ZOLEDRONIC ACID

Zoledronic Acid Solution for infusion must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zoledronic Acid Solution for infusion should be given the package leaflet and the patient reminder card.

Posology Prevention of skeletal related events in patients with advanced malignancies involving bone Adults and elderly The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid every 3 to 4 weeks.

Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily. The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months.

0 mmol/l) is a single dose of 4 mg zoledronic acid.

Renal impairment TIH:

Zoledronic Acid Solution for infusion treatment in TIH patients who also have severe renal impairment should be considered only after evaluating the risks and benefits of treatment. 5 mg/dl were excluded. 4). Prevention of skeletal related events in patients with advanced malignancies involving bone: When initiating treatment with Zoledronic Acid Solution for infusion in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should be determined.

CLcr is calculated from serum creatinine using the Cockcroft-Gault formula. Zoledronic Acid Solution for infusion is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CLcr < 30 ml/min.

0 mg/dl were excluded. For patients with normal renal function (defined as CLcr > 60 ml/min), zoledronic acid solution for infusion may be administered directly without any further preparation. 66 (mg•hr/l) (CLcr=75 ml/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min.

Following initiation of therapy, serum creatinine should be measured prior to each dose of Zoledronic Acid Solution for infusion and treatment should be withheld if renal function has deteriorated. 0 mg/dl or 88 μmol/l. 4). Zoledronic Acid Solution for infusion treatment should be resumed at the same dose as that given prior to treatment interruption.

Summary of the safety profile Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions).

The following are the important identified risks with Zoledronic Acid Solution for infusion in the approved indications: Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis, interstitial lung disease.

The frequencies for each of these identified risks are shown in Table 2. Tabulated list of adverse reactions The following adverse reactions, listed in Table 2, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: Table 2 Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders Common:

Anaemia Uncommon: Thrombocytopenia, leukopenia Rare: Pancytopenia Immune system disorders Uncommon: Hypersensitivity reaction Rare: Angioneurotic oedema Psychiatric disorders Uncommon: Anxiety, sleep disturbance Rare: Confusion Nervous system disorders Common: Headache Uncommon: Very rare: Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia) Eye disorders Common: Conjunctivitis Uncommon: Blurred vision, scleritis and orbital inflammation Rare: Uveitis Very rare: Episcleritis Cardiac disorders Uncommon: Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse Rare: Bradycardia, cardiac arrhythmia (secondary to hypocalcaemia) Respiratory, thoracic and mediastinal disorders Uncommon: Rare: Dyspnoea, cough, bronchoconstriction Interstitial lung disease Gastrointestinal disorders Common: Nausea, vomiting, decreased appetite Uncommon: Diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth Skin and subcutaneous tissue disorders Uncommon: Pruritus, rash (including erythematous and macular rash), increased sweating Musculoskeletal and connective tissue disorders Common: Bone pain, myalgia, arthralgia, generalised pain Uncommon: Very rare: Muscle spasms, osteonecrosis of the jaw Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) and other anatomical sites including femur and hip Renal and urinary disorders Common: Renal impairment Uncommon: Rare: Not known: Acute renal failure, haematuria, proteinuria Acquired Fanconi syndrome Tubulointerstitial nephritis General disorders and administration site conditions Common: Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing) Uncommon: Rare: Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria Arthritis and joint swelling as a symptom of acute phase reaction Investigations Very common: Hypophosphataemia Common: Blood creatinine and blood urea increased, hypocalcaemia Uncommon: Hypomagnesaemia, hypokalaemia Rare: Hyperkalaemia, hypernatraemia Description of selected adverse reactions Renal function impairment Zoledronic acid has been associated with reports of renal dysfunction.

General Patients must be assessed prior to administration of Zoledronic Acid Solution for infusion 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 Solution for infusion 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.

Patients being treated with Zoledronic Acid Solution for infusion 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.

15% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 9% w/v sodium chloride solution) is used for the dilution of Zoledronic Acid Solution for infusion prior to administration then the dose of sodium received would be higher.

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 Solution for infusion 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 2–3 months. Zoledronic acid 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 and other bisphosphonates as well as use of other nephrotoxic medicinal products.

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