Note: When appropriate, correct preexisting hypocalcemia and vitamin D deficiency (eg, to a 25-hydroxyvitamin D level ≥20 ng/mL [≥50 nmol/L]) and establish adequate calcium and vitamin D intake (diet and/or supplement) prior to infusion (Ref). Consider delaying therapy initiation until dental health is optimized to reduce the risk of osteonecrosis of the jaw (Ref). Acetaminophen administration after the infusion may reduce symptoms of acute-phase (influenza-like) reactions.
Oncology uses:
Bone metastases from 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 (Ref). In patients with extensive or highly symptomatic bone disease, consider 4 mg once every 4 weeks initially until bone disease is stabilized, then transition to 4 mg once every 12 weeks (Ref).
Duration of therapy: May continue indefinitely in patients with metastatic breast cancer, although the optimal duration of therapy has not been established in breast cancer or prostate cancer (Ref).
Breast cancer, bone loss associated with aromatase inhibitor therapy in postmenopausal patients (off-label use):
Note: May be used in patients 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 (Ref).
IV: 4 mg once every 6 months (Ref) or 5 mg once every 12 months (Ref). The optimal duration of therapy has not been established; therapy is typically continued for 3 to 5 years (Ref).
Breast cancer, early stage, adjuvant therapy in postmenopausal patients (off-label use):
Note: May be considered in patients with a moderate to high risk of distant recurrence (≥10%) receiving adjuvant systemic therapy (Ref).
IV: 4 mg once every 6 months for 3 years or 4 mg once every 3 months for 2 years (Ref).
Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL [≥3 mmol/L]) (Zometa):
Note: May also be used at the same dose for treatment of hypercalcemia due to excessive bone resorption from other causes (eg, granulomatous diseases, hyperparathyroidism, vitamin D intoxication) (Ref). Asymptomatic or mildly symptomatic patients with chronic hypercalcemia may not require immediate treatment unless albumin-corrected serum calcium level is >14 mg/dL (>3.5 mmol/L) (Ref).
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 (Ref). May consider zoledronic acid for any patient with active multiple myeloma requiring treatment (Ref), although some reserve zoledronic acid for only those with osteolytic lesions, osteoporosis, or osteopenia (Ref).
IV: 4 mg once every 3 to 4 weeks (Ref).
Extended dosing interval (off-label dosing): IV: 4 mg once every 12 weeks may be considered in patients with stable/responsive disease (Ref).
Duration of therapy: Continue for up to 2 years, then reassess risks and benefits; resume therapy upon relapse (Ref).
Prostate cancer, bone loss associated with androgen deprivation therapy (alternative agent) (off-label use):
Note: For use in patients 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) (Ref).
IV: 5 mg once every 12 months (Ref) or 4 mg once every 6 to 12 months (Ref). The optimal duration of therapy has not been established; current studies provide results for up to 36 months of therapy (Ref).
Nononcology uses:
Osteoporosis, fracture risk reduction (alternative agent): Note: Prior to use, evaluate and treat any potential causes of secondary osteoporosis (eg, severe vitamin D deficiency) (Ref).
Males and postmenopausal females:
Patients with high fracture risk, including those with a history of fragility fracture, or males ≥50 years of age and postmenopausal females with a T-score of −2.5 or lower or a T-score between −1 and −2.5 at high fracture risk according to a risk assessment (Ref):
Treatment: IV: 5 mg once every 12 months (Ref).
Patients without high fracture risk, including those with a T-score between −1 and −2.5 and who are not at high fracture risk according to a risk assessment, but who desire pharmacologic therapy for prevention of bone loss or fracture (Ref):
Prevention: IV: 5 mg once every 2 years (Ref) or 5 mg as a single (one-time) dose (Ref).
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 (Ref).
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 (Ref). In younger males and premenopausal females, patient selection must be individualized (Ref). Avoid use in females who are pregnant, who plan on becoming pregnant, or who are not using effective birth control (Ref).
IV: 5 mg once every 12 months (Ref).
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 (Ref).
Paget disease (Ref):
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 (Ref).
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 (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Patients with kidney impairment may be predisposed to nephrotoxicity and symptomatic hypocalcemia (Ref). Prior to each dose, obtain SCr and calculate the CrCl using the Cockcroft-Gault formula with actual body weight (Ref).
Nononcology indications:
Altered kidney function:
CrCl ≥35 mL/minute: No dosage adjustment is necessary; use with caution in patients with CrCl <80 mL/minute (Ref).
CrCl <35 mL/minute or evidence of acute kidney impairment: Use contraindicated due to increased risk of nephrotoxicity and lack of efficacy and safety data. Use in patients with adynamic bone disease may further suppress bone formation and theoretically increase the risk of fracture and vascular calcification (Ref).
Hemodialysis, intermittent (thrice weekly): Unknown dialyzability; use contraindicated due to lack of efficacy and safety data. Use in patients with adynamic bone disease may further suppress bone formation and theoretically increase the risk of fracture and vascular calcification (Ref).
Peritoneal dialysis: Unknown dialyzability; use contraindicated due to lack of efficacy and safety data. Use in patients with adynamic bone disease may further suppress bone formation and theoretically increase the risk of fracture and vascular calcification (Ref).
Oncology indications:
Dosage adjustment for renal impairment prior to initiating zoledronic acid treatment:
Multiple myeloma and bone metastases of solid tumors:
|
CrCl |
Recommended dose |
|---|---|
|
aAnderson 2018; manufacturer's labeling. | |
|
>60 mL/minute |
4 mg (no dosage adjustment necessary) |
|
50 to 60 mL/minute |
3.5 mg |
|
40 to <50 mL/minute |
3.3 mg |
|
30 to <40 mL/minute |
3 mg |
|
<30 mL/minute |
Use not recommended |
Hemodialysis, intermittent (thrice weekly): Unknown dialyzability; use not recommended unless benefit outweighs risk. If necessary, some experts consider usual or reduced doses monthly in patients who are permanently on dialysis (Ref).
Peritoneal dialysis: Use not recommended as nephrotoxicity is a concern and this patient population often has residual kidney function (Ref).
Hypercalcemia of malignancy:
SCr ≤4.5 mg/dL: No dosage adjustment necessary (Ref).
SCr >4.5 mg/dL: Use not recommended unless benefit outweighs risk; these patients were excluded from clinical trials (Ref); consider alternative agent when available. If necessary, some experts administer 2 to 4 mg and extend the infusion duration to 30 to 60 minutes (Ref).
Hemodialysis, intermittent (thrice weekly): Unknown dialyzability: Use not recommended unless benefit outweighs risk (Ref). Based on a single case report (for immobilization-induced hypercalcemia), a reduced dose of 3 mg may also be considered (Ref).
Peritoneal dialysis: Unknown dialyzability: Avoid use; consider alternative agent. If necessary, a reduced dose and/or extending the infusion duration to 30 to 60 minutes may be considered (Ref). Monitor closely for nephrotoxicity since peritoneal dialysis patients often have residual kidney function (Ref).
Dosage adjustment for renal toxicity during zoledronic acid treatment:
Hypercalcemia of malignancy: Evidence of renal deterioration: Evaluate risk versus benefit.
Multiple myeloma (Ref):
Renal deterioration without an apparent cause: Withhold therapy; may resume at the prior dose when renal function returns to within 10% of baseline.
Albuminuria >500 mg per 24 hours (unexplained): Withhold dose until return to baseline, then reevaluate every 3 to 4 weeks; consider reinitiating with a longer infusion time of 30 minutes or longer.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, zoledronic acid is not metabolized hepatically.
(For additional information see "Zoledronic acid: Pediatric drug information")
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 (Ref):
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 (Ref):
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.
There are no pediatric dosage adjustments provided in the manufacturer's labeling; based on adult experience, dosage adjustment may be needed for mild renal impairment (ie, CrCl 35 to 60 mL/minute) and use avoided in moderate and severe impairment (ie, CrCl <35 mL/minute) and acute renal insufficiency (Ref).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, zoledronic acid is not metabolized hepatically.
Refer to adult dosing.
Femoral shaft fracture: Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.
Musculoskeletal pain, severe: Consider discontinuing therapy in patients who experience severe symptoms.
Ocular symptoms (conjunctivitis, uveitis, episcleritis, iritis, scleritis, or orbital inflammation): Ocular symptoms may resolve with topical steroids in some cases.
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])
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Intravenous:
Zometa: 4 mg/5 mL (5 mL)
Generic: 4 mg/5 mL (5 mL)
Solution, Intravenous:
Aclasta: 5 mg/100 mL (100 mL)
Generic: 5 mg/100 mL (100 mL)
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Reclast: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021817s028lbl.pdf#page=25
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 (Ref).
IV: IV infusion over 30 minutes; administer via a central or peripheral line (Ref).
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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 of malignancy (albumin-corrected serum calcium ≥12 mg/dL [≥3 mmol/L]).
Multiple myeloma: Zometa: Treatment of multiple myeloma.
Osteoporosis, fracture risk reduction: 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.
Paget disease: Reclast, Aclasta [Canadian product]: Treatment of Paget disease of bone. 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).
Breast cancer, bone loss associated with aromatase inhibitor therapy in postmenopausal patients; Breast cancer, early stage, adjuvant therapy in postmenopausal patients; Prostate cancer, bone loss associated with androgen deprivation therapy
Zometa may be confused with Jevtana, Xgeva, Xofigo, Xtandi, Zejula, Zofran, Zoladex, Zytiga
Duplicate therapy issues: Reclast and Aclasta contain zoledronic acid, which is the same ingredient contained in Zometa; patients receiving Zometa should not be treated with Reclast or Aclasta
Acute kidney injury, typically presenting as acute tubular necrosis, may occur with zoledronic acid. This adverse reaction may vary in severity and reversibility (Ref).
Mechanism: Dose- and time-related; typical pathology is acute tubular necrosis (Ref).
Risk factors:
• Higher doses (Ref)
• Repeated infusions (Ref)
• Short infusion times (Ref)
• Concurrent nephrotoxic agents (eg, nonsteroidal anti-inflammatory drugs) (Ref)
• History of treatment with other bisphosphonates (Ref)
• Preexisting kidney impairment (Ref)
• Dehydration (Ref)
• Older patients (Ref)
• Myeloma or renal cell cancer (Ref)
• Current or prior therapy with cisplatin (Ref)
Atrial fibrillation may occur with zoledronic acid (Ref). This adverse reaction is debated in the literature; however, a recent meta-analysis noted that although this adverse reaction is rare, it can occur, especially in patients with risk factors (Ref). The same meta-analysis reported no increased risk of stroke or cardiovascular death with the use of zoledronic acid (Ref).
Mechanism: Dose-related; postulated to be a function of the alterations in intracellular ion concentrations, as well as pro-inflammatory and anti-angiogenic properties of the drug (Ref).
Onset: Varied; typically occurs >30 days postinfusion (Ref).
Risk factors:
• Higher doses (Ref)
• Concurrent cardiotoxic chemotherapy agents (Ref)
• Preexisting risk factors for atrial fibrillation (eg, older age) (Ref)
Atypical femur fractures (AFF) have been reported with bisphosphonate use, including zoledronic acid. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). The benefits of therapy (when used for osteoporosis) generally outweigh the absolute risk of AFF within the first 5 years of treatment, especially in patients with high fracture risk (Ref). The risk decreases after bisphosphonate discontinuation (Ref). AFF is estimated to occur in ~0.2% of bisphosphonate users after ≥5 years of therapy (Ref).
Mechanism: Time-related. Long-term suppression of bone turnover may be primarily responsible; however, micro-damage accumulation and alterations of collagen cross-linking have also been postulated (Ref).
Onset: Delayed; Most fractures have occurred in patients receiving bisphosphonates for at least 3 to 5 years (Ref). Patients may experience prodromal pain weeks or months before the fracture occurs (Ref).
Risk factors:
• Long-term treatment (>3 to 5 years) (Ref)
• Asian race (in North America) (Ref)
• Femoral bowing (Ref)
• Glucocorticoid use (>1 year) (Ref)
While transient hypocalcemia is expected with the use of zoledronic acid (and all bisphosphonates) secondary to its mechanism of action; cases are typically mild and asymptomatic (Ref). Hypocalcemia is typically quickly reversible with either discontinuation of zoledronic acid or use of supportive care measures (Ref). In a systematic review of clinically significant hypocalcemia in patients receiving IV bisphosphonates for bone metastases (including zoledronic acid), incidence ranged from 1% to 2% (Ref).
Mechanism: By decreasing osteoclast activity, calcium is not released into the bloodstream, causing a transient decrease in blood calcium. In patients with normally functioning parathyroid glands, calcium homeostasis is regained shortly after starting the bisphosphonate (Ref).
Onset: Varied; dependent on dose and indication. Hypercalcemia of malignancy: 4 to 11 days (Ref); osteoporosis: 9 to 11 days (Ref).
Risk factors:
• Baseline hypocalcemia (Ref)
• Impaired kidney function (Ref)
• Impaired parathyroid function (Ref)
• IV bisphosphonate (Ref)
• Vitamin D deficiency (Ref)
• Hypomagnesemia (Ref)
• Concurrent medications (eg, interferon-alfa, aminoglycosides, loop diuretics) (Ref)
• Close dosing intervals (Ref)
Acute phase reaction-like symptoms/flu-like symptoms are not life-threatening, are reversible, and typically either not observed beyond the first dose of the bisphosphonate or symptoms are less significant with subsequent exposure (Ref). The reaction can manifest as influenza-like symptoms, such as fatigue, arthralgia, and bone pain as well as fever and rigors (Ref). Resolution is usually observed within 2 to 3 days after symptom onset but may last up to 7 to 14 days (Ref).
One study showed decreased persistence with follow-up zoledronic acid infusions in patients who experienced this adverse reaction (Ref).
Mechanism: Appears to be mediated by interleukin-6, tumor necrosis factor (TNF)-alpha and other pro-inflammatory cytokines (Ref).
Onset: Rapid; typically manifests within the first 3 days (Ref).
Risk factors:
• Low pretreatment 25-OH Vitamin D levels (Ref)
• Asian race (other than Japanese) (Ref)
• Younger patients (Ref)
• Nitrogen-containing bisphosphonates (eg, zoledronic acid) (Ref)
Osteonecrosis of the jaw (ONJ) was first described in the dental literature (Ref) with the use of IV bisphosphonates, and several case reports of ONJ with IV zoledronic acid used for osteoporosis exist. The possibility of ONJ increases the risk of nonadherence dramatically (Ref).
Mechanism: Dose- and time-related; the exact mechanism unknown, but several hypothesized mechanisms exist, such as over-suppression of bone turnover (Ref), mucosal toxicity (Ref), cytokine-mediated inflammation (Ref), and infection (Ref).
Onset: Varied; can be spontaneous or after insult, such as tooth extraction and/or dental implant procedures (Ref).
Risk factors:
• Alcohol use disorder (Ref)
• Anemia (Ref)
• Cancer and anticancer therapy (Ref)
• Corticosteroid therapy (Ref)
• Dental extraction and/or dental implant procedures (Ref)
• Diabetes (Ref)
• Extended duration (>3 years) of bisphosphonate (Ref)
• High-dose, IV bisphosphonate (Ref)
• Immunological disorders (Ref)
• Oral surgery or trauma (Ref)
• Poor oral hygiene (Ref)
• Poorly fitting dental appliance (Ref)
• Radiotherapy to head and neck (Ref)
• Tobacco smoking (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Oncology indications:
>10%:
Cardiovascular: Hypotension (11%), lower extremity edema (5% to 21%)
Dermatologic: Alopecia (12%), dermatitis (11%)
Endocrine & metabolic: Dehydration (5% to 14%), hypokalemia (12%), hypomagnesemia (11%), hypophosphatemia (13%), weight loss (16%)
Gastrointestinal: Abdominal pain (14% to 16%), anorexia (9% to 22%), constipation (27% to 31%), decreased appetite (13%), diarrhea (17% to 24%), nausea (29% to 46%), vomiting (14% to 32%)
Genitourinary: Urinary tract infection (12% to 14%)
Hematologic & oncologic: Anemia (22% to 33%), neutropenia (12%), progression of cancer (16% to 20%)
Infection: Candidiasis (12%)
Nervous system: Agitation (13%), anxiety (11% to 14%), confusion (7% to 13%), depression (14%), dizziness (18%), fatigue (39%), headache (5% to 19%), hypoesthesia (12%), insomnia (15% to 16%), paresthesia (15%), rigors (11%)
Neuromuscular & skeletal: Arthralgia (5% to 21%), asthenia (5% to 24%), back pain (15%), limb pain (14%), myalgia (23%), ostealgia (55%), skeletal pain (12%)
Renal: Renal insufficiency (8% to 15%; up to 40% in patients with abnormal baseline creatinine) (table 1)
|
Drug (Zoledronic Acid) |
Comparator (Pamidronate) |
Placebo |
Dose |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Pamidronate) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|---|
|
11% |
9% |
N/A |
4 mg |
Multiple myeloma and breast cancer |
246 |
246 |
N/A |
Normal baseline creatinine (<1.4 mg/dL) |
|
8% |
9% |
N/A |
4 mg |
Multiple myeloma and breast cancer |
26 |
22 |
N/A |
Abnormal baseline creatinine (≥1.4 mg/dL) |
|
40% |
N/A |
20% |
4 mg |
Prostate cancer |
10 |
N/A |
10 |
Abnormal baseline creatinine (≥1.4 mg/dL) |
|
15% |
N/A |
12% |
4 mg |
Prostate cancer |
82 |
N/A |
68 |
Normal baseline creatinine (<1.4 mg/dL) |
|
11% |
N/A |
7% |
4 mg |
Solid tumors |
154 |
N/A |
143 |
Normal baseline creatinine (<1.4 mg/dL) |
|
9% |
N/A |
5% |
4 mg |
Solid tumors |
11 |
N/A |
20 |
Abnormal baseline creatinine (≥1.4 mg/dL) |
Respiratory: Cough (12% to 22%), dyspnea (22% to 27%)
Miscellaneous: Fever (32% to 44%; most common symptom of acute phase reaction) (table 2)
|
Drug (Zoledronic Acid) |
Comparator (Pamidronate) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Pamidronate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|---|
|
32% |
31% |
20% |
4 mg |
IV |
Bone metastases |
1,031 |
556 |
455 |
|
44% |
33% |
N/A |
4 mg |
IV |
Hypercalcemia of malignancy |
86 |
103 |
N/A |
1% to 10%:
Cardiovascular: Chest pain (5% to 10%)
Endocrine & metabolic: Hypermagnesemia (grade 3: 2%), hypocalcemia (5% to 10%)
Gastrointestinal: Dyspepsia (10%), dysphagia (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%)
Nervous system: Drowsiness (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%)
Endocrine & metabolic: Hypocalcemia (osteoporosis: <1%; Paget disease: 3% to 21%) (table 3)
|
Drug (Zoledronic Acid) |
Comparator (Risedronate) |
Dose |
Dosage Form |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Risedronate) |
Comments |
|---|---|---|---|---|---|---|---|
|
0.2% |
N/A |
5 mg once per year |
IV |
Osteoporosis |
3,862 |
N/A |
N/A |
|
21% |
N/A |
5 mg single dose |
IV |
Paget disease of bone |
N/A |
N/A |
Transient; <8.4 mg/dL 9-11 days following Reclast administration |
|
3% |
1% |
5 mg single dose |
IV |
Paget disease of bone |
177 |
172 |
N/A |
Gastrointestinal: Nausea (12% to 18%)
Hypersensitivity: Acute phase reaction-like symptoms (4% to 25%) (table 4)
|
Drug (Zoledronic Acid) |
Comparator (Active Control) |
Comparator (Risedronate) |
Dose |
Dosage Form |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Active Control) |
Number of Patients (Risedronate) |
|---|---|---|---|---|---|---|---|---|
|
4% |
0% |
N/A |
5 mg once per year |
IV |
Osteoporosis, treatment (males) |
153 |
148 |
N/A |
|
25% |
N/A |
8% |
5 mg single dose |
IV |
Paget disease of bone |
177 |
N/A |
172 |
Nervous system: Chills (2% to 18%), fatigue (2% to 18%), headache (4% to 20%), pain (2% to 24%)
Neuromuscular & skeletal: Arthralgia (9% to 27%), back pain (4% to 18%), limb pain (3% to 16%), musculoskeletal pain (3% to 12%), myalgia (5% to 23%)
Respiratory: Flu-like symptoms (≤11%) (table 5)
|
Drug (Zoledronic Acid) |
Comparator |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|---|
|
9% |
Active control: 2% |
N/A |
5 mg once per year |
IV |
Osteoporosis, treatment (males) |
153 |
148 |
N/A |
|
9% |
N/A |
3% |
5 mg once per year |
IV |
Osteoporosis, treatment (postmenopausal females) |
3,862 |
N/A |
3,852 |
|
3% |
N/A |
2% |
5 mg once |
IV |
Osteoporosis, prevention |
181 |
N/A |
202 |
|
2% |
N/A |
2% |
5 mg once per year |
IV |
Osteoporosis, prevention |
198 |
N/A |
202 |
|
0.8% |
N/A |
0.4% |
5 mg once per year |
IV |
Osteoporosis, treatment (patients with recent hip fracture) |
1,054 |
N/A |
1,057 |
|
11% |
Risedronate: 6% |
N/A |
5 mg single dose |
IV |
Paget disease of bone |
177 |
172 |
N/A |
Miscellaneous: Fever (9% to 22%)
1% to 10%:
Cardiovascular: Atrial fibrillation (≤3%) (table 6), chest pain (1% to 8%), palpitations (≤3%), peripheral edema (3% to 6%)
|
Drug (Zoledronic Acid) |
Comparator |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Zoledronic Acid) |
Number of Patients (Comparator) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|---|
|
3% |
Active control: 2% |
N/A |
5 mg once per year |
IV |
Osteoporosis, treatment (males) |
153 |
148 |
N/A |
|
3% |
N/A |
3% |
5 mg once per year |
IV |
Osteoporosis, treatment (patients with recent hip fracture) |
1,054 |
N/A |
1,057 |
|
2% |
N/A |
2% |
5 mg once per year |
IV |
Osteoporosis, treatment (postmenopausal females) |
3,862 |
N/A |
3,852 |
|
0.7% |
Active control: 0% |
N/A |
5 mg |
IV |
Osteoporosis, glucocorticoid-induced |
416 |
417 |
N/A |
Dermatologic: Hyperhidrosis (≤3%), skin rash (2% to 3%)
Endocrine & metabolic: Dehydration (3%)
Gastrointestinal: Abdominal distension (≤2%), abdominal distress (1% to 2%), abdominal pain (≤9%), anorexia (≤2%), constipation (6% to 7%), diarrhea (6%), dyspepsia (5% to 7%), vomiting (2% to 8%)
Hematologic & oncologic: Change in serum protein (C-reactive protein increased; ≤5%)
Infection: Influenza (7%)
Local: Injection site reaction (3%)
Nervous system: Dizziness (6% to 9%), flank pain (≤2%), hyperthermia (≤2%), hypoesthesia (≤6%), lethargy (3% to 5%), malaise (1% to 7%), paresthesia (2%), rigors (8%)
Neuromuscular & skeletal: Arthritis (2% to 4%), asthenia (2% to 6%), jaw pain (2% to 4%), joint swelling (≤3%), muscle spasm (4% to 6%), neck pain (7%), ostealgia (3% to 9%), osteoarthritis (6%), shoulder pain (≤7%), stiffness (1% to 5%)
Ophthalmic: Eye pain (≤2%), iritis (1%), uveitis (1%)
Renal: Increased serum creatinine (2%)
Respiratory: Dyspnea (5% to 7%)
Postmarketing (all indications):
Cardiovascular: Bradycardia
Dermatologic: Diaphoresis, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Fanconi's syndrome (acquired) (Yoshinami 2011), hyperkalemia, hypernatremia, weight gain
Gastrointestinal: Dysgeusia, xerostomia
Genitourinary: Hematuria, proteinuria
Hypersensitivity: Anaphylactic shock, anaphylaxis, angioedema
Nervous system: Hyperesthesia
Neuromuscular & skeletal: Femur fracture (atypical diaphyseal and subtrochanteric) (Park-Wyllie 2011), muscle cramps, osteonecrosis (including ankle, external auditory canal, femur, hip, humerus, knee, and wrist), osteonecrosis of the jaw (Lewiecki 2011), tremor
Ophthalmic: Blurred vision, conjunctivitis, iridocyclitis, periorbital edema, periorbital swelling, scleritis (including episcleritis) (Umunakwe 2017)
Renal: Acute kidney injury (Edwards 2013)
Respiratory: Bronchoconstriction, bronchospasm, exacerbation of asthma, interstitial pulmonary disease
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.
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.
• 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; 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. Use with caution with other medications known to cause hypocalcemia (severe hypocalcemia may develop). 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. 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. 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.
• 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. Invasive dental procedures should be avoided during therapy, 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 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. 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.
• 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: 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: Do not use single doses >5 mg. 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 euvolemic. 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: Use is not recommended in patients with serum creatinine >3 mg/dL and bone metastases (limited data). In patients with cancer, do not use single doses >4 mg. 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.
Special populations:
• Older adult: Because decreased renal function occurs more commonly in older adults, 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.
Influenza-like reactions have been reported, most commonly after the first dose occurring at 12 to 48 hours after the first infusion, and may include fever, nausea and/or vomiting, myalgia, and bone pain; treatment with standard antipyretic therapy is recommended; symptoms usually do not return with subsequent doses (Bowden 2017; Högler 2004; Munns 2007).
May cause hypocalcemia; administration of a lower initial dose helps to reduce the risk and severity of hypocalcemia (Bowden 2017; Högler 2004; Munns 2007).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: 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. Risk C: Monitor therapy
Calcitonin: May enhance the hypocalcemic effect of Zoledronic Acid. Risk C: Monitor therapy
Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypocalcemic effect of Zoledronic Acid. Risk C: 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. Risk C: Monitor therapy
Thalidomide: May enhance the adverse/toxic effect of Zoledronic Acid. Specifically, the risk for ONJ or renal impairment may be increased. Risk C: Monitor therapy
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]).
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).
It is not known if zoledronic acid is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
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. Patients should consume:
Calcium: 1,000 mg/day (males: 50 to 70 years of age) or 1,200 mg/day (females ≥51 years of age and males ≥71 years of age) (IOM 2011; NOF [Cosman 2014]).
Vitamin D: 800 to 1,000 units/day (age ≥50 years) (NOF 2014). Recommended dietary allowance (RDA): 600 units/day (age ≤70 years) or 800 units/day (age ≥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.
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 patients who could become pregnant). Monitor for signs/symptoms of atypical femur fractures, musculoskeletal pain, and signs of ocular inflammation (may require further ophthalmologic evaluation).
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 2020]; 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, (including calcium, phosphate, magnesium), and hemoglobin/hematocrit should be evaluated regularly throughout treatment. 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 >500 mg/24 hours, 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]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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
Protein binding: 23% to 53%
Metabolism: Primarily eliminated intact via the kidney; metabolism not likely
Half-life elimination: Triphasic; Terminal: 146 hours
Excretion: Urine (39% ± 16% as unchanged drug) within 24 hours; feces (<3%)
Altered kidney function: 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.
Concentrate (Zoledronic Acid Intravenous)
4 mg/5 mL (per mL): $9.00 - $167.66
Solution (Reclast Intravenous)
5 mg/100 mL (per mL): $13.01
Solution (Zoledronic Acid Intravenous)
4 mg/100 mL (per mL): $0.57 - $2.16
5 mg/100 mL (per mL): $1.31 - $4.20
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