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General: Patients must be assessed prior to administration of Zoledronic acid Fresenius Kabi to ensure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating Zoledronic acid Fresenius Kabi therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, 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.
Other products containing zoledronic acid as active substances are available for osteoporosis indications and treatment of Paget's disease of the bone. Patients being treated with Zoledronic acid Fresenius Kabi should not be treated with any other medicines containing zoledronic acid or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Renal Insufficiency: Patients with TIH with evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with Zoledronic acid Fresenius Kabi outweighs the possible risk.
The decision to treat patients with bone metastases for the reduction of skeletal related events should consider that the onset of treatment effect is 2-3 months.
Zoledronic acid, used as indicated in Indications and Recommended dose and Mode of administration under Dosage & Administration has 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 Fresenius Kabi and other bisphosphonates as well as use of other nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Development of kidney injury associated with zoledronic acid is potentially related to high peak plasma concentration increasing the intracellular concentration of zoledronic acid and the risk for cellular damage. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 20 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 4 mg zoledronic acid. Increases in serum creatinine also occur in some patients with chronic administration of zoledronic acid at recommended doses for reduction of skeletal related events, although less frequently.
Patients should have their serum creatinine levels assessed prior to each dose of Zoledronic acid Fresenius Kabi. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of Zoledronic acid Fresenius Kabi are recommended. In patients who show evidence of renal deterioration during treatment, Zoledronic acid Fresenius Kabi should be withheld. Zoledronic acid Fresenius Kabi should only be resumed when serum creatinine returns to within 10% of baseline.
Zoledronic acid Fresenius Kabi treatment should be resumed at the same dose as that given prior to treatment interruption.
In view of the potential impact of zoledronic acid, on renal function, the lack of clinical safety data in patients with severe renal impairment (in clinical trials defined as serum creatinine ≥400 µmol/l or ≥4.5 mg/dl for patients with TIH and ≥265 µmol/l or ≥3.0 mg/dl for patients with cancer and bone metastases, respectively) at baseline and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30 ml/min), the use of Zoledronic acid Fresenius Kabi is not recommended in patients with severe renal impairment.
Hepatic Insufficiency: 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 in patients, predominantly those with cancer, receiving treatment with medicinal products that inhibit bone resorption, such as zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction or other dental surgeries. Many had sings of local infection including osteomyelitis.
The following risk factors should be considered when evaluating an individual's risk of developing ONJ: Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose.
Cancer, chemotherapy (see section Interactions with other medicaments), radiotherapy, corticosteroids, smoking and co-morbid conditions (e.g. anaemia, coagulopathies, infection).
History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors.
While on treatment. 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 judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients that were given zoledronic acid as indicated in section Indications and Recommended dose and Mode of administration. However, such reports have been infrequent. 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 zoledronic acid or another bisphosphonate.
Atypical fractures of the femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported with 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 bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate 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.
During bisphosphonate 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially "sodium-free".
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (including seizures, numbness and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some instances, the hypocalcaemia may be life-threatening (see Adverse Reactions).
Effects on ability to drive and use machines: Adverse reactions, such as dizziness and somnolence, may have influence on the ability to drive or use machines, therefore caution should be exercised with the use of Zoledronic acid Fresenius Kabi along with driving and operating of machinery.
