Bisphosphonate

Zoledronic acid

Solution for infusion Clear and colourless solution.

Each bottle with 100 ml of solution contains 5 mg zoledronic acid anhydrous, corresponding to 5.330 mg zoledronic acid monohydrate. One ml solution contains 0.05 mg zoledronic acid anhydrous corresponding to 0.0533 mg zoledronic acid monohydrate.

Treatment of Paget’s disease of the bone.

Aclasta should be prescribed only by physicians with experience in treatment of Paget's disease of the bone. The recommended dose is one intravenous infusion of 5 mg zoledronic acid (anhydrous) in 100 ml aqueous solution administered via a vented infusion line given at a constant infusion rate. The infusion time must not be less than 15 minutes. Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important for patients receiving diuretic therapy.

Adequate vitamin D intake is recommended in association with Aclasta administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following Aclasta administration (See Special Precautions). Retreatment of Paget’s disease: specific retreatment data are not available. After a single treatment with Aclasta in Paget’s disease, an extended remission period is observed in responding patients.

Patients with renal impairment (See Special Precautions) Use of Aclasta in patients with creatinine clearance < 30 ml/min is not recommended due to lack of adequate clinical experience in this population. No dose adjustment is necessary in patients with creatinine clearance = 30 ml/min. Patients with hepatic impairment No dose adjustment is required.

Aclasta has not been tested in children and adolescents and therefore should not be used in these age groups.

Elderly patients (= 65 years) No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Hypersensitivity to the active substance or to any of the excipients. Aclasta is contraindicated for patients with hypocalcaemia (See Special Precautions). Aclasta is contraindicated during pregnancy and in breast-feeding women.

The dose of 5 mg zoledronic acid must be administered over at least 15 minutes. Aclasta is not recommended in patients with severe renal impairment (creatinine clearance < 30 ml/min) due to lack of adequate clinical experience in this population. Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important for patients receiving diuretic therapy. Caution is indicated when Aclasta is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration), See Interactions. Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (See Contraindications). Other disturbances of mineral metabolism must also be effectively treated. Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Aclasta (See Adverse Reactions). Adequate vitamin D intake is recommended in association with Aclasta administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following Aclasta administration (See Adult Dosage). Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk.

Specific drug-drug interaction studies have not been conducted with zoledronic acid. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro. Zoledronic acid is not highly bound to plasma proteins (approximately 56% bound) and interactions resulting from displacement of highly protein-bound drugs are therefore unlikely. Zoledronic acid is eliminated by renal excretion. Caution is indicated when Aclasta is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration). Pregnancy and lactation There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations. The potential risk for humans is unknown. It is not known whether zoledronic acid is excreted into human breast milk. Aclasta is contraindicated during pregnancy and in breast-feeding women (See Contraindications).

Intravenous administration of Aclasta has been most commonly associated with the following symptoms suspected to be related to study drug and which usually occur within 3 days following Aclasta administration: flu-like symptoms (11.9%), fever (6.8%), headache (6.2%), nausea (5.6%), bone pain (4.5%), myalgia (6.2%) and arthralgia (4.0%). The majority of these symptoms resolve within 4 days of the event onset. Very common (>1/10) and common (=1/100, <1/10) adverse reactions suspected (investigator assessment) to be drug related and occurring more than once in Paget’s patients receiving Aclasta over a 6-month study period are listed by system organ class in Table 1. Table 1 Adverse reactions suspected* to be drug related occurring more than once in Paget’s patients receiving Aclasta over a 6-month follow-up period Metabolism and nutrition disorders - Common: Hypocalcaemia. Nervous system disorders - Common Headache, lethargy. Respiratory, thoracic and mediastinal - Common Dyspnoea disorders. Gastrointestinal disorders - Common Diarrhoea, nausea, dyspepsia. Musculoskeletal and connective tissue - Common Bone pain, arthralgia, myalgia disorders. General disorders and administration - Very common Flu-like symptoms site conditions, Common Pyrexia, rigors, fatigue, pain, asthenia * Investigator assessment. Laboratory findings: Early, transient decreases in serum calcium and phosphate levels have been observed commonly. Hypocalcaemia may be symptomatic in some patients (See Adult Dosage and Special Precautions). Class-effects: Renal dysfunction: Renal dysfunction has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise or additional risk factors (e.g oncology patients with chemotherapy, concomitant nephrotoxic medications, severe dehydration, etc). Iritis/uveitis/episcleritis/conjunctivitis: Cases of iritis, uveitis and episcleritis have been reported in patients treated with bisphosphonates, although no cases were reported in the Paget’s disease studies. Conjunctivitis has been reported in patients treated with zoledronic acid. Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported primarily in patients with cancer receiving treatment regimens including bisphosphonates. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene, local infection including osteomyelitis, and the majority of reported cases have been associated with dental procedures such as tooth extractions. A causal relationship between bisphosphonate use and ONJ has not been established. ONJ has not been observed in the Paget’s disease clinical studies.

Novartis

(POM)

11 August 2009