Osenvelt · 4.3 Contraindications · 1

HOS-100632 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Overall safety profile is consistent in all approved indications for denosumab. Hypocalcaemia has very commonly been reported following denosumab administration, mostly within the first 2 weeks. Hypocalcaemia can be severe and symptomatic (see section 4.8 - description of selected adverse reactions). The decreases in serum calcium were generally appropriately managed by calcium and vitamin D supplementation. The most common adverse reactions with denosumab are musculoskeletal pain. Cases of osteonecrosis of the jaw (see sections 4.4 and 4.8 - description of selected adverse reactions) have been commonly observed in patients taking denosumab. Tabulated list of adverse reactions The following convention has been used for the classification of the adverse reactions based on incidence rates in four phase III, two phase II clinical studies and post-marketing experience (see table 1): 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) and not known (cannot be estimated from the available data. Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions reported in patients with advanced malignancies involving bone, multiple myeloma, or with giant cell tumour of bone MedDRA system organ class Frequency category Adverse reactions Neoplasms benign, malignant Common New primary malignancy1 and unspecified (including cysts and polyps) Immune system disorders Rare Drug hypersensitivity1 Rare Anaphylactic reaction1 Metabolism and nutrition Very common Hypocalcaemia1,2 disorders Common Hypophosphataemia Uncommon Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone3 Respiratory, thoracic and Very common Dyspnoea mediastinal disorders Gastrointestinal disorders Very common Diarrho

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HOS-100628 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe, untreated hypocalcaemia (see section 4.4). Unhealed lesions from dental or oral surgery. 3

HOS-100627 · has-indication-information · PDF-Seite 2

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone (see section 5.1). Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

HOS-100630 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed. In clinical trials, denosumab has been administered in combination with standard anti-cancer treatment and in patients previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary N-telopeptide, uNTX/Cr) by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

HOS-100631 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Denosumab is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with denosumab. Any effects of denosumab are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Breast-feeding It is unknown whether denosumab is excreted in human milk. A risk to the newborns/infants cannot be excluded. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision must be made on whether to abstain from breast-feeding or to abstain from denosumab therapy taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy for the woman. Fertility No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-100629 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Calcium and Vitamin D supplementation Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present (see section 4.2). Hypocalcaemia Pre-existing hypocalcaemia must be corrected prior to initiating therapy with denosumab. Hypocalcaemia can occur at any time during therapy with denosumab. Monitoring of calcium levels should be conducted (i) prior to the initial dose of denosumab, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur (see section 4.8 for symptoms). Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient. Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurs while receiving denosumab, additional calcium supplementation and additional monitoring may be necessary. In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but can occur later. Renal impairment Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients. Osteonecrosis of the jaw (ONJ) ONJ has been reported commonly in patients receiving denosumab (see section 4.8). The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab. The following risk factors should be considered when evaluating a patient’s risk of developing ONJ: • potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy. • cancer, co-morbid conditions (e.g. a

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