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General: Patients receiving zoledronic acid should be under the supervision of a physician experienced in the administration of intravenous bisphosphonates.
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be monitored after initiating zoledronic acid therapy. Short-term supplemental therapy may be necessary if hypocalcemia occurs.
Serum creatinine concentration must be evaluated prior to administration of each dose of zoledronic acid. Lower doses of zoledronic acid are recommended in patients with bone metastases with mild to moderate renal impairment. Zoledronic acid should be withheld in patients who show evidence of renal deterioration. Treatment should only be resumed (at the same dose as that given prior to treatment interruption) when serum creatinine returns to within 10% of baseline.
Hydration and Electrolyte Monitoring: Prior to administration, patients (including pediatric patients) should be assessed to assure that they are adequately hydrated. The use of loop diuretics is not recommended. Use zoledronic acid with caution with other nephrotoxic drugs. (see Dosing Recommendations under Dosage & Administration)
Renal Impairment: Bisphosphonates, including zoledronic acid, have been associated with renal toxicity (manifested as deterioration of renal function and potential renal failure). Using the usual recommended dose of zoledronic acid may reduce the risk of renal impairment. However, deterioration in renal function may still occur. In some cases, renal deterioration (which progressed to renal failure) occurred after administration of the initial dose of zoledronic acid.
Risk factors predisposing patients to renal deterioration include dehydration, pre-existing renal impairment, chemotherapy, concomitant therapy with other nephrotoxic drugs, dosage, infusion volume and rate, and multiple cycles of treatment.
Transient increases in serum creatinine concentration may be greater in patients with impaired renal function.
Musculoskeletal Pain: Severe and occasionally incapacitating bone, joint and/or muscle pain have been reported infrequently in patients taking bisphosphonates. This may occur from one day to several months after initiation of treatment. Recurrence of symptoms has been observed in some patients when rechallenged with the same medicine or another bisphosphonate.
Osteonecrosis of the Jaw (ONJ): ONJ has been associated with the use of bisphosphonates. ONJ has been reported mostly in cancer patients treated with intravenous bisphosphonates, including zoledronic acid.
Signs and symptoms (which may occur months to years after commencing bisphosphonate therapy) of ONJ include altered local sensation (hyperesthesia or numbness), maxillofacial pain, "toothaches", denture sore spots, loose teeth, exposed bone in the oral cavity, impaired healing, recurrent or persistent soft tissue infection in the oral cavity and marked oral odor.
Known risk factors for ONJ include: invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (such as chemotherapy, radiotherapy, corticosteroids, immunosuppressive drugs), poor oral hygiene, co-morbid disorders (such as periodontal and/or other pre-existing dental disease, and poorly fitting dentures). Patients should consider a dental examination with appropriate preventive dentistry prior to treatment with bisphosphonates. All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and report any oral symptoms (e.g., dental mobility, pain, swelling) during bisphosphonate treatment.
For patients requiring invasive dental procedures, the risk for ONJ may be reduced by stopping bisphosphonate treatment. The management plan for each patient should be based on the clinical judgment of the physician and on individual risk/benefit assessment.
Patients who develop ONJ while on bisphosphonate therapy should receive appropriate antibiotic therapy and be seen by an oral surgeon. In these patients, extensive dental surgery may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
Atypical Fractures of the Femur: In bisphosphonate-treated patients, atypical, low-energy, or low trauma fractures of the femoral shaft have been reported. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients experience prodromal pain (presenting as dull, aching thigh pain) in the affected area weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral, therefore, the contralateral femur should be examined in zoledronic acid treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported.
Evaluate any patient with a history of bisphosphonate exposure who presents with thigh or groin pain to rule out an incomplete femoral fracture. Discontinuation of bisphosphonate therapy should be considered, pending a benefit/risk assessment, on an individual basis.
Patients with Asthma: There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. However, this effect was not observed in clinical trials of zoledronic acid.
Ophthalmic: Zoledronic acid may cause ocular disturbances (conjunctivitis, uveitis, episcleritis, scleritis, and orbital inflammation). Patients with ocular events other than uncomplicated conjunctivitis should be referred to an ophthalmologist for evaluation. Treatment may need to be discontinued.
Effects on Ability to Drive or Use Machines: Rarely, zoledronic acid causes somnolence and/or dizziness. Patients receiving zoledronic acid should be advised to take precautions while performing activities requiring mental alertness or physical coordination. It should be carefully considered whether it is advisable to drive or operate machinery under these circumstances.
Hepatic Impairment: The clinical data available for the use of zoledronic acid in patients with hepatic impairment is limited; no dosage recommendations may be given in this group.
Use in Children: The safety and efficacy of zoledronic acid in children 1 to 17 years old have not been established.
Use in Elderly: There are no age-related differences in zoledronic acid's adverse events profile. However, since decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.
