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    Injectable Bisphosphonate Bone Calcium Regulators

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral IV bisphosphonate
    Used for hypercalcemia of malignancy and bone metastases (e.g., Zometa product)
    Given as a single-dose for Paget's disease, once-yearly for osteoporosis, and every other year for osteoporosis prophylaxis in at-risk adult patients (e.g., Reclast product)

    COMMON BRAND NAMES

    Reclast, Zometa

    HOW SUPPLIED

    Reclast/Zoledronic Acid/Zometa Intravenous Inj Sol: 4mg, 5mL, 5mg, 100mL
    Zoledronic Acid/Zometa Intravenous Inj Pwd F/Sol: 4mg

    DOSAGE & INDICATIONS

    For the treatment of hypercalcemia of malignancy (i.e., albumin-corrected serum calcium 12 mg/dL or higher).
    Intravenous dosage (Zometa)
    Adults

    4 mg intravenously 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 baseline and prior to each subsequent dose. Patients with deterioration in renal function should be appropriately evaluated as to whether the potential benefit of continued treatment outweighs the possible risk. A reduction in dose for patients with mild to moderate renal insufficiency (i.e., SCr 4.5 mg/dL or less) is not necessary for this indication.

    For the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.
    NOTE: When used for bone metastases of prostate cancer, the disease should have progressed after treatment with at least one hormonal therapy.
    NOTE: To avoid hypocalcemia and maintain proper status, patients should also receive an oral calcium supplement of 500 mg and a multiple vitamin containing 400 International Units of Vitamin D every day during treatment.
    Intravenous dosage (Zometa)
    Adults

    4 mg intravenously over a minimum of 15 minutes every 3 to 4 weeks. Monitor serum creatinine (SCr) at baseline and each subsequent dose; if renal function has deteriorated (i.e., an increase in the SCr of 0.5 mg/dL or more in patients with normal renal function at baseline or an increase in the SCr of 1 mg/dL or more in patients with an abnormal SCr at baseline), zoledronic acid should be withheld until renal function returns to within 10% of baseline.

    For the treatment of active Paget's disease.
    NOTE: To reduce the risk of hypocalcemia, all patients should receive an intake of 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 International Units vitamin D daily, particularly in the 2 weeks following drug administration.
    Intravenous dosage (Reclast)
    Adults

    5 mg as a single intravenous infusion over no less than 15 minutes. After a single treatment, an extended remission period is observed. During clinical trials, most patients showed a therapeutic response within 60 days of treatment, with maintenance of effect at 24 months. Specific retreatment data are not available. However, retreatment may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

    For the treatment of osteoporosis.
    In postmenopausal women.
    Intravenous dosage (Reclast)
    Postmenopausal females

    5 mg intravenously infused once yearly. Administer the infusion over no less than 15 minutes at a constant rate of infusion. To reduce the risk of hypocalcemia and maintain proper bone health, postmenopausal women require an average of 1,200 mg calcium orally and 800 to 1,000 International Units vitamin D orally each day. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal duration of bisphosphonate therapy for osteoporosis has not been determined. Periodically re-evaluate the need for continued therapy in all patients on bisphosphonate therapy. For those patients determined to be at low-risk for fracture, consider stopping treatment after 3 to 5 years. After discontinuation of therapy, continue to periodically re-evaluate the fracture risk. According to the North American Menopause Society (NAMS), bisphosphonates are considered to be first-line therapy for the treatment of postmenopausal osteoporosis. The HORIZON Pivotal Fracture study indicates that the annual 5 mg IV regimen, as compared to placebo, is associated with a 70% reduction in fracture of the spine, a 40% reduction in fracture of the hip, and a 25% reduction in other non-vertebral fractures after 3 years (p less than 0.001 for all comparisons). In a second phase III trial, patients taking alendronate (70 mg orally once weekly for 1 year) were able to switch to a single 5 mg intravenous infusion of zoledronic acid and maintain similar BMD for at least 12 months.

    To treat men with osteoporosis.
    Intravenous dosage (Reclast)
    Adult males

    5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily. Men require at least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D daily. In a 2-year study of men with osteoporosis, including osteoporosis secondary to hypogonadism, 2 once-yearly infusions of zoledronic acid were found to be non-inferior to an oral bisphosphonate administered weekly as demonstrated by changes in bone mineral density at 24 months (increase in 6.2% relative to baseline in zoledronic acid group vs. 6.1% in control group).

    For secondary fracture prophylaxis in high-risk patients (i.e., recent low-trauma hip fracture).
    Intravenous dosage (Reclast)
    Adults

    5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily. Zoledronic acid was initiated within 90 days of surgical repair in one study. Patients were randomized to receive a 15-minute intravenous infusion of zoledronic acid 5 mg (n = 1,065) or placebo (n = 1,062) once yearly for up to 5 years; the trial was stopped after a median follow-up of 1.9 years as the boundaries for efficacy in favor of zoledronic acid had been met. Zoledronic acid was initiated within 90 days of surgical repair. The rate of any new clinical fracture (minus digital or facial fractures or fractures in abnormal bone) was reduced significantly in patients receiving zoledronic acid (8.6% vs. 13.9% for placebo, RR 0.65, 95% CI 0.5 to 0.84, p = 0.001). In addition, vertebral and non-vertebral fractures, but not hip fractures, were decreased (p = 0.02 for vertebral fractures, and p = 0.03 for non-vertebral fractures). Bone mineral density of the total hip and the femoral neck increased in patients taking zoledronic acid at 12, 24, and 36 months as compared to placebo (p less than 0.001). In addition, death from any cause was significantly reduced in patients receiving zoledronic acid (9.6% vs. 11.5% for placebo, HR 0.72, 95% CI 0.56 to 0.93, p = 0.01), although the reasons for the improvement in mortality are not known. At baselinie, 41.8% of patients had a T-score of -2.5 SD of the femoral neck.

    For the treatment of glucocorticoid-induced osteoporosis in men and women taking systemic glucocorticoids (i.e., oral prednisone 7.5 mg/day or more, or equivalent) and expected to continue glucocorticoid therapy for 12 months or longer.
    Intravenous dosage (Reclast)
    Adults

    5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily. If dietary intake is not sufficient, patients should also take at least 1,200 mg calcium orally and 800 to 1,000 International Units of vitamin D orally each day. In a randomized, controlled trial of 833 patients, zoledronic acid was compared to an oral bisphosphonate for 1 year for the prevention and treatment of glucocorticoid-induced osteoporosis. All groups also received 1,000 mg of elemental calcium and 400 to 1,000 International Units of vitamin D daily. The mean increase in lumbar spine bone mineral density was higher at 1 year with the use of zoledronic acid compared to the active control in the osteoporosis treatment group (4.1% vs. 2.7%, p less than 0.001).

    For osteoporosis prophylaxis.
    In postmenopausal women.
    Intravenous dosage (Reclast)
    Postmenopausal females

    5 mg infused IV once every other year. Administer over no less than 15 minutes at a constant rate of infusion. Supplement with calcium and vitamin D daily if dietary intake is not sufficient. If dietary intake is not sufficient, administer at least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D daily. In a randomized, multi-center, double-blind, placebo-controlled study of 581 females 45 years of age and older, women were stratified into 2 groups based on years since menopause (Stratum I less than 5 years; Stratum II 5 years or more), and then randomized to 3 treatment regimens: zoledronic acid administered at randomization and at 12 months, zoledronic acid at randomization and placebo at 12 months, or placebo at randomization and 12 months. The percent change of lumbar spine and total hip bone mineral density (BMD) was assessed at 24 months. Compared to placebo, zoledronic acid administered at randomization and placebo administered at 12 months resulted in statistically significant increases in both lumbar spine and total hip BMD at 24 months for both Stratum I (lumbar spine BMD, 6.3% and total hip BMD, 4.7%, p less than 0.0001 for both measurements) and Stratum II (lumbar spine BMD, 5.4% and total hip BMD, 3.2% p less than 0.0001 for both measurements).

    For the prevention of glucocorticoid-induced osteoporosis in men and women taking systemic glucocorticoids (i.e., oral prednisone 7.5 mg/day or more, or equivalent) and expected to continue glucocorticoid therapy for 12 months or longer.
    Intravenous dosage (Reclast)
    Adults

    5 mg infused IV once every year. Administer over no less than 15 minutes at a constant rate of infusion. Supplement with calcium and vitamin D daily if dietary intake is not sufficient. If dietary intake is not sufficient, patients should also take at least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D daily. In a randomized, controlled trial of 833 patients, zoledronic acid was compared to an oral bisphosphonate for 1 year for the prevention and treatment of glucocorticoid-induced osteoporosis. All groups also received supplements of calcium and  vitamin D daily. The mean increase in lumbar spine bone mineral density was higher at 1 year with the use of zoledronic acid compared to the active control in the osteoporosis prevention group (2.6% vs. 0.6%, p less than 0.001).

    In postmenopausal women taking letrozole for early breast carcinoma†.
    Intravenous dosage
    Postmenopausal females

    Preliminary data suggest that 4 mg IV infused every 6 months is effective in increasing bone mineral density (BMD) in postmenopausal women taking letrozole 2.5 mg PO/day for early breast carcinoma; calcium and vitamin D is supplemented if dietary intake is inadequate. In a study of 602 patients without osteoporosis, 301 patients received zoledronic acid from study start (up-front group) and 301 patients received zoledronic acid only if their BMD of the lumbar spine or total hip decreased to less than -2 SD or they developed a nontraumatic clinical fracture (delayed group). All patients received letrozole 2.5 mg/day plus calcium and vitamin D supplementation. Per protocol, 4.3% and 8.3% of patients in the delayed group required initiation of zoledronic acid by months 6 and 12, respectively. Additionally, at 12 months, lumbar spine BMD was 4.4% higher in the up-front group vs. the delayed group (95% CI 3.7% to 5%, p less than 0.0001). Similarly, total hip BMD was 3.3% higher (95% CI 2.8% to 3.8%, p less than 0.0001). Fracture rates at 12 months were not different between the 2 groups; reported adverse events were similar between the 2 study groups except that bone pain was reported more frequently in the up-front group.

    In patients that have undergone a liver transplantation†.
    Intravenous dosage
    Adults

    Limited data suggest 4 mg IV infused within 7 days of transplantation and at months 1, 3, 6, and 9 after transplantation is effective in increasing BMD at the lumbar spine, femoral neck, and total hip. Calcium and vitamin D are supplemented if dietary intake is inadequate. In 62 post-liver transplant patients, after 6 months and as compared to placebo, zoledronic acid significantly increased the BMD of the lumbar spine by 4.2% (95% CI 0.9 to 7.7%, p = 0.015), the femoral neck by 4.6% (95% CI 1.8 to 7.4, p = 0.002), and the total hip by 3.8% (95% CI 1.7 to 6, p less than 0.001). At 12 months, the improvement in BMD was significant only at the total hip. All patients were receiving calcium carbonate, vitamin D, tacrolimus or cyclosporine, azathioprine or mycophenolate, and methylprednisolone. Hypocalcemia was reported more often in patients taking zoledronic acid.

    In men with prostate cancer receiving androgen deprivation therapy (e.g., gonadotropin releasing hormone agonist with or without antiandrogen therapy)†.
    Intravenous dosage
    Adult males

    Studies suggest 4 mg IV infused every 3 months is effective in increasing BMD; a dose of 4 mg IV once yearly has also been shown to be effective. Patients receive calcium and vitamin D supplementation if dietary intake is inadequate. In patients with nonmetastatic and metastatic prostate cancer (with or without bony metastases), zoledronic acid every 3 months for 4 doses significantly increased lumbar spine BMD (increases of approximately 7% compared to placebo); BMD also increased significantly at the femoral neck by 3.3 to 4.2% compared to placebo and at the total hip by 3.8 to 3.9% compared to placebo. Additionally, a small study of 40 men with nonmetastatic breast carcinoma found that a single 4 mg IV dose increased lumbar spine BMD by 4% in patients taking zoledronic acid (between group difference compared to placebo of 7.1%, p less than 0.001) at 1 year. In all 4 studies, all patients also took calcium and vitamin D daily. None of the studies were powered to assess the effects of zoledronic acid on fracture rate.

    For the adjuvant treatment of early breast cancer† in women with postmenopausal reproductive hormone levels.
    Intravenous dosage
    Adults

    4 mg IV once every 6 months administered in combination with goserelin (3.6 mg subcutaneously once a month) and tamoxifen (20 mg PO once daily) or anastrozole (1 mg PO once daily). The regimen was administered for 3 years. In a phase III trial, 1802 patients were randomized to receive the combination of goserelin and tamoxifen or goserelin and 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 III trial, 3360 patients with stage II/III breast cancer were randomized to receive (neo)adjuvant chemotherapy and/or endocrine therapy with or without zoledronic acid (4 mg IV every 3—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 v. 375 DFS events for control arm, p = 0.79). In addition, a subgroup analysis of 1185 patients with ER(+) disease also revealed no benefit with the addition of zoledronic acid. In a pre-planned subgroup analysis of 1101 women who were > 5 years postmenopausal or > 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 mg/dose IV infusion for hypercalcemia/oncology indications; 5 mg/dose IV infusion for Paget's disease/osteoporosis.

    Geriatric

    4 mg/dose IV infusion for hypercalcemia/oncology indications; 5 mg/dose IV infusion for Paget's disease/osteoporosis.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustment in hepatic impairment have not been established; it appears no dosage adjustments are needed.

    Renal Impairment

    For Hypercalcemia of Malignancy Indication:
    SCr <= 4.5 mg/dl: No dosage adjustment needed.
    SCr > 4.5 mg/dl: Use only after careful consideration of the risks and benefits; no dosing recommendations are available. Patients with SCr > 4.5 mg/dl were excluded from clinical trials.
     
    For Multiple Myeloma or Bone Metastases of Solid Tumors Indications:
    NOTE: Zoledronic acid is not recommended in patients with bone metastases who have severe renal impairment; patients with SCr > 3 mg/dl were excluded from clinical trials.
    CrCl > 60 ml/min: No dosage adjustment needed.
    CrCl 50—60 ml/min: Reduce dose to 3.5 mg IV.
    CrCl 40—49 ml/min: Reduce dose to 3.3 mg IV.
    CrCl 30—39 ml/min: Reduce dose to 3 mg IV.
    CrCl < 30 ml/min: Use not recommended due to lack of clinical data.
     
    For Paget's Disease or Osteoporosis-related Indications:
    CrCl >= 35 ml/min: No dosage adjustment needed.
    CrCl < 35 ml/min: Use is contraindicated.

    ADMINISTRATION

    Injectable Administration

    Zoledronic acid is available as more than one indication-specific brand name product (e.g., Zometa, Reclast). Avoid duplications.
    Assess serum creatinine 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.

    Intravenous Administration

    Dilution of zoledronic acid 4 mg/5 mL concentrate for infusion (e.g., Zometa):
    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 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 syringe.
    Storage: If not used immediately after dilution, the solution should be refrigerated at 2—8 degrees C (36—46 degrees F). If refrigerated, return the solution to room temperature before administration. The total time between dilution and administration must not exceed 24 hours.
     
    Preparation of zoledronic acid 4 mg/100 mL ready-to-use solution for infusion (e.g., Zometa):
    This product does not require further dilution.
    After removing overwrap, check for small leaks by squeezing inner bag. Use container only if no leaks are found and solution is clear and container undamaged.
    Preparation for reduced doses: For dose of 3.5 mg remove and discard 12 mL of solution; for dose of 3.3 mg remove and discard 18 mL; for 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 diluted for dose adjustment and not used immediately, the solution should be refrigerated at 2—8 degrees C (36—46 degrees F). If refrigerated, return the solution to room temperature before administration. The total time between dilution and administration must not exceed 24 hours.
     
    Preparation of zoledronic acid 5 mg/100 mL solution for infusion (e.g., Reclast):
    This product does not require further dilution.
    If refrigerated, allow the refrigerated solution to reach room temperature before administration.
     
    Intravenous (IV) infusion administration:
    Administer via a separate vented IV line; do not administered with other intravenous agents.
    Do not allow to come in contact with any calcium or divalent cation-containing solutions.
    Due to risk of clinically significant renal toxicity, do not exceed recommended dose and 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 normal saline flush of the IV line.

    STORAGE

    Reclast:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Reconstituted product should be refrigerated and used within 24 hours if not used immediately
    - Store at 77 degrees F; excursions permitted to 68 to 77 degrees F
    Zometa:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Reconstituted product should be refrigerated and used within 24 hours if not used immediately
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Acute bronchospasm, asthma, phosphonate hypersensitivity

    Zoledronic acid is contraindicated in patients with bis-phosphonate hypersensitivity or hypersensitivity to zoledronic acid or any other constituent of the formulation. While not observed with zoledronic acid, treatment with bisphosphonates has been associated with acute bronchospasm in patients with aspirin-sensitive asthma and phosphonate hypersensitivity.

    Dehydration, diarrhea, fever, hypovolemia, vomiting

    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.

    Diabetes mellitus, hypertension, multiple myeloma, renal disease, renal failure, renal impairment

    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.

    Cardiac arrhythmias, electrolyte imbalance, hypocalcemia, hypomagnesemia, hypophosphatemia, seizures

    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). Correct pre-existing hypocalcemia prior to initiating zoledronic acid therapy. 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.

    Pregnancy

    Zoledronic acid is classified as FDA pregnancy risk category D; use should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. The drug should be avoided during pregnancy whenever possible. In reproductive studies in the pregnant rat, doses 2.4—4.8 times the human systemic exposure resulted in pre-and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no formal studies of zoledronic acid therapy in pregnant women. 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.

    Breast-feeding

    According to the manufacturers, zoledronic acid is not recommended for use during lactation (breast-feeding) 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 breast-feeding women are not available. Bisphosphonates bind to bone long-term, may be released over weeks to years, and can present a potential serious risk to an exposed infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safe and effective use of zoledronic acid in neonates, infants, children, and adolescents has not been established. Bisphosphonates have been used successfully in children for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). 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 (see Adverse Reactions).

    Anemia, chemotherapy, coagulopathy, corticosteroid therapy, dental disease, dental work, infection

    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.

    Geriatric

    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.

    ADVERSE REACTIONS

    Severe

    pancytopenia / Delayed / 5.0-9.9
    atrial fibrillation / Early / 0.7-3.3
    azotemia / Delayed / 2.0-2.0
    uveitis / Delayed / 0-1.1
    renal failure (unspecified) / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known

    Moderate

    bone pain / Delayed / 3.1-55.0
    hypophosphatemia / Delayed / 12.0-51.0
    anemia / Delayed / 4.4-33.0
    constipation / Delayed / 6.0-31.0
    dyspnea / Early / 5.0-27.0
    hypocalcemia / Delayed / 0-22.0
    hypokalemia / Delayed / 0-15.0
    depression / Delayed / 14.0-14.0
    dehydration / Delayed / 0.6-14.0
    confusion / Early / 7.0-13.0
    hypertension / Early / 5.1-12.7
    neutropenia / Delayed / 12.0-12.0
    hypomagnesemia / Delayed / 0-11.0
    hypotension / Rapid / 11.0-11.0
    thrombocytopenia / Delayed / 5.0-9.9
    dysphagia / Delayed / 5.0-9.9
    chest pain (unspecified) / Early / 1.3-9.9
    stomatitis / Delayed / 8.0-8.0
    palpitations / Early / 2.6-2.6
    flank pain / Delayed / 0.6-2.0
    hypermagnesemia / Delayed / 2.0-2.0
    iritis / Delayed / 0-1.1
    proteinuria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    hypernatremia / Delayed / Incidence not known
    tetany / Early / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    ocular inflammation / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known

    Mild

    nausea / Early / 4.5-46.0
    vomiting / Early / 2.0-32.0
    arthralgia / Delayed / 5.0-27.3
    diarrhea / Early / 5.2-24.0
    myalgia / Early / 4.9-23.0
    anorexia / Delayed / 1.0-22.0
    cough / Delayed / 12.0-22.0
    back pain / Delayed / 4.0-18.2
    dizziness / Early / 6.1-18.0
    insomnia / Early / 15.0-16.0
    weight loss / Delayed / 16.0-16.0
    abdominal pain / Early / 0.9-16.0
    paresthesias / Delayed / 2.0-15.0
    anxiety / Delayed / 11.0-14.0
    agitation / Early / 13.0-13.0
    musculoskeletal pain / Early / 0.4-12.4
    hypoesthesia / Delayed / 2.2-12.0
    alopecia / Delayed / 12.0-12.0
    dyspepsia / Early / 1.7-10.0
    infection / Delayed / 5.0-9.9
    pharyngitis / Delayed / 8.0-8.0
    influenza / Delayed / 7.0-7.0
    lethargy / Early / 5.0-5.0
    vertigo / Early / 1.3-4.3
    rash (unspecified) / Early / 2.2-3.0
    hyperhidrosis / Delayed / 2.6-2.6
    ocular pain / Early / 2.0-2.0
    muscle cramps / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    dysgeusia / Early / Incidence not known
    tremor / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    xerostomia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aluminum Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    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.
    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) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Carisoprodol: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Dipyridamole: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Omeprazole: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Oxycodone: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Pravastatin: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    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.
    Calcium Carbonate: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Carbonate; Risedronate: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Salts: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium; Vitamin D: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Chromium: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Cidofovir: (Severe) 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.
    Cobicistat; Elvitegravir; 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.
    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.
    Collagenase: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Cyanocobalamin, Vitamin B12: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Diclofenac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diclofenac; Misoprostol: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diflunisal: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diphenhydramine; Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diphenhydramine; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Efavirenz; Emtricitabine; Tenofovir: (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 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 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.
    Esomeprazole; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Etodolac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Famotidine; Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Fenoprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Flurbiprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen; Oxycodone: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen; Pseudoephedrine: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    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.
    Iron Salts: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Iron: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Kanamycin: (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.
    Ketoprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ketorolac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Lansoprazole; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Meclofenamate Sodium: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Mefenamic Acid: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Meloxicam: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Nabumetone: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen; Pseudoephedrine: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen; Sumatriptan: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Pantothenic Acid, Vitamin B5: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Polymyxins: (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.
    Polysaccharide-Iron Complex: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Pyridoxine, Vitamin B6: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Rofecoxib: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing 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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Telbivudine: (Moderate) Drugs that alter renal function such as zoledronic acid may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tenofovir Alafenamide: (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 alafenamide 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, and urine glucose and protein.
    Tenofovir, PMPA: (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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Valdecoxib: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Zinc Salts: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.

    PREGNANCY AND LACTATION

    Pregnancy

    Zoledronic acid is classified as FDA pregnancy risk category D; use should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. The drug should be avoided during pregnancy whenever possible. In reproductive studies in the pregnant rat, doses 2.4—4.8 times the human systemic exposure resulted in pre-and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no formal studies of zoledronic acid therapy in pregnant women. 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.

    According to the manufacturers, zoledronic acid is not recommended for use during lactation (breast-feeding) 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 breast-feeding women are not available. Bisphosphonates bind to bone long-term, may be released over weeks to years, and can present a potential serious risk to an exposed infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals.Zoledronic acid is incorporated into osteoclastic bone surfaces, where it inhibits bone resorption by inhibiting osteoclastic activity and inducing osteoclastic apoptosis. The presence of bisphosphonates in the bone structure appears to prevent acid extrusion, an important step stimulated by osteoclasts during the bone resorption process. Following subsequent resorption, bone tissue surrounding the bisphosphonate containing bone tends to lack ruffled borders and has fewer vacuoles, which are changes consistent with lower resorptive capacity. Therefore, osteoclasts may be inhibited not only when bisphosphonates are directly incorporated into the bone matrix, but after they engulf bisphosphonate-containing mineral during active bone resorption, as well.Zoledronic acid affects chemical and hormonal mediators of bone degradation. The exact molecular and biochemical changes leading to osteoclast activity suppression remain unidentified, but are postulated to include reduced production of lactic acid, lysosomal enzymes, pyrophosphatases, and prostaglandins. Bisphosphonates also appear to reduce parathyroid hormone induced bone resorption, where osteoblasts are involved in regulating osteoclast activity.Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. This may be due to the mediation of release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF) by monocytes. These cytokines are involved in osteoclast recruitment and activation.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.

    PHARMACOKINETICS

    Zoledronic acid is administered by intravenous infusion. It distributes primarily to the bone in a triphasic process. The early distribution half-life is 0.23 hours, early elimination half-life is 1.75 hours, and terminal elimination half-life is 167 hours, with low plasma concentrations observed up to 28 days post dose. Plasma protein binding is approximately 22% and independent concentrations.
     
    Zoledronic acid does not inhibit P450 enzymes in vitro. A study of 32 patients with cancer and bone metastases found that 44 +/- 18% of the administered dose was recovered unchanged in the urine within 24 hours. The remaining drug, representing drug presumably bound to bone, is slowly released back into systemic circulation, giving rise to the prolonged terminal half-life.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  none

    Intravenous Route

    A complete response to zoledronic acid, when treating hypercalcemia of malignancy, to a single dose of zoledronic acid is typically seen within 4 to 10 days, lasting up to 3—4 weeks.