce symptoms. The incidence of symptoms may decrease with subsequent infusions.

• Musculoskeletal pain: Severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with the same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• Ocular effects: Conjunctivitis, uveitis, episcleritis, iritis, scleritis, and orbital inflammation have been reported with zoledronic acid; patients presenting with signs of ocular inflammation may require further ophthalmologic evaluation. Ocular symptoms resolved with topical steroids in some cases.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, bony surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental disease). Risk may increase with duration of bisphosphonate use and/or may be reported at a greater frequency based on tumor type (eg, advanced breast cancer or multiple myeloma). According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with monthly IV antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The manufacturer's labeling states that there are no data to suggest whether discontinuing bisphosphonates in patients requiring invasive dental procedures reduces the risk of ONJ. The manufacturer recommends a dental exam and preventive dentistry be performed prior to placing patients with risk factors on chronic bisphosphonate therapy and that during therapy, invasive dental procedures be avoided, if possible. The AAOMS suggests that if medically permissible, initiation of IV bisphosphonates for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiresorptive therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once IV bisphosphonate therapy is initiated for oncologic disease, procedures that involve direct osseous injury and placement of dental implants be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]).

Disease-related concerns:

• Aspirin-sensitive asthma: Use with caution in patients with aspirin-sensitive asthma; may cause bronchoconstriction.

• Breast cancer (metastatic): The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) has updated guidelines on the role of bone-modifying agents (BMAs) in metastatic breast cancer patients (ASCO/CCO [Van Poznak 2017]). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. One BMA is not recommended over another (evidence supporting one BMA over another is insufficient). The optimal duration of BMA therapy is not defined; however, the guidelines recommend continuing BMA therapy indefinitely. The analgesic effect of BMAs are modest and BMAs should not be used alone for pain management; supportive care, analgesics, adjunctive therapies, radiation therapy, surgery, and/or systemic anticancer therapy should be utilized. The ASCO/CCO guidelines are in alignment with prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. BMAs are not the first-line therapy for pain.

• Multiple myeloma: The American Society of Clinical Oncology (ASCO) has updated guidelines on bone-modifying agents in multiple myeloma (ASCO [Anderson 2018]). Bisphosphonate (pamidronate or zoledronic acid) therapy should be initiated in patients with radiographic or imaging evidence of lytic bone disease. Bisphosphonates may also be considered in patients with pain secondary to osteolytic disease and as adjunct therapy in patients receiving other interventions for fractures or impending fractures. The guidelines support utilizing IV bisphosphonates in patients with multiple myeloma and osteopenia (osteoporosis) but no radiographic evidence of lytic bone disease. Bisphosphonates are not recommended in patients with solitary plasmacytoma, smoldering (asymptomatic) or indolent myeloma with osteopenia in the absence of lytic bone disease. Bisphosphonates are also not recommended in monoclonal gammopathy of undetermined significance unless osteopenia (osteoporosis) also is present. The guidelines recommend monthly treatment for a period of up to 2 years (less frequent dosing may be considered in patients with stable/responsive disease). After 2 years, consider discontinuing in responsive and stable patients, and reinitiate upon relapse if a new-onset skeletal-related event occurs. The ASCO guidelines are in alignment with prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. According to the guidelines, in patients with a serum creatinine >3 mg/dL or CrCl <30 mL/minute or extensive bone disease, an alternative bisphosphonate (pamidronate) should be used. Monitor for albuminuria every 3 to 6 months; in patients with unexplained albuminuria >500 mg/24 hours, withhold the dose until level returns to baseline, then recheck every 3 to 4 weeks. Upon reinitiation, the guidelines recommend considering increasing the zoledronic acid infusion time to at least 30 minutes; however, one study has demonstrated that extending the infusion to 30 minutes did not change the safety profile (Berenson 2011).

• Osteoporosis in survivors of adult cancers (nonmetastatic disease): Survivors of adult cancers with nonmetastatic disease who have osteoporosis (T score of -2.5 or lower in femoral neck, total hip, or lumbar spine) or who are at increased risk of osteoporotic fractures, should be offered bone-modifying agents (utilizing the osteoporosis-indicated dose) to reduce the risk of fracture. For patients without hormonal responsive cancers, when clinically appropriate, estrogens may be administered along with other bone-modifying agents (ASCO [Shapiro 2019]). The choice of bone-modifying agent (eg, oral or IV bisphosphonates or subcutaneous denosumab) should be based on several factors (eg, patient preference, potential adverse effects, quality of life considerations, availability, adherence, cost). Adequate calcium and vitamin D intake, exercise (using a combination of exercise types), as well as lifestyle modifications (if indicated) should also be encouraged.

• Prostate cancer: According to guidelines, denosumab is preferred over bisphosphonates in men with nonmetastatic prostate cancer receiving androgen deprivation therapy; however, bisphosphonates may be considered in situations where denosumab is unavailable or contraindicated. Bisphosphonates are not recommended to reduce the risk of first bone metastasis in men with high-risk localized prostate cancer. For preventing or delaying skeletal-related events in men with metastatic castrate-resistant prostate cancer (mCRPC), either zoledronic acid (minimally symptomatic or asymptomatic disease) or denosumab (independent of symptoms) is recommended (both at bone metastasis-indicated dosages). There is not enough evidence to make a recommendation for men with castrate-sensitive prostate cancer and bone metastases. IV bisphosphonates may be considered for palliation in men with mCRPC and bone pain. Adequate calcium and vitamin D intake, exercise (using a combination of exercise types), as well as lifestyle modifications (if indicated) are also recommended (ASCO [Saylor 2020]; CCO [Alibhai 2017]).

• Renal impairment: Use with caution in mild to moderate renal impairment. Single and multiple infusions in patients with both normal and impaired renal function have been associated with renal deterioration, resulting in renal failure and dialysis (rare). Preexisting renal compromise, severe dehydration, and concurrent use with diuretics or other nephrotoxic drugs may increase the risk for renal impairment. Adequate hydration is required during treatment (urine output ~2 L/day); avoid overhydration, especially in patients with heart failure.

Nononcology indications: Use is contraindicated in patients with CrCl <35 mL/minute and in patients with evidence of acute renal impairment. Do not use single doses >5 mg and do not infuse over less than 15 minutes. Patients with underlying moderate to severe renal impairment, increased age, concurrent use of nephrotoxic or diuretic medications, or severe dehydration prior to or after zoledronic acid administration may have an increased risk of acute renal impairment or renal failure. Others with increased risk include patients with renal impairment or dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic use. If history or physical exam suggests dehydration, treatment should not be given until the patient is normovolemic. Obtain serum creatinine and calculate creatinine clearance (using actual body weight) with the Cockcroft-Gault formula prior to each administration. Transient increases in serum creatinine may be more pronounced in patients with impaired renal function; monitoring creatinine clearance in at-risk patients taking other renally eliminated drugs is recommended.

Oncology indications: Dosage adjustment required with renal impairment. Use is not recommended in patients with severe renal impairment (serum creatinine >3 mg/dL or CrCl <30 mL/minute) and bone metastases (limited data); use in patients with hypercalcemia of malignancy and severe renal impairment (serum creatinine >4.5 mg/dL for hypercalcemia of malignancy) should only be done if the benefits outweigh the risks. In cancer patients, do not use single doses >4 mg and do not infuse over less than 15 minutes (renal toxicity has been reported with doses >4 mg or infusions administered over less than 15 minutes). Risk factors for renal deterioration include preexisting renal insufficiency and repeated doses and other bisphosphonates therapy. Dehydration and the use of other nephrotoxic drugs which may contribute to renal deterioration should be identified and managed. Diuretics should not be used before correcting hypovolemia. Assess renal function (eg, serum creatinine) prior to each dose and withhold for renal deterioration (increase in serum creatinine of 0.5 mg/dL [if baseline level normal] or increase of 1 mg/dL [if baseline level abnormal]); treatment should be withheld until renal function returns to within 10% of baseline.

Special populations:

• Elderly: Because decreased renal function occurs more commonly in elderly patients, take special care to monitor renal function.

Other warnings/precautions:

• Duplicate therapy: Do not administer Zometa and Reclast (Aclasta [Canadian product]) to the same patient for different indications.

Monitoring Parameters

Prior to initiation of therapy, dental exam and preventive dentistry for patients at risk for osteonecrosis, including all cancer patients. Evaluate pregnancy status prior to use (in females of reproductive potential).

Nononcology uses: Serum creatinine prior to each dose, especially in patients with risk factors, calculate creatinine clearance before each treatment (consider interim monitoring in patients at risk for acute renal failure), evaluate fluid status and adequately hydrate patients prior to and following administration.

Osteoporosis: Serial bone mineral density (BMD) should be evaluated at baseline and every 1 to 3 years on treatment (usually at ~2 years following initiation of therapy, then more or less frequently depending on patient-specific factors and stability of BMD) (AACE/ACE [Camacho 2016]; ES [Eastell 2019]; NOF [Cosman 2014]); evaluate BMD every 2 to 4 years during a drug holiday (ES [Eastell 2019]); in patients with combined zoledronic acid and glucocorticoid treatment, evaluate BMD at initiation of glucocorticoid therapy and after 6 to 12 months, then every 2 to 3 years if patient continues to have significant osteoporosis risk factors (ACR [Buckley 2017]); serum calcium and 25(OH)D; annual measurements of height and weight, assessment of chronic back pain; phosphorus and magnesium; may consider monitoring biochemical markers of bone turnover (eg, fasting serum CTX or urinary NTX) at baseline, 3 months, and 6 months, to assess treatment response (ES [Eastell 2019]).

Paget disease: Serum total alkaline phosphatase at 6 to 12 weeks for initial response to treatment (when bone turnover will have shown a substantial decline) and potentially at 6 months (maximal suppression of high bone turnover); following treatment completion, monitor at ~1- to 2-year intervals (ES [Singer 2014]); monitoring more specific biochemical markers of bone turnover (eg, serum P1NP, NTX, serum beta-CTx) is generally only warranted in patients with Paget disease who have abnormal liver or biliary tract function or when early assessment of response to treatment is needed (eg, spinal compression, very active disease) (ES [Singer 2014]); serum calcium and 25(OH)D; phosphorus and magnesium; symptoms of hypocalcemia, pain (posttreatment pain may not strictly correlate with increased biochemical markers [Ralston 2019]).

Oncology uses: Serum creatinine prior to each dose; serum electrolytes, phosphate, magnesium, and hemoglobin/hematocrit should be evaluated regularly. Monitor serum calcium to assess response and avoid overtreatment. In patients with multiple myeloma, monitor urine every 3 to 6 months for albuminuria.

Multiple myeloma: Monitor serum creatinine (prior to each dose), serum calcium (regularly); vitamin D levels (intermittently), spot urine sample for albuminuria (every 3 to 6 months; for unexplained albuminuria, obtain 24 urine collection to assess urinary albumin; reassess every 3 to 4 weeks with 24-hour urine collection for total protein and urine protein electrophoresis until renal function returns to baseline) (ASCO [Anderson 2018]).

Reproductive Considerations

Evaluate pregnancy status prior to use. Females of reproductive potential should use effective contraception during and after treatment with zoledronic acid.

Underlying causes of osteoporosis should be evaluated and treated prior to considering bisphosphonate therapy in premenopausal women; effective contraception is recommended when bisphosphonate therapy is required (Pepe 2020). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Because exposure prior to pregnancy may theoretically increase the risk of fetal harm, most sources recommend discontinuing bisphosphonate therapy in females of reproductive potential as early as possible prior to a planned pregnancy. Use in premenopausal females should be reserved for special circumstances when rapid bone loss is occurring; a bisphosphonate with the shortest half-life should be then used (Bhalla 2010; Pereira 2012; Stathopoulos 2011).

Oral bisphosphonates can be considered for the prevention of glucocorticoid-induced osteoporosis in premenopausal females with moderate to high risk of fracture who do not plan to become pregnant during the treatment period and are using effective birth control (or are not sexually active); intravenous therapy should be reserved for high risk patients only (ACR [Buckley 2017]).

Pregnancy Considerations

It is not known if bisphosphonates cross the placenta, but fetal exposure is expected (Djokanovic 2008; Stathopoulos 2011).

Information specific to zoledronic acid exposure during pregnancy is limited (Djokanovic 2008; Richa 2018). Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by dose and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy; however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic 2008; Green 2014; Levy 2009; Machairiotis 2019; Sokol 2019; Stathopoulos 2011). Because hypocalcemia has been described following in utero bisphosphonate exposure, exposed infants should be monitored for hypocalcemia after birth (Djokanovic 2008; Stathopoulos 2011).

Patient Education

What is this drug used for?

• It is used to treat high calcium levels in patients with cancer.

• It is used when treating some cancers.

• It is used to treat Paget's disease.

• It is used to prevent or treat soft, brittle bones (osteoporosis).

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness

• Upset stomach

• Throwing up

• Stomach pain

• Heartburn

• Flu-like symptoms

• Diarrhea

• Back pain

• Neck pain

• Painful extremities

• Anxiety

• Hair loss

• Trouble sleeping

• Not hungry

• Constipation

• Cough

• Weight loss

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, feeling tired or weak, not hungry, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or upset stomach or throwing up

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower stomach pain, or pelvic pain

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Severe bone pain

• Severe joint pain

• Severe muscle pain

• Groin, hip, or thigh pain

• Agitation

• Shortness of breath

• Burning or numbness feeling

• Depression

• Chest pain

• Vision changes

• Eye pain

• Severe eye irritation

• Trouble swallowing

• Severe pain with swallowing

• Chills

• Sore throat

• Bruising

• Bleeding

• Feeling very tired or weak

• Swelling of arms or legs

• Vaginal pain, itching, and discharge

• Jaw pain or swelling

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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