ZOLEDRONIC ACID

Zoledronic Acid Concentrate must only be used by clinicians experienced in the administration of intravenous bisphosphonates. 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.

9% w/v sodium chloride or 5% w/v glucose solution and given in no less than a 15- minute intravenous infusion every 3 to 4 weeks. Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily. 0 mmol/l) is a single dose of 4 mg zoledronic acid.

Renal impairment TIH:

Zoledronic Acid Concentrate 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 Concentrate 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 Concentrate 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. 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 Concentrate and treatment should be withheld if renal function has deteriorated.

0 mg/dl or 88 μmol/l. 4). Zoledronic Acid Concentrate treatment should be resumed at the same dose as that prior to treatment interruption. Paediatric population The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been established.

1 but no recommendation on a posology can be made. 6. 9% w/v sodium chloride solution or 5% w/v glucose solution. The dose must be given as a single intravenous infusion over no less than 15 minutes. Zoledronic Acid Concentrate must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer's solution, and should be administered as a single intravenous solution in a separate infusion line.

Patients must be maintained well hydrated prior to and following administration of Zoledronic Acid Concentrate. Method of administration Intravenous use. Patients treated with Zoledronic Acid Concentrate should be given the package leaflet and the patient reminder card.

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

The following are the important identified risks with Zoledronic Acid Concentrate 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 1. Tabulated list of adverse reactions The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: Table 1 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: • Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence • Very rare • Convulsions, hypoaestheisa 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: • Dyspnoea, cough, bronchoconstriction • Rare: • 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: • Muscle spasms, osteonecrosis of the jaw • Very rare • 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: • Acute renal failure, haematuria, proteinuria • Rare • Acquired Fanconi syndrome • Not known • Tubulointerstitial nephritis • General disorders and administration site conditions • Common: • Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing) • Uncommon: • Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria • Rare • 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 Concentrate has been associated with reports of renal dysfunction.

2%). Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic Acid Concentrate or other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a shorter infusion time than currently recommended.

4). 4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.

Atrial fibrillation In one 3-year, randomised, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid 5 mg once yearly vs. 9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively.

6% (22 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in other trials with zoledronic acid, including those with Zoledronic acid 4 mg every 3-4 weeks in oncology patients.

The mechanism behind the increased […]

General Patients must be assessed prior to administration of Zoledronic Acid Concentrate 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 Concentrate 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.

Zoledronic Acid Concentrate contains the same active substance as found in Aclasta (zoledronic acid). Patients being treated with Zoledronic Acid Concentrate should not be treated with Aclasta 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 Concentrate 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 Concentrate 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 Concentrate and other bisphosphonates as well as use of other nephrotoxic drugs.

While the risk is reduced with a dose of Zoledronic Acid Concentrate 4 mg administered over 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 Concentrate.

Increases in serum creatinine also occur in some patients with chronic administration of Zoledronic Acid Concentrate at recommended doses for prevention of skeletal related events, although less frequently. Patients should have their serum creatinine levels assessed prior to each dose of Zoledronic Acid Concentrate.

Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of Zoledronic Acid Concentrate are recommended. In patients who show evidence of renal deterioration during treatment, Zoledronic Acid Concentrate should be withheld.

Zoledronic Acid Concentrate should only be resumed when serum creatinine returns to within 10% of baseline. Zoledronic Acid Concentrate should be resumed at the same dose as that given prior to treatment interruption. 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 Concentrate 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 Osteonecrosis of the jaw (ONJ) Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials in patients receiving Zoledronic Acid Concentrate.

Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma). 1). The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth, except in medical emergency situations.

A dental examination with preventive dentistry and an individual benefit- risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors. The following should be considered when evaluating an individual’s risk of developing ONJ: - Potency of bisphosphonates (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonates.

g. anaemia, coagulopathies, infection), smoking. 5), radiotherapy to head and neck. g. tooth extractions) and poorly fitting dentures. All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of sores or discharge during treatment with zoledronic acid.

While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment. 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. The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.

Temporary interruption of zoledronic acid treatment should be […]

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