Xofigo · 4.4 Special warnings and precautions for use · 1

HOS-096532 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The overall safety profile of Xofigo is based on data from 600 patients treated with Xofigo in the phase III study. The most frequently observed adverse reactions (≥ 10%) in patients receiving Xofigo were diarrhoea, nausea, vomiting, thrombocytopenia and bone fracture. The most serious adverse reactions were thrombocytopenia and neutropenia (see section 4.4 and ‘Description of selected adverse reactions’ below). Tabulated list of adverse reactions The adverse reactions observed with Xofigo are represented in the table below (see Table 1). They are classified according to System Organ Class. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Adverse reactions from clinical studies are classified according to their frequencies. Frequencies are defined as 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions reported in clinical studies in patients treated with Xofigo System organ class Very Common Uncommon (MedDRA) common Blood and lymphatic Neutropenia Thrombocytopenia Lymphopenia system disorders Pancytopenia Leukopenia Gastrointestinal Diarrhoea disorders Vomiting Nausea Musculoskeletal and Bone fracture Osteoporosis connective tissue disorders General disorders and Injection site reactions administration site conditions 7 Description of selected adverse reactions Bone fractures Xofigo increases the risk of bone fractures (see section 5.1). In clinical studies, concurrent use of bisphosphonates or denosumab reduced the incidence of fractures in patients treated with radium-223 monotherapy. Fractures have occurred for up to 24 months after the first dose of radium-223. Thrombocytopenia and neutropenia Thrombocytopenia (

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HOS-096528 · has-contraindication-information · PDF-Seite 4

Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone (see section 4.4).

HOS-096527 · has-indication-information · PDF-Seite 3

Xofigo monotherapy or in combination with luteinising hormone releasing hormone (LHRH) analogue is indicated for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC), symptomatic bone metastases and no known visceral metastases, in progression after at least two prior lines of systemic therapy for mCRPC (other than LHRH analogues), or ineligible for any available systemic mCRPC treatment (see section 4.4).

HOS-096530 · has-interaction-information · PDF-Seite 6

No clinical interaction studies have been performed. As interactions with calcium and phosphate cannot be excluded, pausing supplementation with these substances and/or Vitamin D should be considered some days before starting with Xofigo treatment. Concomitant chemotherapy with Xofigo may have additive effects on bone marrow suppression (see section 4.4). Safety and efficacy of concomitant chemotherapy with Xofigo have not been established.

HOS-096531 · has-pregnancy-information · PDF-Seite 6

Contraception in males Animal reproduction studies have not been conducted with Xofigo. Because of potential effects on spermatogenesis associated with radiation, men should be advised to use effective contraceptive methods during and up to 6 months after treatment with Xofigo. 6 Pregnancy and breast-feeding Xofigo is not indicated in women. Xofigo is not to be used in women who are, or may be, pregnant or breast-feeding. Fertility There are no human data on the effect of Xofigo on fertility. Based on studies in animals, there is a potential risk that radiation from Xofigo may potentially have toxic effects on male gonads and spermatogenesis (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment.

HOS-096529 · has-warning-information · PDF-Seite 4

Combination with abiraterone and prednisone/prednisolone or with systemic cancer therapies other than LHRH analogues An interim analysis from a clinical study in chemotherapy-naïve patients with asymptomatic or mildly symptomatic castration resistant prostate cancer and progressive disease with bone metastases showed an increased risk of fractures and a trend for increased mortality among patients receiving Xofigo in combination with abiraterone acetate and prednisone/prednisolone compared to patients receiving placebo in combination with abiraterone acetate and prednisone/prednisolone (see section 5.1). Therefore, Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone (see section 4.3). Safety and efficacy of Xofigo in combination with cancer therapies other than LHRH analogues have not been established; an increased risk of mortality and fractures is possible. The combination of radium-223 with other systemic cancer therapies other than LHRH analogues is therefore not recommended. Data on a safe period after which Xofigo can be administered following treatment with abiraterone acetate in combination with prednisone/prednisolone and vice versa is limited. Based on the elimination half-life of Xofigo and abiraterone, it is recommended that subsequent treatment with Xofigo is not initiated for at least 5 days after the last administration of abiraterone acetate in combination with prednisone/prednisolone. Subsequent systemic cancer treatment should not be initiated for at least 30 days after the last administration of Xofigo. Treatment of patients with asymptomatic or mildly symptomatic bone metastases An increased risk of death and fractures was observed in a clinical study, where Xofigo was added to abiraterone acetate and prednisone/prednisolone in patients with asymptomatic or mildly symptomatic castration resistant prostate cancer. Treatment benefit of Xofigo in adults with castration-resistant prostate cancer and only asymptomatic bone metastases is not established. The use of Xofigo is therefore not recommended for treatment of adults with castration-resistant prostate cancer and only asymptomatic bone metastases. In adults with castration- resistant prostate cancer and mildly symptomatic bone metastases the benefit of treatment should be carefully assessed to outweigh the risks considering that high osteoblastic activity is likely to be required for treatment benefit (see section 5.1).

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