Reblozyl · 4.3 Contraindications · 1

HOS-217701 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile • Myelodysplastic syndromes The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were fatigue, diarrhoea, nausea, asthenia, dizziness, oedema peripheral and back pain. The most commonly reported Grade ≥ 3 adverse drug reactions (at least 2% of patients) included hypertension events (12.5%), syncope (3.6%), dyspnoea (2.7%), fatigue (2.4%) and thrombocytopenia (2.4%). The most commonly reported serious adverse drug reactions (at least 1% of patients) were urinary tract infection (1.8%), dyspnoea (1.5%) and back pain (1.2%). 8 Asthenia, fatigue, nausea, diarrhoea, hypertension, dyspnoea, dizziness and headache occurred more frequently during the first 3 months of treatment. Treatment discontinuation due to an adverse event occurred in 10.1% of patients treated with luspatercept. The most common reason for discontinuation in the luspatercept treatment arm was progression of underlying MDS. Dose delays due to pre-dose Hb ≥ 12 g/dL occurred in 24.3% of luspatercept treated patients. • Transfusion-dependent β-thalassaemia The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were headache, bone pain and arthralgia. The most commonly reported Grade ≥ 3 adverse drug reaction was hyperuricaemia. The most serious adverse reactions reported included thromboembolic events of deep vein thrombosis, ischaemic stroke portal vein thrombosis and pulmonary embolism (see section 4.4). Bone pain, asthenia, fatigue, dizziness and headache occurred more frequently during the first 3 months of treatment. Treatment discontinuation due to an adverse reaction occurred in 2.6% of patients treated with luspatercept. The adverse reactions leading to treatment discontinuation in the luspatercept treatment arm were arthralgia, back pain, bone pain and headache. • Non-transfusion-dependent β-thalassaemia The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were bone pain, headache, arthralgia, back pain, prehypertension and hypertension. The most commonly reported Grade ≥ 3 and most serious adverse reaction (at least 2% of patients) reported was traumatic fracture. Spinal cord compression due to EMH masses occurred in 1% of patients. Bone pain, back pain, upper respiratory tract infection, arthralgia, headache and prehype

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HOS-217697 · has-contraindication-information · PDF-Seite 6

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Pregnancy (see section 4.6). • Patients requiring treatment to control the growth of EMH masses (see section 4.4).

HOS-217696 · has-indication-information · PDF-Seite 2

Reblozyl is indicated in adults for the treatment of transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) (see section 5.1). Reblozyl is indicated in adults for the treatment of anaemia associated with transfusion-dependent and non-transfusion-dependent beta-thalassaemia (see section 5.1).

HOS-217699 · has-interaction-information · PDF-Seite 8

No formal clinical interaction studies have been performed. Concurrent use of iron-chelating agents had no effect on luspatercept pharmacokinetics.

HOS-217700 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential / Contraception in females Women of childbearing potential have to use effective contraception during treatment with Reblozyl and for at least 3 months after the last dose. Prior to starting treatment with Reblozyl, a pregnancy test has to be performed for women of childbearing potential and the patient card has to be provided. Pregnancy Treatment with Reblozyl should not be started if the woman is pregnant (see section 4.3). There are no data from the use of Reblozyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Reblozyl is contraindicated during pregnancy (see section 4.3). If a patient becomes pregnant, Reblozyl should be discontinued. Breast-feeding It is unknown whether luspatercept or its metabolites are excreted in human milk. Luspatercept was detected in the milk of lactating rats (see section 5.3). Because of the unknown adverse effects of luspatercept in newborns/infants, a decision must be made whether to discontinue breast-feeding during therapy with Reblozyl and for 3 months after the last dose or to discontinue Reblozyl therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effect of luspatercept on fertility in humans is unknown. Based on findings in animals, luspatercept may compromise female fertility (see section 5.3).

HOS-217698 · has-warning-information · PDF-Seite 6

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. Thromboembolic events In β-thalassaemia patients, thromboembolic events (TEEs) were reported in 3.6% (8/223) of patients treated with luspatercept in the double-blind phase of the pivotal study in transfusion-dependent patients and in 0.7% (1/134) of patients during the open-label phase of the pivotal study in non-transfusion-dependent patients. Reported TEEs included deep vein thrombosis (DVT), portal vein thrombosis, pulmonary emboli, ischaemic stroke and superficial thrombophlebitis (see section 4.8). All patients with TEEs were splenectomised and had at least one other risk factor for developing TEE (e.g. history of thrombocytosis or concomitant use of hormone replacement therapy). The occurrence of TEE was not correlated with elevated Hb levels. The potential benefit of treatment with luspatercept should be weighed against the potential risk of TEEs in β-thalassaemia patients with a splenectomy and other risk factors for developing TEE. Thromboprophylaxis according to current clinical guidelines should be considered in patients with β-thalassaemia at higher risk. 6 In MDS patients, TEEs were reported in 3.9% (13/335) of patients treated with luspatercept. Reported TEEs included cerebral ischemia and cerebrovascular accident in 1.2% (4/335) of patients. All TEEs occurred in patients with significant risk factors (atrial fibrillation, stroke or heart failure and peripheral vascular disease) and were not correlated with elevated Hb, platelet levels or hypertension. Extramedullary haemopoiesis masses In transfusion-dependent β-thalassaemia patients, extramedullary haemopoiesis (EMH) masses were observed in 3.2% (10/315) of patients treated with luspatercept in the pivotal study and in the long-term follow-up study. Spinal cord compression symptoms due to EMH masses occurred in 1.9% (6/315) of patients treated with luspatercept (see section 4.8). In non-transfusion-dependent β-thalassaemia patients, EMH masses were observed in 6.3% (6/96) of patients treated with luspatercept in the pivotal study. Spinal cord compression due to EMH masses occurred in 1.0% (1/96) of patients treated with luspatercept. During the open-label portion of the study, EMH masses were observed in 2 additional patients for a total of 8/134 (6.0%) of patients (s

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