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General: Patients must be assessed prior to administration of Zoledronic Acid Monohydrate to ensure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcemia-related metabolic parameters, such as serum albumin-corrected levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored after initiating Zoledronic Acid Monohydrate therapy. If hypocalcemia, hypophosphatemia, or hypomagnesaemia occur, short-term supplemental therapy may be necessary. Untreated hypercalcemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zoledronic Acid Monohydrate should also not be given together with other bisphosphonates since the combined effects of these agents are unknown.
The safety and efficacy of Zoledronic Acid Monohydrate in paediatric patients have not been established. There have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Renal impairment: Adult patients with HCM and evidence of impairment in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with Zoledronic Acid Monohydrate outweighs the possible risk. 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 function deterioration. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic Acid Monohydrate 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 Monohydrate 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 Monohydrate. Increases in serum creatinine also occur in some patients with chronic administration of Zoledronic Acid Monohydrate at recommended doses for prevention of skeletal related events, although less frequently.
Serum creatinine levels should be measured before each Zoledronic Acid Monohydrate dose. In patients with mild to moderate renal impairment at the initiation of Zoledronic Acid Monohydrate treatment, lower doses are recommended in adult patients with bone metastases. In patients who show evidence of renal deterioration during treatment, Zoledronic Acid Monohydrate should only be resumed when creatinine level returns to within 10% of baseline value (see Dosage & Administration). The use of Zoledronic Acid Monohydrate is not recommended in patients with severe renal impairment, there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zoledronic Acid Monohydrate.
The use of Zoledronic Acid Monohydrate is not recommended in patients with severe renal impairment, because there are limited clinical safety and pharmacokinetic data in population and there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zoledronic Acid Monohydrate.
Renal function deterioration is defined as follows: Serum creatinine ≥ 400 micromol/L or ≥ 4.5 mg/mL for patients with HCM.
Serum creatinine ≥ 265 micromol/L or ≥ 3.0 mg/mL for patients with cancer and bone metastases respectively.
In pharmacokinetics studies, patients with severe renal impairment were defined as those with baseline creatinine clearance < 30 mL/minute.
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 Monohydrate-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zoledronic Acid Monohydrate 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 Monohydrate, however causality with Zoledronic Acid Monohydrate therapy has not been established. During Zoledronic Acid Monohydrate 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.
Hepatic impairment: As only limited 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 bisphosphonate, including Zoledronic Acid Monohydrate. 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 tumour 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 bisphosphonate.
While on treatment with bisphosphonate, 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 of 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 Zoledronic Acid Monohydrate.
Musculoskeletal pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including Zoledronic Acid Monohydrate. However, such reports have been infrequent. This category includes Zoledronic Acid Monohydrate. 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 re-challenged with the same drug or another bisphosphonate.
Hypocalcemia: Hypocalcemia has been reported in patients treated with Zoledronic Acid Monohydrate. Cardiac arrhythmias and neurologic adverse events (seizures, tetany and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, the hypocalcemia may be life-threatening. Caution is advised when Zoledronic Acid Monohydrate is administrated with other hypocalcemia causing drugs, as they may have synergistic effect resulting in severe hypocalcemia. Serum calcium should be measured and hypocalcemia must be corrected before initiating Zoledronic Acid Monohydrate therapy. Patients should be adequately supplemented with calcium and vitamin D.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
Women of Child-bearing potential: Women of Child-bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the fetus while receiving Zoledronic Acid Monohydrate. There may be risk of fetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant while receiving bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established.
Fertility: The Fertility was decreased in rats dosed subcutaneously with 0.1 mg/kg/day of Zoledronic Acid Monohydrate. There are no data available in humans.
Use in Pregnancy: Studies in rats have shown reproductive toxicological effects. The potential risk in humans is unknown Zoledronic Acid Monohydrate should not be used during pregnancy (see Contraindications).
Use in Lactation: It is not known whether Zoledronic Acid Monohydrate is excreted into human milk. Zoledronic Acid Monohydrate should not be used by breast-feeding women (see Contraindications).
