Zoledronic acid (also known as zoledronate) is an intravenous (IV), heterocyclic, nitrogen-containing bisphosphonate; it is considered a third-generation bisphosphonate. Zoledronic acid is a potent inhibitor of bone resorption, making it useful in a variety of skeletal-related conditions, including hypercalcemia of malignancy, multiple myeloma, bone metastases due to solid tumors, Paget's disease, and the treatment and prevention of osteoporosis. The drug also displays some antitumor activity. Zoledronic acid has a shorter IV administration time and a prolonged response time compared to other bisphosphonates, and medication adherence may be improved in using this drug over other bisphosphonates for selected patients. Generally, either IV zoledronic acid and pamidronate are considered to be appropriate and equally effective treatments for hypercalcemia of malignancy; however, one pooled analysis comparing the two drugs found that zoledronic acid was more potent than pamidronate in reducing serum calcium and provided a longer duration of response. Clinical practice guidelines support the use of bisphosphonates for the treatment of bone metastases in patients with multiple myeloma and breast cancer; IV pamidronate and zoledronic acid are generally considered equally effective in reducing skeletal-related adverse events in cancer patients at risk. Bisphosphonates are generally considered to be first-line therapy for the treatment of osteoporosis in postmenopausal women. Bisphosphonates are effective in men with osteoporosis to increase bone density and reduce the risk for vertebral fracture; however, study data are less robust in men regarding reductions in nonvertebral fractures. For osteoporosis prevention, the second and third-generation bisphosphonates appear to offer similar benefits across the class to increase bone mineral density; the balance of costs, benefits, and harms of treating osteopenic patients with bisphosphonates is most favorable when the estimated risk for fracture is high. Zoledronic acid is also indicated for osteoporosis prevention and treatment in adults receiving chronic corticosteroid treatment. Guidelines for Paget's disease consider zoledronic acid the treatment of choice for these patients due to its ability to normalize alkaline phosphatase in 89% of patients with a single dose, stabilize osteolytic lesions, improve quality of life, and provide a durable response; retreatment is rarely needed within 5 years. Zoledronic has been used off-label to preserve bone density in selected cancer or organ transplant patients at risk due to underlying conditions or medical therapy that commonly produce osteopenia. Zoledronic acid products are based on the indication for use and clinicians are advised to use care in product selection and dosage to ensure the proper product and dosage is administered to patients. Adequate calcium and vitamin D intake are necessary for all patients during treatment with any potent bisphosphonate therapy for indications other than hypercalcemia.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
-Zoledronic acid is available as more than one indication-specific brand name product (e.g., Zometa, Reclast). Be sure to choose the proper product for the patient's indication for use prior to preparation and administration. Avoid duplications.
-Assess serum creatinine and ensure the proper hydration of the patient prior to each administration of zoledronic acid.
-For intravenous infusion only.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-For patients receiving Reclast regimens, ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.
Intravenous Administration
Dilution of zoledronic acid 4 mg/5 mL concentrate prior to infusion (e.g., Zometa):
-Must be diluted for infusion prior to use.
-Determine patient-specific dose, then use aseptic technique to withdraw 5 mL of concentrate for 4 mg dose, 4.4 mL for 3.5 mg dose, 4.1 mL for 3.3 mg dose, or 3.8 mL for 3 mg dose.
-Further dilute the dose in 100 mL of 0.9% Sodium Chloride injection or 5% Dextrose injection immediately.
-Do NOT mix in calcium-containing solutions (such as Lactated Ringer's).
-Vials are intended for single-use only. Discard any unused concentrate; do not store undiluted concentrate in a syringe.
-Storage of prepared infusions: If not used immediately after dilution, the solution should be refrigerated at 2 to 8 degrees C (36 to 46 degrees F). If refrigerated, allow the infusion to reach room temperature before administration. The total time between dilution and administration must not exceed 24 hours.
Zoledronic acid 4 mg/100 mL ready-to-use solution for IV infusion (e.g., Zometa):
-This product does not require further dilution for a 4-mg dose.
-Remove infusion overwrap just before use.
-After removing overwrap, check for small leaks by squeezing inner bag. Use the container only if no leaks are found and the solution is clear and container undamaged.
-Preparation for reduced doses:
--For a dose of 3.5 mg remove and discard 12 mL of solution.
-For a dose of 3.3 mg remove and discard 18 mL.
-For a 3 mg dose remove and discard 25 mL.
-Replace the solution that was removed with an equal amount of 0.9% Sodium Chloride injection or 5% Dextrose injection. Do not store or reuse any removed solution.
-Storage: If the infusion is diluted for dose adjustment and not used immediately, the solution should be refrigerated at 2 to 8 degrees C (36 to 46 degrees F). If refrigerated, allow the infusion to reach room temperature before administration. The total time between removal from storage, dilution, and administration must not exceed 24 hours.
Zoledronic acid 5 mg/100 mL ready-to-use solution for infusion (e.g., Reclast):
-This product does not require further dilution.
-Remove infusion overwrap just before use.
-After removing overwrap, check for small leaks by squeezing inner bag. Use the container only if no leaks are found and the solution is clear and container undamaged.
-If refrigerated, allow the infusion to reach room temperature before administration.
Intravenous (IV) infusion administration:
-Administer via a separate, vented IV line. Do NOT administer with other intravenous agents.
-Do not allow to come in contact with any calcium- or divalent cation-containing solutions.
-Due to a risk of clinically significant renal toxicity, do not exceed the recommended dose for the specific indication. Do not infuse over less than 15 minutes. Administer at a constant infusion rate.
-Following the infusion, the manufacturer of Reclast recommends a 10 mL 0.9% Sodium Chloride injection flush of the IV line.
-Administration of acetaminophen following administration may reduce the incidence of acute-phase reaction symptoms.
Conflicting data exists regarding the use of bisphosphonates and an increased risk of serious atrial fibrillation. In the HORIZON Pivotal Fracture Trial, the incidence of serious atrial fibrillation (life-threatening or resulting in hospitalization or disability) was significantly higher in patients receiving zoledronic acid than placebo (50 patients or 1.3% vs. 20 patients or 0.5%, p < 0.001), although the incidence of any atrial fibrillation (serious and non-serious) was not different between the 2 groups. Similarly, in a re-analysis of the Fracture Intervention Trial, patients taking alendronate also experienced a trend towards a higher incidence of serious atrial fibrillation vs. those taking placebo (47 patients or 1.5% vs. 31 patients or 1%, HR 1.51, 95% CI 0.97 to 2.40, p = 0.07). Similar to the HORIZON trial, any atrial fibrillation was not higher in patients taking alendronate. No difference in serious or any occurrence of atrial fibrillation (adjudicated) was demonstrated in a controlled trial of zoledronic acid in men and women with osteoporosis and recent hip fracture, 11 patients or 1% (active drug) vs. 13 patients or 1.2% (placebo). In a trial involving men with osteoporosis, atrial fibrillation occurred in 5 patients or 3.3% who received zoledronic acid vs. 3 patients or 2% in an active control group; no serious atrial fibrillation occurred in either group. The incidence of atrial fibrillation was 0.7% in a trial evaluating zoledronic acid for the treatment and prevention of glucocorticoid-induced osteoporosis. Postmarketing surveillance of reports of atrial fibrillation in patients receiving oral and intravenous bisphosphonates has not revealed a subset of patients at risk for the adverse effect. In the majority of cases in patients who received zoledronic acid, atrial fibrillation occurred > 1 month after drug infusion. In order to review the potential risk of atrial fibrillation in patients receiving bisphosphonates, the FDA requested placebo-controlled clinical trial data from manufacturers. Information submitted to the FDA by 4 manufacturers included data from 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed up for 6 months through 3 years. After reviewing these data, the FDA concluded that most studies contained 2 or fewer events of atrial fibrillation. The absolute difference in event rates between each of the bisphosphonate and placebo arms varied from 0 to 3 per 1,000. No association between bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was found. In addition, an increase in dose or duration of bisphosphonate therapy did not correlate with an increased rate of atrial fibrillation. Because of the conflicting data in the literature, the FDA is exploring the feasibility of conducting additional epidemiologic studies to gather more data. The FDA continues to monitor postmarketing reports of atrial fibrillation in patients who have taken bisphosphonates. Currently, the FDA does not recommend a change in prescribing practices for this class of drugs; a causal relationship has not been identified.
Symptoms including arthralgia, myalgia, and bone pain, sometimes reported as severe and even incapacitating, may be experienced by patients receiving injectable zoledronic acid. In clinical trials, arthralgia occurred in 5% to 27.3% of patients and myalgia occurred in 4.9% to 23%. Bone pain occurred in 3.1% to 9% of patients during trials for osteoporosis treatment and prevention, 12% in trials of hypercalcemia of malignancy, and 55% in bone metastases trials. Musculoskeletal pain was reported in 0.4% to 12.4% of patients during osteoporosis trials and musculoskeletal stiffness in 2% to 4.6%. Other types of pain with respective incidences include extremity or limb pain (3.1% to 14%), shoulder pain (6.9%), neck pain (1.4% to 6.6%), back pain (4% to 18.2%), flank pain (0.6% to 2%), and jaw pain (2% to 3.9%). Joint swelling, joint stiffness, and arthritis occurred in up to 3%, 3.5%, and 9.1% of patients, respectively. Muscle spasms were reported in 1.5% to 5.6% of patients, and muscle cramps have been reported during postmarketing surveillance. The time to onset of symptoms varies from 1 day to years after drug initiation. Most patients have relief of symptoms after stopping the medication; a subset have had recurrence when rechallenged with the same drug or another bisphosphonate. Risk factors for and the incidence of bone, muscle, and/or joint pain are not known. In children with osteogenesis imperfecta, arthralgia was reported by 26% of the patients receiving zoledronic acid. These reactions are different than the acute phase reaction of bone, muscle, and/or joint pain that accompanies intermittent intravenous or weekly or monthly oral bisphosphonates. The acute phase reaction tends to resolve with continued use. Bisphosphonates should be considered as a cause for any patient who presents with severe musculoskeletal or joint pain; furthermore, if zoledronic acid is determined to be the cause, temporary or permanent discontinuation in drug therapy should be considered.
Systemic adverse reactions have been reported with zoledronic acid with sustained use during treatment courses and in acute phase reactions, occurring within 3 days after a dose and typically resolving 3 to 14 days after onset. Acute phase reactions have occurred in up to 25% of patients. During clinical trials for osteoporosis and Paget's disease (using Reclast), fever was reported in up to 21.7% of patients, with 7% to 19.3% occurring during acute phase reactions. The total incidence of fever was 32% to 44% in trials for hypercalcemia of malignancy and bone metastases (using Zometa), with 44% occurring during acute phase reactions; 61% of children with osteogenesis imperfecta reported fever during 1 clinical trial. Other reactions with noticeable differences in incidence rates between Reclast and Zometa trial patient populations include chills and asthenia (or weakness). Chills have been reported in up to 18.2% of patients given Reclast, with 9.8% to 18.2% occurring during the acute phase. Asthenia or weakness has been reported in up to 6.1% and 24% of patients given Reclast and Zometa, respectively, with none noted during the acute phase. Flu-like symptoms or an influenza-like illness occurred in less than 15% of patients given zoledronic acid during acute and chronic phases. An influenza-like illness that has persisted more than 30 days has been noted in postmarketing surveillance. Headache occurred in up to 20.4% of patients, with 7% to 13% of patients experiencing headache during the acute phase. Malaise and fatigue were experienced by 1% to 7.2% and 2.1% to 39% of patients overall, and they occurred in 5.2% and 8.3% to 12.4% of patients in the acute phase, respectively. Musculoskeletal events that have been reported over the course of treatment and in acute phase reactions with respective incidence rates are: myalgia (4.9% to 23%; 9% to 20.4%), arthralgia (5% to 27.3%; 3% to 11.1%), extremity pain (3.1% to 14%; 3.9%), and back pain (4% to 18.2%; 1.7% to 3.3%). Bone pain (overall 3.1% to 55%) has occurred during the acute phase, but the true incidence during the acute phase is unknown. General pain associated with zoledronic acid has been reported in up to 24.2% of patients, with up to 13.8% experienced during the acute phase. Rigors have been reported in 8% to 11% of patients, and flushing has been noted. An injection site reaction, such as erythema, redness, or swelling, was observed in up to 2.6% of patients, and resolved in most cases without treatment within 24 to 48 hours. Other general disorders associated with zoledronic acid include hyperthermia (0.3% to 2.3%), peripheral edema, including lower limb edema (3% to 21%), elevations in C-reactive protein (4.6%), cancer progression (16%), and malignant neoplasm aggravation (20%).
Renal impairment, including renal failure (unspecified), has been associated with zoledronic acid therapy. Renal impairment has been reported after a single dose; however, the risk of renal function deterioration increases with underlying renal disease, concomitant nephrotoxic or diuretic medications, multiple cycles of zoledronic acid or other bisphosphonates, and dehydration (secondary to fever, gastrointestinal losses, diuretic therapy, etc.). Use of zoledronic acid is not recommended in patients with pre-existing severe renal impairment (CrCl less than 35 mL/minute); dose patients with mild to moderate renal impairment according to indication specific guidelines. During clinical trials, decreases in creatinine clearance or increases in serum creatinine have been reported in 2% to 2.1% of patients. Grade 3 elevations in serum creatinine (more than 3 times upper limit of normal) occurred in 1% to 2% with a 4 mg dose, compared to 2% to 3% with pamidronate 90 mg. Grade 4 elevations in serum creatinine (more than 6 times upper limit of normal or ULN) occurred in less than 1% of patients receiving zoledronic acid. Azotemia has been reported to occur in approximately 2% of patients. In clinical trials, the incidence of renal toxicity that may progress to renal failure (as measured by increases in serum creatinine) was significantly increased in patients who received zoledronic acid over 5 vs. 15 minutes or who had received doses of 8 mg vs. 4 mg over 15 minutes; administer by an intravenous infusion over no less than 15 minutes. In a cohort of 6 elderly patients (mean age 69.2 years) who received 4 mg IV over 15 minutes for 3 to 9 months, all patients had renal biopsies reveal acute renal tubular necrosis (ATN). The necrosis was characterized by tubular cell degeneration, loss of brush border, and apoptosis. All patients were previously treated with pamidronate, but renal biopsies did not exhibit any characteristics associated with pamidronate nephrotoxicity. Zoledronic acid was discontinued in all 6 patients post renal biopsy and all patients showed improvement in renal function over time. Additionally, in clinical trials for multiple myeloma and bone metastases of solid tumors and in postmarketing experience, renal deterioration and progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function. The incidence of renal deterioration (0.5 mg/dL or more serum creatinine increase) in patients with normal baseline renal function was 11% to 15%; the incidence of deterioration (1 mg/dL or more serum creatinine increase) in those with baseline abnormal renal function was 8% to 40%. In clinical trials of patients with osteoporosis, a transient increase in the serum creatinine within 10 days of the dose occurred in 1.8% compared to 0.8% of placebo patients; change in creatinine clearance and incidence of renal failure or renal impairment were similar in patients with baseline creatinine clearances of 30 to 60 mL/minute over the 3-year study period; patients with a creatinine clearance less than 30 mL/minute were excluded from clinical trials. Evaluate serum creatinine prior to each zoledronic acid cycle in all patients. For patients at risk for renal impairment, continue monitoring renal function as appropriate for each clinical situation. Patients who show evidence of deterioration in renal function should have subsequent doses withheld until serum creatinine returns to within 10% of baseline. Proteinuria, hematuria, and acquired Fanconi syndrome have been reported during postmarketing use.
Electrolyte imbalances may occur during treatment with zoledronic acid. Patients with Paget's disease are particularly susceptible to hypocalcemia after administration. During clinical trials, approximately 21% of patients with Paget's disease had serum calcium concentrations less than 8.4 mg/dL about 9 to 11 days following administration; during a clinical trial in children with osteogenesis imperfecta, 22% experienced hypocalcemia. Overall, across clinical trials of osteoporosis, Paget's disease, hypercalcemia of malignancy, and bone metastases, hypophosphatemia occurred in 12% to 51% of patients, hypokalemia in less than 15%, hypomagnesemia in less than 11%, and hypermagnesemia in 2%. Grade 3 electrolyte abnormalities included hypocalcemia (1%; defined as less than 7 mg/dL), hypophosphatemia (12% to 51%; less than 2 mg/dL), hypomagnesemia (less than 1%; less than 0.9 mEq/L), and hypermagnesemia (2%; greater than 3 mEq/L). Grade 4 electrolyte abnormalities included hypocalcemia (less than 1%; less than 6 mg/dL), hypophosphatemia (less than 1%; less than 1 mg/dL), and hypomagnesemia (less than 1%; less than 0.7 mEq/L). Additionally, hyperkalemia, hypophosphatemia, and hypernatremia have been reported during postmarketing surveillance. Cardiac arrhythmia exacerbation, seizures, tetany, and numbness have been reported due to severe hypocalcemia. Monitor these electrolytes during therapy; correction of these electrolytes may be necessary.
Rare cases of hypersensitivity reactions including pruritus and urticaria have been reported with zoledronic acid use. Rash (unspecified) and dermatitis occurred in 2.2% to 3% and 11% of patients, respectively, during clinical trials. Although not reported during clinical trials of zoledronic acid, bronchospasm has been reported in postmarketing surveillance. Bronchoconstriction has been reported in aspirin-sensitive patients receiving other bisphosphonates. Additional hypersensitivity reactions reported during postmarketing surveillance include asthma exacerbations, angioedema, anaphylactoid reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, and shock.
Neurologic and psychiatric adverse effects have been associated with zoledronic acid therapy, most commonly dizziness (6.1% to 18%), insomnia (15% to 16%), paresthesias (2% to 15%), depression (14%), anxiety (11% to 14%), agitation (13%), confusion (7% to 13%), and hypoesthesia (2.2% to 12%). Other adverse events that have been reported include vertigo (1.3% to 4.3%), lethargy or drowsiness (5%), and somnolence (5% to 9.9%). Dysgeusia, hyperesthesia, and tremor have been noted during postmarketing surveillance. Convulsions, tetany, or numbness (hypoesthesia) may indicate electrolyte imbalance, such as hypocalcemia; monitor serum electrolytes as clinically indicated.
Ocular reactions including uveitis and iritis occurred in up to 1.1% of patients during clinical trials with zoledronic acid; episcleritis occurred in up to 0.2%. For comparison, uveitis, iritis, and episcleritis occurred in < 0.1% of patients taking placebo. Zoledronic acid has been associated with eye pain in 2% of patients. Conjunctivitis, iridocyclitis, scleritis, orbital inflammation or edema, and blurred vision have been reported during postmarketing surveillance. Nonspecific conjunctivitis seldom requires treatment and usually decreases in intensity during subsequent exposure to a bisphosphonate. However, no reported case of unilateral or bilateral scleritis resolved until the bisphosphonate was discontinued. More than 1 ocular side effect can occur at the same time; for instance, episcleritis may occur in conjunction with uveitis. In some instances, the drug may need to be discontinued in order for the ocular inflammation to resolve; for scleritis to resolve the bisphosphonate must be discontinued. Some cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation or edema have resolved with topical steroids. Patients with visual impairment or ocular pain should be referred to an ophthalmologist.
Postmarketing cases of osteonecrosis, primarily of the jaw but also including hip, femur, and external auditory canal, have been reported predominately in cancer patients being treated with intravenous bisphosphonates including zoledronic acid. Many patients were also receiving chemotherapy and corticosteroids which may be a risk factor for osteonecrosis of the jaw. During a postmenopausal osteoporosis trial, osteonecrosis of the jaw was reported in 1 patient out of 3,862 that received zoledronic acid; a patient in the placebo group also developed the disorder. It is not possible to determine if the reported events are related to zoledronic acid or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to a patient's underlying disease state, or to other comorbid risk factors (e.g., advanced breast cancer, multiple myeloma, anemia, infection, preexisting oral disease). The risk may increase with duration of exposure to the bisphosphonate. Typical signs and symptoms of osteonecrosis of the jaw include pain, swelling, infection, or poor healing of the gums, loosening of the teeth, numbness or a feeling of heaviness in the jaw, and drainage of exposed bone. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The treating physician and dentist should use their best clinical judgment to guide the management plan of each patient based on individual benefit and risk assessments. Based on a review of the available literature, treatments that have been used include local debridement, bone resection or other surgery, antimicrobials, antiseptic mouthwash, and hyperbaric oxygen. While a consensus on the best treatment strategies does not exist, the American Academy of Oral Medicine recommends prevention. Preventive measure include evaluation by a dentist prior to intravenous bisphosphonate initiation and within 3 months of oral bisphosphonate initiation, correction of dental complications prior to drug initiation, and continued regular follow-up with a dentist. For the treatment of osteonecrosis, recommendations include superficial debridement, bone resection when indicated, systemic antimicrobial for infections with culture-directed therapy or penicillin, amoxicillin, or clindamycin empirically, or use of chlorhexidine mouthwash 3 to 4 times daily. Discontinuation of the bisphosphonate once osteonecrosis occurs is controversial as the half-life of bisphosphonates within the bone is estimated to be years.
During a postmenopausal osteoporosis treatment trial using zoledronic acid, anemia was reported in 4.4% to 5.3% of patients. In trials of hypercalcemia of malignancy and bone metastases, anemia occurred in 22% to 33%, while neutropenia occurred in 12% of patients. Granulocytopenia, thrombocytopenia, and pancytopenia have been reported in less than 9.9% of patients.
In October 2010, the FDA issued a safety communication warning of atypical subtrochanteric and diaphyseal femoral bone fractures in patients receiving long-term bisphosphonate therapy for osteoporosis, including zoledronic acid. Definitive risk is not known, but most atypical fractures have been reported in patients taking long-term bisphosphonates. The FDA encourages patients to continue bisphosphonate therapy as directed, and encourages clinicians to periodically re-evaluate the need for continued therapy. If an atypical fracture occurs, discontinue the anti-resorptive agent. Advise patients to report new onset of groin or thigh pain, and evaluate the patient to rule out femoral fracture. If a femoral shaft fracture is confirmed, the contralateral femur should be examined, as fractures are often bilateral. Poor healing of these fractures has occurred. Unlike most hip fractures, which usually occur at the femoral neck and/or in the intertrochanteric regions of the femur, these atypical femoral fractures occur in the subtrochanteric and/or proximal diaphyseal region of the femur; further, the atypical fractures are characterized as simple transverse or short oblique fractures within hypertrophied cortices, and are sustained with little to no trauma and without comminution. The estimated incidence of subtrochanteric fractures has increased since the introduction of bisphosphonates and yet constitutes less than 1% of all hip and femur fractures in the United States. Other co-morbid conditions associated with the development of atypical femoral fracture include: use of other anti-resorptive agents, glucocorticoid or proton pump inhibitor use, diabetes mellitus, rheumatoid arthritis, and vitamin D-deficiency. The optimal duration of treatment for osteoporosis is unknown; consider patients at low-risk for fracture for drug discontinuation after 3 to 5 years of therapy. Continue to periodically re-evaluate for fracture risk after discontinuation of therapy.
Zoledronic acid may cause adverse events affecting the digestive system. Nausea has frequently been associated with therapy, occurring in up to 17.7% of patients during osteoporosis and Paget's disease trials (using Reclast), and in up to 46% among trials of hypercalcemia of malignancy and bone metastases (using Zometa). Vomiting and anorexia with Reclast were reported in 2% to 7.6% and 1% to 6% of patients, respectively; greater incidences were observed with Zometa use (14% to 32% and 9% to 22%, respectively). Nausea, vomiting, and anorexia may occur over the course of treatment or during an acute phase reaction. Constipation occurred in 6% to 7.2% of patients using Reclast and in 27% to 31% using Zometa. Other frequently reported GI events associated with zoledronic acid include diarrhea (5.2% to 24%), abdominal pain (0.9% to 16%), dehydration (which may be secondary to fever) (0.6% to 14%), dyspepsia (1.7% to 10%), decreased appetite (13%), and weight loss (16%). Events occurring in less than 10% of patients include dysphagia (5% to 9.9%), stomatitis (8%), abdominal discomfort (1.1% to 2%), and abdominal distension (0.6% to 2%). Xerostomia and weight gain have been reported.
Various non-specific infections have been reported in up to 9.9% of patients given zoledronic acid. Specific infections reported during clinical trials with incidence rates include influenza (7%), moniliasis (12%), urinary tract infection (12% to 14%), upper respiratory tract infection (10%), mucositis (5% to 9.9%), and pharyngitis (8%).
Dermatologic reactions including alopecia and hyperhidrosis have been reported with zoledronic acid. Hyperhidrosis occurred in 2.6% of male patients during osteoporosis trials, while alopecia occurred in 12% of patients during 3 bone metastases trials.
Dyspnea occurred in 5% to 27% of patients given zoledronic acid across trials of osteoporosis, Paget's disease, hypercalcemia of malignancy, and bone metastases. The occurrence of cough was 12% to 22% in trials of hypercalcemia of malignancy and bone metastases, which used Zometa.
Cardiovascular reactions associated with zoledronic acid with respective incidence rates include hypertension (5.1% to 12.7%), palpitations (2.6%), and hypotension (11%). Hypotension has primarily been observed in patients with underlying risk factors; syncope and circulatory collapse have occurred. Chest pain (unspecified) has been reported in 1.3% to 9.9% of patients, with non-cardiac chest pain reported in 3.5% to 7.7%. Bradycardia has occurred during postmarketing surveillance.
The use of zoledronic acid should be avoided during pregnancy due to the bone resorptive effects and potential risk for teratogenesis. Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data regarding fetal risk in humans, bisphosphonates do cause fetal harm (e.g., skeletal and other abnormalities, embryofetal lethality) in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. The impact of variables such as time between cessation of bisphosphonate therapy to conception space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. It is also possible, based on animal data, that women of childbearing potential may have impaired fertility or infertility during therapy.
Zoledronic acid use is contraindicated in any patient with a history of angioedema, serious rash, anaphylaxis or another severe hypersensitivity reaction to the drug or product excipients. Allergic reactions with intravenous zoledronic acid including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported. While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive asthma patients receiving bisphosphonates; use with caution in these patients. If anaphylactic or another severe hypersensitivity/allergic reaction occurs, immediately discontinue zoledronic acid and initiate appropriate treatment. Zoledronic acid should be used cautiously in patients with known phosphonate hypersensitivity. Zoledronic acid infusion therapy requires a specialized care setting. Proper medical support and monitoring measures should be readily available when the drug is administered in case there is hypersensitivity or another severe reaction. Administer by intravenous infusion only. When prescribing zoledronic acid, practitioners should ensure correct formulation selection for the indication to be treated. Zoledronic acid is available as Zometa and Reclast, which are indicated for different therapeutic uses and are available in different strengths. Patients receiving Zometa should not receive Reclast and vice versa.
Dehydration or hypovolemia, including dehydration or hypovolemia secondary to fever, gastrointestinal losses (e.g., vomiting, diarrhea), or diuretic therapy, before or after zoledronic acid administration increases the risk of post-infusion serum creatinine elevations and renal deterioration. Before each dose, check serum creatinine and ensure proper hydration. In patients with Paget's disease or osteoporosis, withhold treatment for signs or symptoms of dehydration; use only once the patient is normovolemic. Advise patients with osteoporosis or Paget's disease to drink at least 2 glasses of fluid within a few hours prior to infusion. During treatment of hypercalcemia of malignancy, it is recommended to maintain patient's urine output at 2 L/day.
The risks of zoledronic acid treatment must be carefully considered in patients with renal disease or renal impairment; indication-specific dosing adjustments are recommended. Treatment of Paget's disease and osteoporosis-related indications (Reclast brand) is contraindicated in patients with evidence of acute renal impairment and in those with a creatinine clearance of less than 35 mL/min or those with renal failure. Further, treatment of multiple myeloma and metastatic bone lesions from solid tumors is not recommended in patients with severe renal impairment and treatment of hypercalcemia of malignancy should be undertaken with extreme caution in such patients. Regardless of indication, measure serum creatinine prior to each dose and consider interim monitoring for transient increases in serum creatinine in at-risk patients and in those on other renally-eliminated drugs. Risk factors for renal deterioration include pre-existing renal insufficiency, multiple cycles of zoledronic acid or other bisphosphonates, severe dehydration occurring either before or after zoledronic acid use, multiple myeloma (see also osteonecrosis for other associated risks in patients with multiple myeloma), other advanced cancers, diabetes mellitus, hypertension, concomitant nephrotoxic (e.g., NSAIDs, radiopaque contrast media, thalidomide) or diuretic therapy, and advanced age. Take the following steps to minimize risk of adverse renal effects in all patients: ensure patients are well-hydrated prior to therapy, avoid concomitant use of nephrotoxic drugs in the post-infusion period (especially in patients with preexisting renal disease), administer over a minimum of 15 minutes, and do not exceed indication-specific dosage limits. Limited clinical experience indicates that infusing zoledronic acid over 30 minutes in those patients with preexisting renal disease may reduce the risk of further renal impairment. Renal deterioration with progression to renal failure, the need for dialysis, and fatalities have been reported in patients with pre-existing moderate to severe renal impairment or with risk factors for renal deterioration. Acute renal failure may occur following use at recommended doses and infusion rates and with a single dose.
When used for osteoporosis or Paget's disease, zoledronic acid (e.g., Reclast) is contraindicated for use in patients with hypocalcemia. It is important to correct pre-existing hypocalcemia prior to initiating zoledronic acid therapy for any indication. Severe, potentially life-threatening, hypocalcemia has been reported in patients treated with zoledronic acid. In some cases, hypocalcemia was severe enough to cause cardiac arrhythmias and neurologic adverse events (i.e., seizures, tetany, numbness). Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored during treatment. If an electrolyte imbalance (i.e., hypocalcemia, hypomagnesemia, or hypophosphatemia) occurs during therapy, short-term supplementation, including adequate calcium and vitamin D, may be necessary. Patients with vitamin D deficiency should receive adequate supplementation to correct the deficiency. To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years and males older than 70 years. Target daily elemental calcium intake for males 70 years or younger is 1,000 mg. Daily vitamin D intake of 20 to 25 mcg (800 to 1,000 international units) is recommended for patients age 50 years and older.
Post-marketing surveillance has revealed reports of osteonecrosis, primarily of the jaw (but also reported in the hip, femur, and external auditory canal), in patients with cancer receiving treatment regimens which included bisphosphonates (most commonly pamidronate and zoledronic acid), but also occasionally in patients receiving chronic oral bisphosphonate therapy for osteoporosis. The risk may increase with duration of exposure to the bisphosphonate. In patients with cancer receiving intravenous bisphosphonates, many patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures, such as tooth extraction, and many of these patients had signs of local infection including osteomyelitis; however cases have appeared spontaneously. It would be prudent for all patients who are initiatin bisphosphonate therapy, including those with concomitant risk factors such as anemia, cancer (especially advanced breast cancer and multiple myeloma), chemotherapy, coagulopathy, corticosteroid therapy, dental disease, infection, or poor oral hygiene, to receive a dental examination with appropriate preventive dentistry and correction of dental complications prior to beginning treatment. Preventive measures such as these as well as continued regular follow-up with a dentist during bisphosphonate therapy are recommended by the American Academy of Oral Medicine as the best way to minimize the risk of osteonecrosis. Invasive dental procedures should be avoided, if possible, during treatment, but if they are necessary, should be performed by an experienced dentist with close patient follow-up. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. In addition, discontinuing the bisphosphonate once osteonecrosis develops is controversial as the estimated half-life of bisphosphonates in the bone is years. The Mayo Clinic has developed guidelines for the use of bisphosphonates in patients with multiple myeloma. Per their guidelines, pamidronate is preferred over zoledronic acid in this population because the incidence of osteonecrosis appears to be highest for zoledronic acid. Furthermore, they recommend discontinuing the bisphosphonate after 2 years of treatment if the patient has achieved a complete response or has reached a plateau; for other patients, prolonging the duration between doses to every 3 months is recommended, although clinical evidence supporting this recommendation is not available.
The use of zoledronic acid should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. If a patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid and the importance of using effective contraception during and after treatment. Pregnancy status should be determined prior to the start of zoledronic acid therapy. Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm (e.g., skeletal and other abnormalities, embryo-fetal lethality) in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. A single case of zoledronic acid during the second and third trimesters of pregnancy has been reported. A 33-year old woman with breast cancer was given IV zoledronic acid every 28 days (dosage not specified) throughout her second and third trimesters of pregnancy. A healthy infant was born via cesarean delivery at 35 weeks; additionally, the patient appeared to be developing normally at 12 months of age.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid. Pregnancy status (e.g., pregnancy testing) should be determined before the start of zoledronic acid therapy. Due to the reproductive risk should the woman become pregnant, contraception requirements are advised. Advise females of childbearing age to use effective contraception before and after zoledronic acid therapy. Zoledronic acid may also impair fertility or cause infertility in females of reproductive potential. In animal studies involving female rats that received zoledronic acid, the following effects were observed: inhibition of ovulation, increase in preimplantation losses, decrease in the number of implantations, decrease in pregnancies, and decrease in live fetuses.
Breast-feeding is not recommended during or after zoledronic acid treatment, and a decision should be made to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known if zoledronic acid is excreted into breast milk. Reports describing use in lactating women are not available. Bisphosphonates bind to bone long-term, may be released over weeks to years, and can present a potentially serious risk to an exposed infant.
Safe and effective use of zoledronic acid in infants, children, and adolescents has not been established. Bisphosphonates have been used successfully in children for treatment of specific disease states (i.e., osteogenesis imperfecta). However, extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone mineral density (BMD). In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). It may be advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children to help assure clinicians that skeletal resorption is not excessively suppressed. Additionally, in a study of children and adolescents with severe osteogenesis imperfecta, zoledronic acid increased the BMD after 1 year; however, the increase in BMD did not correlate to risk of fracture or the incidence or severity of chronic bone pain. Adverse reactions reported by children were similar in nature to those reported by adults.
During clinical trials, overall differences in efficacy or safety were observed between geriatric patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients. There is an age-related decline in renal function in geriatric patients, which may increase the risk of adverse renal effects during administration of zoledronic acid. Cautious use and special care in renal monitoring are recommended in the elderly. The risk of adverse renal effects may be minimized by ensuring that patients are well-hydrated prior to therapy, avoiding concomitant use of nephrotoxic drugs in the post-infusion period, administering the drug over a minimum of 15 minutes, and not exceeding indication-specific dosage limits.
Ensure proper product selection
Zoledronic acid is available in two different products, which are indicated for different therapeutic uses and are available in different strengths. Choose the proper dosage form for the indication for use and avoid therapeutic duplication.
For the treatment of hypercalcemia of malignancy (i.e., albumin-corrected serum calcium 12 mg/dL or higher):
Intravenous dosage (i.e., Zometa or generic equivalents):
Adults: 4 mg IV infusion over a minimum of 15 minutes. Retreatment may be considered if serum calcium does not return to normal after 7 days. Monitor serum creatinine (SCr) at each dose. Evaluate a patient with deterioration from baseline renal function as to whether the benefit of continued treatment outweighs possible risks. For this indication, a reduction in dose for baseline mild to moderate renal insufficiency (i.e., SCr 4.5 mg/dL or less) is not necessary.
For the treatment of patients with multiple myeloma or with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy:
NOTE: If using for patients with prostate cancer, prostate cancer should have progressed after treatment with at least one hormonal therapy.
Intravenous dosage (e.g., Zometa or generic equivalents):
Adults: 4 mg IV infusion over a minimum of 15 minutes once every 3 to 4 weeks. Supplement with oral calcium 500 mg and vitamin D 400 International Units per day. Monitor serum creatinine (SCr) at baseline and each subsequent dose. Monitor serum creatinine (SCr) at each dose. If renal function deteriorates (i.e., SCr increase of 0.5 mg/dL or more for normal SCr at baseline or 1 mg/dL or more with abnormal SCr at baseline), hold further doses until renal function is within 10% of baseline. Reinitiate at the same dose used before treatment interruption.
For the treatment of Paget's disease:
Intravenous dosage (i.e., Reclast and generic equivalents):
Adults: 5 mg IV infusion over at least 15 minutes as a single dose. All patients should take 1,500 mg elemental calcium daily in divided doses (750 mg twice daily or 500 mg 3 times daily) and 800 International Units vitamin D per day, particularly in the 2 weeks following a dose. Guidelines recommend zoledronic acid as the agent of choice due to the durability of response (rare need for retreatment within 5 years), patient adherence to treatment, and the long-term data for reducing pain and lytic lesions and improving quality of life. After a single dose, an extended remission period is observed, with histologic and radiologic evidence of disease improvement. Specific re-treatment data are not available. However, may consider re-treatment in patients who have relapsed (based on increases in serum alkaline phosphatase), in those who fail to achieve normalization of their serum alkaline phosphatase, or in symptomatic patients. During clinical trials, most patients showed a therapeutic response within 60 days, and this response was sustained.
For the treatment of osteoporosis:
-for treatment of osteoporosis in men or postmenopausal women:
Intravenous dosage (i.e., Reclast and generic equivalents):
Adults: 5 mg IV infusion over at least 15 minutes, given once yearly. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low or moderate risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Continue zoledronic acid for up to 6 years in postmenopausal patients who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 3 years of stability in high-risk postmenopausal patients. Bisphosphonates are first-line therapy for the treatment of osteoporosis in postmenopausal women; the drug is additionally effective in men with osteoporosis.
-for corticosteroid-induced osteoporosis in men and women:
Intravenous dosage (i.e., Reclast and generic equivalents):
Adults: 5 mg IV infusion over at least 15 minutes, given once yearly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. An average of at least 1,200 mg calcium and 800 to 1000 International Units vitamin D per day is recommended. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.
For osteoporosis prophylaxis:
-for osteoporosis prevention in postmenopausal women:
Intravenous dosage (i.e., Reclast and generic equivalents):
Adult postmenopausal females: 5 mg IV infusion over at least 15 minutes, given once every other year. Supplement with calcium and vitamin D daily if dietary intake is not sufficient. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low or moderate risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Use of bisphosphonates to prevent bone loss can be considered in postmenopausal women with low bone mineral density (T-score less than -1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment.
-for prevention of corticosteroid-induced osteoporosis in men and women:
Intravenous dosage (i.e., Reclast and generic equivalents):
Adults: 5 mg IV infusion over at least 15 minutes, given once yearly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. An average of at least 1,200 mg calcium and 800 to 1000 International Units vitamin D per day is recommended. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.
-for osteoporosis prevention in postmenopausal women taking letrozole for early breast cancer*:
Intravenous dosage (i.e., Zometa or generic equivalents):
Adult postmenopausal females: 4 mg IV infusion over at least 15 minutes and given every 6 months appears effective at increasing or preserving bone mineral density (BMD) and reducing fracture risk; calcium and vitamin D is supplemented if dietary intake is inadequate.
-for osteoporosis prevention in men with prostate cancer receiving androgen deprivation therapy*:
Intravenous dosage (i.e., Zometa or generic equivalents):
Adults: 4 mg IV infusion over at least 15 minutes and given every 3 months appears effective at preserving or increasing bone density; a dose of 4 mg IV infusion once yearly also appears effective. Patients receive calcium and vitamin D supplementation if dietary intake is inadequate.
For the adjuvant treatment of early breast cancer* in women with postmenopausal reproductive hormone levels:
Intravenous dosage:
Adult postmenopausal females: 4 mg IV infusion once every 6 months, in combination with goserelin (3.6 mg subcutaneously once a month) and tamoxifen (20 mg/day PO) or anastrozole (1 mg/day PO). The regimen was administered for 3 years in one phase 3 trial in which 1,802 patients were randomized to receive the combination of goserelin with either tamoxifen or anastrozole, with or without zoledronic acid. With a median follow-up of 62 months, the addition of zoledronic acid reduced the risk of disease-free survival (DFS) events by 32% (HR = 0.68 [95% CI = 0.51, 0.91]; p = 0.009). In another phase 3 trial, 3,360 patients with stage 2/3 breast cancer were randomized to receive (neo)adjuvant chemotherapy and/or endocrine therapy with or without zoledronic acid (4 mg IV every 3 to 4 weeks x 6 doses, then every 3 months x 8 doses, then every 6 months x 5 doses; 5 years total treatment). The primary endpoint, DFS, was not significantly improved with the addition of zoledronic acid at a median follow-up of 59 months (377 DFS events for zoledronic acid arm vs. 375 DFS events for control arm, p = 0.79). A subgroup analysis of 1,185 patients with ER(+) disease also revealed no benefit with the addition of zoledronic acid. In a pre-planned subgroup analysis of 1,101 women who were more than 5 years postmenopausal or more than 60 years of age (low-estrogen environment), DFS (HR 0.76, 95% CI 0.60, 0.98) and OS (HR 0.71, 95% CI 0.54, 0.94, p = 0.017) were significantly improved in the zoledronic acid arm.
For the treatment of osteogenesis imperfecta*:
Intravenous dosage:
Adults: 5 mg IV once yearly.
Children and Adolescents 3 to 17 years: 5 mg IV once yearly, or alternatively, 0.05 to 0.1 mg/kg/dose IV once every 6 months or 0.05 mg/kg/dose IV once daily for 2 consecutive days every 4 months.
Children 2 years: 5 mg IV once yearly, or alternatively, 0.05 to 0.1 mg/kg/dose IV once every 6 months or 0.025 mg/kg/dose IV once daily for 2 consecutive days every 3 months.
Infants and Children younger than 2 years: 0.05 to 0.1 mg/kg/dose IV once every 6 months or 0.025 mg/kg/dose IV once daily for 2 consecutive days every 3 months.
Maximum Dosage Limits:
-Adults
4 mg/dose IV for hypercalcemia/oncology indications; 5 mg/dose IV for Paget's disease/osteoporosis.
-Geriatric
4 mg/dose IV for hypercalcemia/oncology indications; 5 mg/dose IV for Paget's disease/osteoporosis.
-Adolescents
Safety and efficacy have not been established; however, 5 mg IV once yearly or doses up to 0.1 mg/kg/cycle IV every 4 to 6 months have been used off-label for osteogenesis imperfecta.
-Children
3 to 12 years: Safety and efficacy have not been established; however, 5 mg IV once yearly or doses up to 0.1 mg/kg/cycle IV every 4 to 6 months have been used off-label for osteogenesis imperfecta.
2 years: Safety and efficacy have not been established; however, 5 mg IV once yearly or doses up to 0.05 mg/kg/cycle IV every 3 months or 0.1 mg/kg/cycle IV every 6 months have been used off-label for osteogenesis imperfecta.
1 year: Safety and efficacy have not been established; however, doses up to 0.05 mg/kg/cycle IV every 3 months or 0.1 mg/kg/cycle IV every 6 months have been used off-label for osteogenesis imperfecta.
-Infants
Safety and efficacy have not been established; however, doses up to 0.05 mg/kg/cycle IV every 3 months or 0.1 mg/kg/cycle IV every 6 months have been used off-label for osteogenesis imperfecta.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustment in hepatic impairment have not been established; it appears no dosage adjustments are needed.
Patients with Renal Impairment Dosing
For Hypercalcemia of Malignancy Indication (Zometa):
Serum creatinine 4.5 mg/dL or less: No dosage adjustment needed.
Serum creatinine more than 4.5 mg/dL: Use only after careful consideration of the risks and benefits; no dosing recommendations are available. These patients were excluded from clinical trials.
For Multiple Myeloma or Bone Metastases of Solid Tumors Indications (Zometa):
CrCl more than 60 mL/minute: No dosage adjustment needed.
CrCl 50 to 60 mL/minute: Reduce dose to 3.5 mg IV.
CrCl 40 to 49 mL/minute: Reduce dose to 3.3 mg IV.
CrCl 30 to 39 mL/minute: Reduce dose to 3 mg IV.
CrCl less than 30 mL/minute: Use not recommended due to lack of clinical data. Zoledronic acid is not recommended in patients with bone metastases who have severe renal impairment; patients with a serum creatinine greater than 3 mg/dL were excluded from clinical trials.
For Paget's Disease or Osteoporosis-related Indications (Reclast):
CrCl 35 mL/minute: No dosage adjustment needed.
CrCl less than 35 mL/minute: Use is contraindicated.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Ibuprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Aldesleukin, IL-2: (Major) Avoid concomitant use of zoledronic acid and aldesleukin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Amikacin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Aminoglycosides: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Amlodipine; Celecoxib: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as zoledronic acid, as the risk of renal impairment may be increased.
Aspirin, ASA: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity. (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Aspirin, ASA; Dipyridamole: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Omeprazole: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Oxycodone: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Bumetanide: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Bupivacaine; Meloxicam: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Celecoxib: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Celecoxib; Tramadol: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as zoledronic acid, is contraindicated. Zoledronic acid should be discontinued at least 7 days prior to beginning cidofovir.
Clindamycin: (Moderate) Concomitant use of zoledronic acid and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Colistimethate, Colistin, Polymyxin E: (Major) Coadministration of these drugs systemically may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may theoretically increase serum concentrations of either drug.
Colistin: (Major) Coadministration of these drugs systemically may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may theoretically increase serum concentrations of either drug.
Cyclosporine: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other nephrotoxic drugs, such as cyclosporine, may increase serum concentrations of either zoledronic acid and/or these coadministered drugs.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Diclofenac: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diclofenac; Misoprostol: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diflunisal: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diphenhydramine; Ibuprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diphenhydramine; Naproxen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Entecavir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including zoledronic acid.
Ethacrynic Acid: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Ethiodized Oil: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Etodolac: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Fenoprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Flurbiprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Furosemide: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Gentamicin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like zoledronic acid. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Hydrocodone; Ibuprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Famotidine: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Oxycodone: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like zoledronic acid. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Indomethacin: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and zoledronic acid due to the risk of glomerulonephritis and nephrotoxicity.
Iodixanol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Iohexol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Iomeprol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Iopamidol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Iopromide: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Ioversol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Isosulfan Blue: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Ketoprofen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ketorolac: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Lanthanum Carbonate: (Moderate) To limit absorption problems, the oral bisphosphonates should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like the oral bisphosphonates, may also be bound by lanthanum carbonate. Separating times of administration will maximize absorption and clinical benefit of the bisphosphonate. Separate the times of administration appropriately. Monitor the patient's clinical status and bone density as recommended to ensure the appropriate response to bisphosphonate therapy is obtained.
Loop diuretics: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Mannitol: (Major) Avoid use of mannitol and zoledronic acid, if possible. Concomitant administration of nephrotoxic drugs, such as zoledronic acid, increases the risk of renal failure after administration of mannitol.
Meclofenamate Sodium: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Mefenamic Acid: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Meloxicam: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Nabumetone: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen; Esomeprazole: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Non-Ionic Contrast Media: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Omeprazole; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Oxaprozin: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Paromomycin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Piroxicam: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Plazomicin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Polymyxin B: (Major) Coadministration of parenteral polymyxin B with other potentially nephrotoxic drugs, including zoledronic acid, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since polymyxin B injection is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may theoretically increase serum concentrations of either drug.
Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Streptomycin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Sulindac: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Sumatriptan; Naproxen: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Tacrolimus: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs, such as tacrolimus, may increase serum concentrations of either zoledronic acid and/or tacrolimus.
Telavancin: (Moderate) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as zoledronic acid may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Thalidomide: (Moderate) In multiple myeloma patients, the risk of renal dysfunction may be increased when zoledronic acid is used in combination with thalidomide.
Tobramycin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
Tolmetin: (Moderate) Monitor renal function during concomitant zoledronic acid and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Torsemide: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Vancomycin: (Moderate) Coadministration of zoledronic acid with other potentially nephrotoxic drugs, such as vancomycin, may increase serum concentrations of either drug and increase the risk of nephrotoxicity. Monitor patients for changes in renal function if these drugs are coadministered.
Voclosporin: (Moderate) Concomitant use of voclosporin and zoledronic acid may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Zoledronic acid is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to the bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Hypercalcemia is a common problem affecting cancer patients. Malignancy-associated hypercalcemia arises from accelerated bone resorption. This form of hypercalcemia could result from direct skeletal action by various tumors inducing osteoclast hyperactivity. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy. Zoledronic acid does not lower the level of parathyroid hormone-related protein (PTHrP) in patients with hypercalcemia of malignancy. The drug inhibits bone resorption without inhibiting bone formation or mineralization. Clinical studies in patients with hypercalcemia of malignancy showed that single-dose infusions of zoledronic acid are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
Like other bisphosphonates, the exact mechanism of zoledronic acid's therapeutic effect in patients with Paget's disease has not been clearly established. Paget's disease is a progressive, idiopathic disease of bone. Increasing numbers of unusually large osteoclasts are produced at affected sites. Increased bone resorption follows, which is compensated for by an increase in new bone formation. This new bone is inferior and often deformed, and can fracture easily. Bisphosphonates are believed to reduce the solubility of the mineralized bone matrix by adsorption to hydroxyapatite crystals in the matrix. The matrix becomes less soluble and resistant to osteoclastic resorption. Like other bisphosphonates, zoledronic acid can also block the formation of mature osteoclasts by affecting the attachment of osteoclast precursors to the mineralized matrix.
Zoledronic acid appears to have direct anti-tumor effects in specific types of cancer cells. When studied in breast cancer cell lines, zoledronic acid has been noted to cause dose- and time-dependent reductions in cell numbers and concomitant increases in tumor cell apoptosis. These changes were seen in vitro when zoledronic acid was used alone or in combination with paclitaxel. Although the exact mechanism is unknown, zoledronic acid may mediate this anti-tumor effect by inhibiting the mevalonate pathway. Zoledronic acid has been found to exert effects on certain prostate cancer cell lines, as well. There is no evidence of zoledronic acid inducing prostate cancer cell death, although the drug does appear to inhibit cell proliferation. The exact mechanism of this inhibition is unknown.
Zoledronic acid is administered by intravenous infusion. Pharmacokinetic data in patients with hypercalcemia, Paget's disease, or osteoporosis are not available; the pharmacokinetics of the drug have been studied in cancer patients with bone metastases. The drug distributes primarily to the bone in a triphasic process. The early distribution half-life is 0.24 hours, early elimination half-life is 1.87 hours, and the terminal elimination half-life is approximately 146 hours. Low plasma concentrations observed up to 28 days post-dose. In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5,000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2,000 ng/mL of zoledronic acid. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of radiolabeled zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized. In 64 patients with cancer and bone metastases, on average (+/- SD) 39% +/- 16% of the administered dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-day 2. The cumulative percent of drug excreted in the urine over 0 to 24 hours was independent of dose. The balance of drug not recovered in urine during the first 24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations and long terminal half-life. The 0 to 24 hour renal clearance of zoledronic acid was 3.7 +/- 2 L/hour. Zoledronic acid clearance was independent of dose but dependent upon the patient's creatinine clearance.
Affected cytochrome P450 isoenzymes and drug transporters: None
Zoledronic acid does not inhibit any CYP450 enzymes in vitro.
-Route-Specific Pharmacokinetics
Intravenous Route
Single or multiple (every 28 days) 5-minute or 15-minute IV infusions of 2, 4, 8, or 16 mg of zoledronic acid were given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process and distribution into bone, showing a rapid decrease from peak concentrations (Cmax) at end of the infusion to less than 1% of Cmax 24 hours postinfusion.
-Special Populations
Hepatic Impairment
Zoledronic acid has not been specifically studied in patients with hepatic impairment; however, the drug is not metabolized, and the elimination is dependent on renal function.
Renal Impairment
The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately-impaired renal function. Compared to patients with creatinine clearance (CrCl greater than 80 mL/min), patients with a CrCl of 50 to 80 mL/minute showed an average increase in plasma AUC (exposure) of 15%, whereas patients with a CrCl of 30 to 50 mL/minute showed an average increase in plasma AUC of 43%. Therefore, dosage adjustments are necessary in patients with renal impairment based on the indication for use and dosage regimen to be given. Treatment is not recommended in patients with bone metastases with severe renal impairment (e.g., serum creatinine greater than 3 mg/dL). Consider treatment in patients with hypercalcemia of malignancy with severe renal impairment only after evaluating the risks and benefits of treatment; patients with serum creatinine greater than 4.5 mg/dL were excluded from the clinical study. Limited pharmacokinetic data exist in patients with a creatinine clearance less than 30 mL/minute. The use of zoledronic acid for osteoporosis or Paget's disease is contraindicated in patients with CrCl less than 35 mL/minute and those with evidence of acute renal impairment due to an increased risk of renal failure. Based on data, the risk for renal deterioration appears to increase as the zoledronic acid AUC increases.
Systemic clearance in individual patients can be calculated from the population clearance of zoledronic acid, CL (L/hour) = 6.5(CrCl/90)0.4. The following formulae can be used to predict the zoledronic acid AUC in patients, where CL = Dose/AUC (0 to infinity). The average AUC(0-24) in patients with normal renal function was 0.42 mg x hour/L, and the calculated AUC(0 to infinity) for a patient with creatinine clearance of 75 mL/min was 0.66 mg x hour/L following a 4-mg IV dose. However, the efficacy and safety of adjusted dosing based on these calculations have not been prospectively assessed.
Pediatrics
Pharmacokinetic data are not available for pediatric patients.
Geriatric
The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 to 84 years.
Ethnic Differences
Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese, Caucasian, and African American patients with cancer and bone metastases.