Aclasta · 4.3 Contraindications · 1

HOS-093976 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), arthralgia (4.8%) and headache (5.1%), see “acute phase reactions” below. Tabulated list of adverse reactions Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Infections and infestations Uncommon Influenza, nasopharyngitis Blood and lymphatic system disorders Uncommon Anaemia Immune system disorders Not known** Hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock Metabolism and nutrition disorders Common Hypocalcaemia* Uncommon Decreased appetite Rare Hypophosphataemia Psychiatric disorders Uncommon Insomnia Nervous system disorders Common Headache, dizziness Uncommon Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia Eye disorders Common Ocular hyperaemia Uncommon Conjunctivitis, eye pain Rare Uveitis, episcleritis, iritis Not known** Scleritis and parophthalmia Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Commo

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HOS-093972 · has-contraindication-information · PDF-Seite 3

- Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients listed in section 6.1. - Patients with hypocalcaemia (see section 4.4). - Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4). - Pregnancy and breast-feeding (see section 4.6). 3

HOS-093971 · has-indication-information · PDF-Seite 2

Treatment of osteoporosis • in post-menopausal women • in adult men at increased risk of fracture, including those with a recent low-trauma hip fracture. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy • in post-menopausal women • in adult men at increased risk of fracture. Treatment of Paget’s disease of the bone in adults.

HOS-093974 · has-interaction-information · PDF-Seite 6

No interaction studies with other medicinal products have been performed. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound medicinal products are therefore unlikely. Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4). In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

HOS-093975 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential Aclasta is not recommended in women of childbearing potential. Pregnancy Aclasta is contraindicated during pregnancy (see section 4.3). 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 (see section 5.3). The potential risk for humans is unknown. Breast-feeding Aclasta is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic acid is excreted into human milk. Fertility Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered related to the compound’s inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of Aclasta on fertility in humans.

HOS-093973 · has-warning-information · PDF-Seite 4

Renal function The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. Renal impairment has been observed following the administration of Aclasta (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after Aclasta administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above. The following precautions should be taken into account to minimise the risk of renal adverse reactions: • Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula before each Aclasta dose. • Transient increase in serum creatinine may be greater in patients with underlying impaired renal function. • Monitoring of serum creatinine should be considered in at-risk patients. • Aclasta should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5). • Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Aclasta. • A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2). Hypocalcaemia Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients. 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 section 4.8). Adequate calcium and vitamin D intake are recommended in association with Aclasta administration. In addition, in patients with Paget's dis

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