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General: All patients, including patients with mild to moderate renal impairment, must be assessed prior to administration of Zoledronic acid to assure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcaemia-related metabolic parameters, such as albumin-corrected serum levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored after initiating Zoledronic acid therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occur, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zoltero contains the same active ingredient as in Aclasta (zoledronic acid). Patients being treated with Zoledronic acid should not be treated with Aclasta concomitantly. Zoledronic acid should also not be given together with other bisphosphonates since the combined effects of these agents are unknown.
While not observed in clinical trials with Zoledronic acid, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Renal impairment: Adult patients with HCM and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with Zoledronic acid outweighs the possible risk (see Dosage & Administration).
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2 to 3 months.
Bisphosphonates have been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic acid or other bisphosphonates as well as use of nephrotoxic drugs or using a shorter infusion time than currently recommended. While the risk is reduced with a dose of Zoledronic acid 4 mg administered over no less than 15 minutes, deterioration in renal function may still occur. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Zoledronic acid. Increases in serum creatinine also occur in some patients with chronic administration of Zoledronic acid at recommended doses for prevention of skeletal related events, although less frequently.
Serum creatinine levels should be measured before each Zoledronic acid dose. In patients with mild to moderate renal impairment at the initiation of Zoledronic acid treatment, lower doses are recommended in all adult patients except patients with HCM. In patients who show evidence of renal deterioration during treatment, Zoledronic acid should only be resumed when creatinine level returns to within 10% of baseline value (see Dosage & Administration).
The use of Zoledronic acid is not recommended in patients with severe renal impairment because there are limited clinical safety and pharmacokinetic data in this population, and there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zoledronic acid. In clinical trials, patients with severe renal impairment were defined as those with baseline serum creatinine ≥ 400 micromol/L or ≥4.5 mg/dL for patients with HCM and ≥ 265 micromol/L or ≥ 3.0 mg/dL for all other patients, respectively.
In pharmacokinetic studies, patients with severe renal impairment were defined as those with baseline creatinine clearance <30 mL/min (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Hepatic impairment: As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in adult cancer patients treated with bisphosphonates, including Zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. Many had signs of local infection including osteomyelitis.
Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
Patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
While on treatment with bisphosphonates, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Osteonecrosis of other anatomical sites: Cases of osteonecrosis of other anatomical sites including the hip, femur and external auditory canal have been reported predominantly in adult cancer patients treated with bisphosphonates, including Zoltero.
Atypical fractures of the femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, 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. Discontinuation of Zoledronic acid therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. Reports of atypical femoral fracture have been received in patients treated with Zoledronic acid; however causality with Zoledronic acid therapy has not been established.
During Zoledronic acid treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Musculoskeletal pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including Zoledronic acid (see Adverse Reactions). The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with Zoledronic acid. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcaemia. In some instances, the hypocalcaemia may be life- threatening. Caution is advised when Zoledronic acid is administered with other hypocalcaemia causing drugs, as they may have synergistic effect resulting in severe hypocalcaemia (see Inetractions). Serum calcium should be measured and hypocalcaemia must be corrected before initiating Zoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D.
