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  • CLASSES

    Injectable Bisphosphonates

    DEA CLASS

    Rx

    DESCRIPTION

    Potent third-generation intravenous bisphosphonate; carefully select product based on indication for use
    Used for hypercalcemia of malignancy and bone metastases (e.g., Zometa); given as a single dose for Paget's disease (e.g., Reclast)
    Given once-yearly for osteoporosis and corticosteroid-induced osteoporosis and prevention in both men and women, and every 2 years for osteoporosis prophylaxis in postmenopausal women (e.g., Reclast)

    COMMON BRAND NAMES

    Reclast, Zometa

    HOW SUPPLIED

    Reclast/Zoledronic Acid/Zometa Intravenous Inj Sol: 4mg, 5mg, 5mL, 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 (i.e., Zometa or generic equivalents)
    Adults

    4 mg IV infusion over a minimum of 15 minutes. Retreatment may be considered if serum calcium does not return to normal after 7 days. Monitor serum creatinine (SCr) at each dose. Evaluate a patient with deterioration from baseline renal function as to whether the benefit of continued treatment outweighs possible risks. For this indication, a reduction in dose for baseline mild to moderate renal insufficiency (i.e., SCr 4.5 mg/dL or less) is not necessary.

    For the treatment of patients with multiple myeloma or with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.
    NOTE: If using for patients with prostate cancer, prostate cancer should have progressed after treatment with at least one hormonal therapy.
    Intravenous dosage (e.g., Zometa or generic equivalents)
    Adults

    4 mg IV infusion over a minimum of 15 minutes once every 3 to 4 weeks. Supplement with oral calcium 500 mg and vitamin D 400 International Units per day. Monitor serum creatinine (SCr) at baseline and each subsequent dose. Monitor serum creatinine (SCr) at each dose. If renal function deteriorates (i.e., SCr increase of 0.5 mg/dL or more for normal SCr at baseline or 1 mg/dL or more with abnormal SCr at baseline), hold further doses until renal function is within 10% of baseline. Reinitiate at the same dose used before treatment interruption.

    For the treatment of Paget's disease.
    Intravenous dosage (i.e., Reclast and generic equivalents)
    Adults

    5 mg IV infusion over at least 15 minutes as a single dose. All patients should take 1,500 mg elemental calcium daily in divided doses (750 mg twice daily or 500 mg 3 times daily) and 800 International Units vitamin D per day, particularly in the 2 weeks following a dose. Guidelines recommend zoledronic acid as the agent of choice due to the durability of response (rare need for retreatment within 5 years), patient adherence to treatment, and the long-term data for reducing pain and lytic lesions and improving quality of life. After a single dose, an extended remission period is observed, with histologic and radiologic evidence of disease improvement. Specific re-treatment data are not available. However, may consider re-treatment in patients who have relapsed (based on increases in serum alkaline phosphatase), in those who fail to achieve normalization of their serum alkaline phosphatase, or in symptomatic patients. During clinical trials, most patients showed a therapeutic response within 60 days, and this response was sustained.

    For the treatment of osteoporosis.
    For treatment of osteoporosis in men or postmenopausal women.
    Intravenous dosage (i.e., Reclast and generic equivalents)
    Adult men and postmenopausal females

    5 mg IV infusion over at least 15 minutes, given once yearly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. An average of at least 1,200 mg calcium and 800 to 1000 International Units vitamin D per day is recommended. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk.[43421] Bisphosphonates are first-line therapy for the treatment of osteoporosis in postmenopausal women; the drug is additionally effective in men with osteoporosis.[41628] [62806] [61918]

    For corticosteroid-induced osteoporosis in men and women.
    Intravenous dosage (i.e., Reclast and generic equivalents)
    Adults

    5 mg IV infusion over at least 15 minutes, given once yearly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. An average of at least 1,200 mg calcium and 800 to 1000 International Units vitamin D per day is recommended. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.

    For osteoporosis prophylaxis.
    For osteoporosis prevention in postmenopausal women.
    Intravenous dosage (i.e., Reclast and generic equivalents)
    Postmenopausal females

    5 mg IV infusion over at least 15 minutes, given once every other year. Supplement with calcium and vitamin D daily if dietary intake is not sufficient. At least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D per day is recommended. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk.

    For osteoporosis prevention in postmenopausal women taking letrozole for early breast cancer†.
    Intravenous dosage (i.e., Zometa or generic equivalents)
    Adult postmenopausal females

    4 mg IV infusion over at least 15 minutes and given every 6 months appears effective at increasing or preserving bone mineral density (BMD) and reducing fracture risk; calcium and vitamin D is supplemented if dietary intake is inadequate.

    For osteoporosis prevention in men with prostate cancer receiving androgen deprivation therapy†.
    Intravenous dosage (i.e., Zometa or generic equivalents)
    Adult males

    4 mg IV infusion over at least 15 minutes and given every 3 months appears effective at preserving or increasing bone density; a dose of 4 mg IV infusion once yearly also appears effective. Patients receive calcium and vitamin D supplementation if dietary intake is inadequate.

    For prevention of corticosteroid-induced osteoporosis in men and women.
    Intravenous dosage (i.e., Reclast and generic equivalents)
    Adults

    5 mg IV infusion over at least 15 minutes, given once yearly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. An average of at least 1,200 mg calcium and 800 to 1000 International Units vitamin D per day is recommended. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping zoledronic acid after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.

    For 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 (Zometa):
    Serum creatinine 4.5 mg/dL or less: No dosage adjustment needed.
    Serum creatinine more than 4.5 mg/dL: Use only after careful consideration of the risks and benefits; no dosing recommendations are available. These patients were excluded from clinical trials.
     
    For Multiple Myeloma or Bone Metastases of Solid Tumors Indications (Zometa):
    CrCl more than 60 mL/minute: No dosage adjustment needed.
    CrCl 50 to 60 mL/minute: Reduce dose to 3.5 mg IV.
    CrCl 40 to 49 mL/minute: Reduce dose to 3.3 mg IV.
    CrCl 30 to 39 mL/minute: Reduce dose to 3 mg IV.
    CrCl less than 30 mL/minute: Use not recommended due to lack of clinical data. Zoledronic acid is not recommended in patients with bone metastases who have severe renal impairment; patients with a serum creatinine greater than 3 mg/dL were excluded from clinical trials.
     
    For Paget's Disease or Osteoporosis-related Indications (Reclast):
    CrCl 35 mL/minute: No dosage adjustment needed.
    CrCl less than 35 mL/minute: Use is contraindicated.

    ADMINISTRATION

    Injectable Administration

    Zoledronic acid is available as more than one indication-specific brand name product (e.g., Zometa, Reclast). Be sure to choose the proper product for the patient's indication for use prior to preparation and administration. Avoid duplications.
    Assess serum creatinine and ensure the proper hydration of the patient prior to each administration of zoledronic acid.
    For intravenous infusion only.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Dilution of zoledronic acid 4 mg/5 mL concentrate prior to infusion (e.g., Zometa):
    Must be diluted for infusion prior to use.
    Determine patient-specific dose, then use aseptic technique to withdraw 5 mL of concentrate for 4 mg dose, 4.4 mL for 3.5 mg dose, 4.1 mL for 3.3 mg dose, or 3.8 mL for 3 mg dose.
    Further dilute the dose in 100 mL of 0.9% Sodium Chloride injection or 5% Dextrose injection immediately.
    Do NOT mix in calcium-containing solutions (such as Lactated Ringer's).
    Vials are intended for single-use only. Discard any unused concentrate; do not store undiluted concentrate in a syringe.
    Storage of prepared infusions: If not used immediately after dilution, the solution should be refrigerated at 2 to 8 degrees C (36 to 46 degrees F). If refrigerated, allow the infusion to reach room temperature before administration. The total time between dilution and administration must not exceed 24 hours.[58640]
     
    Zoledronic acid 4 mg/100 mL ready-to-use solution for IV infusion (e.g., Zometa):
    This product does not require further dilution for a 4-mg dose.
    Remove infusion overwrap just before use.
    After removing overwrap, check for small leaks by squeezing inner bag. Use the container only if no leaks are found and the solution is clear and container undamaged.
    Preparation for reduced doses:
    For a dose of 3.5 mg remove and discard 12 mL of solution.
    For a dose of 3.3 mg remove and discard 18 mL.
    For a 3 mg dose remove and discard 25 mL.
    Replace the solution that was removed with an equal amount of 0.9% Sodium Chloride injection or 5% Dextrose injection. Do not store or reuse any removed solution.
    Storage: If the infusion is diluted for dose adjustment and not used immediately, the solution should be refrigerated at 2 to 8 degrees C (36 to 46 degrees F). If refrigerated, allow the infusion to reach room temperature before administration. The total time between removal from storage, dilution, and administration must not exceed 24 hours.[43420] [58640]
     
    Zoledronic acid 5 mg/100 mL ready-to-use solution for infusion (e.g., Reclast):
    This product does not require further dilution.
    Remove infusion overwrap just before use.
    After removing overwrap, check for small leaks by squeezing inner bag. Use the container only if no leaks are found and the solution is clear and container undamaged.
    If refrigerated, allow the infusion to reach room temperature before administration.[43421]
     
    Intravenous (IV) infusion administration:
    Administer via a separate, vented IV line. Do NOT administer with other intravenous agents.
    Do not allow to come in contact with any calcium- or divalent cation-containing solutions.
    Due to a risk of clinically significant renal toxicity, do not exceed the recommended dose for the specific indication. Do not infuse over less than 15 minutes. Administer at a constant infusion rate.[43420] [43421] [58640]
    Following the infusion, the manufacturer of Reclast recommends a 10 mL 0.9% Sodium Chloride injection flush of the IV line.[43421]
    Administration of acetaminophen following administration may reduce the incidence of acute-phase reaction symptoms.[43421]

    STORAGE

    Reclast:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original package until time of use
    - Store in original unopened pouch
    Zometa:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Asthma, ensure correct formulation selection, history of angioedema, phosphonate hypersensitivity

    Zoledronic acid use is contraindicated in any patient with a history of angioedema, serious rash, anaphylaxis or another severe hypersensitivity reaction to the drug or product excipients. Allergic reactions with intravenous zoledronic acid including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported. While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive asthma patients receiving bisphosphonates; use with caution in these patients. If anaphylactic or another severe hypersensitivity/allergic reaction occurs, immediately discontinue zoledronic acid and initiate appropriate treatment. Zoledronic acid should be used cautiously in patients with known phosphonate hypersensitivity. Zoledronic acid infusion therapy requires a specialized care setting. Proper medical support and monitoring measures should be readily available when the drug is administered in case there is hypersensitivity or another severe reaction. Administer by intravenous infusion only. When prescribing zoledronic acid, practitioners should ensure correct formulation selection for the indication to be treated. Zoledronic acid is available as Zometa and Reclast, which are indicated for different therapeutic uses and are available in different strengths. Patients receiving Zometa should not receive Reclast and vice versa.

    Dehydration, 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

    When used for osteoporosis or Paget's disease, zoledronic acid (e.g., Reclast) is contraindicated for use in patients with hypocalcemia. It is important to correct pre-existing hypocalcemia prior to initiating zoledronic acid therapy for any indication. Severe, potentially life-threatening, hypocalcemia has been reported in patients treated with zoledronic acid. In some cases, hypocalcemia was severe enough to cause cardiac arrhythmias and neurologic adverse events (i.e., seizures, tetany, numbness). Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored during treatment. If an electrolyte imbalance (i.e., hypocalcemia, hypomagnesemia, or hypophosphatemia) occurs during therapy, short-term supplementation, including adequate calcium and vitamin D, may be necessary.

    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.

    Pregnancy

    The use of zoledronic acid should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. If a patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid and the importance of using effective contraception during and after treatment. Pregnancy status should be determined prior to the start of zoledronic acid therapy.[43421] [58724] Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm (e.g., skeletal and other abnormalities, embryo-fetal lethality) in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.[43421] [58724] 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.[32877]

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid. Pregnancy status (e.g., pregnancy testing) should be determined before the start of zoledronic acid therapy. Due to the reproductive risk should the woman become pregnant, contraception requirements are advised. Advise females of childbearing age to use effective contraception before and after zoledronic acid therapy.[43421] [58724] Zoledronic acid may also impair fertility or cause infertility in females of reproductive potential. In animal studies involving female rats that received zoledronic acid, the following effects were observed: inhibition of ovulation, increase in preimplantation losses, decrease in the number of implantations, decrease in pregnancies, and decrease in live fetuses.[43421] [58724]

    Breast-feeding

    Breast-feeding is not recommended during or after zoledronic acid treatment, and a decision should be made to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known if zoledronic acid is excreted into breast milk. Reports describing use in lactating women are not available. Bisphosphonates bind to bone long-term, may be released over weeks to years, and can present a potentially serious risk to an exposed infant.[43421] [58724]

    Children, infants

    Safe and effective use of zoledronic acid in infants, children, and adolescents has not been established. Bisphosphonates have been used successfully in children for treatment of specific disease states (i.e., osteogenesis imperfecta). However, extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone mineral density (BMD). In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). It may be advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children to help assure clinicians that skeletal resorption is not excessively suppressed. Additionally, in a study of children and adolescents with severe osteogenesis imperfecta, zoledronic acid increased the BMD after 1 year; however, the increase in BMD did not correlate to risk of fracture or the incidence or severity of chronic bone pain. Adverse reactions reported by children were similar in nature to those reported by adults.

    Geriatric

    During clinical trials, overall differences in efficacy or safety were observed between geriatric patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients. There is an age-related decline in renal function in geriatric patients, which may increase the risk of adverse renal effects during administration of zoledronic acid. Cautious use and special care in renal monitoring are recommended in the elderly. The risk of adverse renal effects may be minimized by ensuring that patients are well-hydrated prior to therapy, avoiding concomitant use of nephrotoxic drugs in the post-infusion period, administering the drug over a minimum of 15 minutes, and not exceeding indication-specific dosage limits.

    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 tubular necrosis / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    teratogenesis / Delayed / 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
    hematuria / Delayed / Incidence not known
    proteinuria / 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
    infertility / 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 / 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.
    Amlodipine; 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.
    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: (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; Caffeine; Orphenadrine: (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; Citric Acid; Sodium Bicarbonate: (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. (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
    Aspirin, ASA; Dipyridamole: (Moderate) 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.
    Bupivacaine; 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.
    Calcium Acetate: (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: (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; Famotidine; 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; 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 Carbonate; Simethicone: (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 Chloride: (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 Gluconate: (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.
    Chlorpheniramine; 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.
    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: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as zoledronic acid, is contraindicated. Zoledronic acid should be discontinued at least 7 days prior to beginning cidofovir.
    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.
    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.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Emtricitabine; Rilpivirine; Tenofovir 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.
    Ethacrynic Acid: (Moderate) Loop diuretics should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
    Ethiodized Oil: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
    Etodolac: (Moderate) 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.
    Ferric Maltol: (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.
    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.
    Gallium Ga 68 Dotatate: (Major) Avoid use of mannitol and zoledronic acid, if possible. Concomitant administration of nephrotoxic drugs, such as zoledronic acid, increases the risk of renal failure after administration of mannitol.
    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.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and zoledronic acid due to the risk of glomerulonephritis and nephrotoxicity.
    Iodixanol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
    Iohexol: (Moderate) Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as radiopaque contrast agents, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function.
    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.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    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.
    Mannitol: (Major) Avoid use of mannitol and zoledronic acid, if possible. Concomitant administration of nephrotoxic drugs, such as zoledronic acid, increases the risk of renal failure after administration of mannitol.
    Meclofenamate Sodium: (Moderate) 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; Esomeprazole: (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.
    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.
    Norethindrone Acetate; Ethinyl Estradiol; 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.
    Norethindrone; Ethinyl Estradiol; 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.
    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.
    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.
    Plazomicin: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs may increase serum concentrations of either zoledronic acid and/or these coadministered drugs. Theoretically, the chronic coadministration of zoledronic acid with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity.
    Polymyxin B: (Major) Coadministration of parenteral polymyxin B with other potentially nephrotoxic drugs, including zoledronic acid, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since polymyxin B injection is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including zoledronic acid, may theoretically increase serum concentrations of either drug.
    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.
    Sumatriptan; 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.
    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.
    Voclosporin: (Moderate) Concomitant use of voclosporin and zoledronic acid may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

    PREGNANCY AND LACTATION

    Pregnancy

    The use of zoledronic acid should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. If a patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid and the importance of using effective contraception during and after treatment. Pregnancy status should be determined prior to the start of zoledronic acid therapy.[43421] [58724] Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm (e.g., skeletal and other abnormalities, embryo-fetal lethality) in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.[43421] [58724] 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.[32877]

    Women of childbearing potential should be advised to avoid becoming pregnant while receiving zoledronic acid. Pregnancy status (e.g., pregnancy testing) should be determined before the start of zoledronic acid therapy. Due to the reproductive risk should the woman become pregnant, contraception requirements are advised. Advise females of childbearing age to use effective contraception before and after zoledronic acid therapy.[43421] [58724] Zoledronic acid may also impair fertility or cause infertility in females of reproductive potential. In animal studies involving female rats that received zoledronic acid, the following effects were observed: inhibition of ovulation, increase in preimplantation losses, decrease in the number of implantations, decrease in pregnancies, and decrease in live fetuses.[43421] [58724]

    MECHANISM OF ACTION

    Zoledronic acid is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to the bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.[43421] [58724] [50514]
     
    Hypercalcemia is a common problem affecting cancer patients. Malignancy-associated hypercalcemia arises from accelerated bone resorption. This form of hypercalcemia could result from direct skeletal action by various tumors inducing osteoclast hyperactivity. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy. Zoledronic acid does not lower the level of parathyroid hormone-related protein (PTHrP) in patients with hypercalcemia of malignancy. The drug inhibits bone resorption without inhibiting bone formation or mineralization. Clinical studies in patients with hypercalcemia of malignancy showed that single-dose infusions of zoledronic acid are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.[43421] [58724] [50514]
    Like other bisphosphonates, the exact mechanism of zoledronic acid's therapeutic effect in patients with Paget's disease has not been clearly established. Paget's disease is a progressive, idiopathic disease of bone. Increasing numbers of unusually large osteoclasts are produced at affected sites. Increased bone resorption follows, which is compensated for by an increase in new bone formation. This new bone is inferior and often deformed, and can fracture easily. Bisphosphonates are believed to reduce the solubility of the mineralized bone matrix by adsorption to hydroxyapatite crystals in the matrix. The matrix becomes less soluble and resistant to osteoclastic resorption. Like other bisphosphonates, zoledronic acid can also block the formation of mature osteoclasts by affecting the attachment of osteoclast precursors to the mineralized matrix.[43421] [58724] [50514]
     
    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.[26652] [26653]

    PHARMACOKINETICS

    Zoledronic acid is administered by intravenous infusion. Pharmacokinetic data in patients with hypercalcemia, Paget's disease, or osteoporosis are not available; the pharmacokinetics of the drug have been studied in cancer patients with bone metastases. The drug distributes primarily to the bone in a triphasic process. The early distribution half-life is 0.24 hours, early elimination half-life is 1.87 hours, and the terminal elimination half-life is approximately 146 hours. Low plasma concentrations observed up to 28 days post-dose. In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5,000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2,000 ng/mL of zoledronic acid. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of radiolabeled zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized. In 64 patients with cancer and bone metastases, on average (+/- SD) 39% +/- 16% of the administered dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-day 2. The cumulative percent of drug excreted in the urine over 0 to 24 hours was independent of dose. The balance of drug not recovered in urine during the first 24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations and long terminal half-life. The 0 to 24 hour renal clearance of zoledronic acid was 3.7 +/- 2 L/hour. Zoledronic acid clearance was independent of dose but dependent upon the patient's creatinine clearance.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None
    Zoledronic acid does not inhibit any CYP450 enzymes in vitro.

    Intravenous Route

    Single or multiple (every 28 days) 5-minute or 15-minute IV infusions of 2, 4, 8, or 16 mg of zoledronic acid were given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process and distribution into bone, showing a rapid decrease from peak concentrations (Cmax) at end of the infusion to less than 1% of Cmax 24 hours postinfusion.