Phelinun · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-099283 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently reported adverse reactions were haematologic and gastrointestinal toxicities, and immune system disorders, these being considered as expected consequences of myelosuppression. Infections, acute and chronic Graft versus Host Disease (GvHD) were reported as the major causes of morbidity and mortality in the allo HSCT setting. Bone marrow failure, stomatitis, mucosal inflammation, gastrointestinal haemorrhage, diarrhea, nausea, vomiting, amenorrhoea, ovarian disorders and premature menopause were also commonly reported. Tabulated list of adverse reactions 9 The adverse drug reactions (ADRs) described in this section were identified from information included in other melphalan containing products, the screening of the published literature and the European database EudraVigilance concerning the use of melphalan as part of combination regimens for allo-HSCT setting. With the exception of Stevens-Johnson syndrome and Toxic epidermal necrolysis identified for only one patient, ADRs reported for at least two patients have been captured in the table below. Frequencies are described 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), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. MedDRA System Organ Class Frequency Adverse Drug Reactions Common Infection Infections and infestations Uncommon Septic shock Secondary primary malignancy, Neoplasms benign, malignant and unspecified Secondary acute myeloid Uncommon (incl cysts and polyps) leukaemia Myelodysplastic syndrome Myelosuppression leading to Very Neutropenia, Common Thrombocytopenia Blood and lymphatic system disorders

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HOS-099279 · has-contraindication-information · PDF-Seite 5

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pregnancy (only with respect to the treatment prior to HSCT) and breat-feeding (see section 4.6).

HOS-099278 · has-indication-information · PDF-Seite 2

High-dose of PHELINUN used alone or in combination with other cytotoxic medicinal products and/or total body irradiation is indicated in the treatment of: - multiple myeloma, - malignant lymphoma (Hodgkin, non-Hodgkin lymphoma), - acute lymphoblastic and myeloblastic leukemia, - childhood neuroblastoma, 2  - ovarian cancer, - mammary adenocarcinoma. PHELINUN in combination with other cytotoxic medicinal products is indicated as reduced intensity conditioning (RIC) treatment prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT) in malignant haematological diseases in adults. PHELINUN in combination with other cytotoxic medicinal products is indicated as conditioning regimen prior to allogeneic haematopoietic stem cell transplantation in haematological diseases in the paediatric population as: - Myeloablative conditioning (MAC) treatment in case of malignant haematological diseases - RIC treatment in case of non-malignant haematological diseases.

HOS-099281 · has-interaction-information · PDF-Seite 8

Nalidixic acid The administration of high-dose intravenous PHELINUN together with nalidixic acid in children has caused haemorrhagic entercolitis with fatal outcome. Combined treatment of melphalan with nalidixic acid should be avoided. Busulfan In the paediatric population, for the busulfan-melphalan regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities. Cyclosporin Impaired renal function has been described in bone marrow transplant patients who were pre-conditioned with high-dose intravenous melphalan and subsequently received cyclosporin to prevent graft versus host disease. 8 Attenuated live vaccines A risk of general illness which may lead to fatal outcome has described. This risk is increased in patients who are already immunosuppressed by their underlying disease. An inactivated vaccines should be used when such a vaccine exists (poliomyelitis).

HOS-099282 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in males and females As with all cytotoxic treatments, male and female patients that receive melphalan should use effective reliable contraceptive methods up until six months after cessation of treatment. Pregnancy There are no or limited amount of data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Risk for human is not know, but due to the mutagenic properties and structural similarity of melphalan with known teratogenic compounds, it is possible that melphalan can induce congenital malformations in offspring of treated patients. The use of melphalan as anti-cancer treatment should be avoided whenever possible during pregnancy, particularly during the first trimester. In each case, the benefit of the treatment outweighing the potential risk to the fetus should be evaluated. HSCT is contraindicated in pregnant women. Therefore melphalan is contraindicated during pregnancy for this indication (see section 4.3). Breast-feeding It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenic properties, melphalan is contraindicated during breast-feeding (see section 4.3). Fertility Melphalan causes suppression of ovarian function in pre-menopausal women resulting in amenorrhoea in a significant number of patients. There is evidence from animal studies that melphalan can have an adverse effect on spermatogenesis (see section 5.3). Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients. Cryopreservation of semen before treatment is advised.

HOS-099280 · has-warning-information · PDF-Seite 5

Melphalan can cause local tissue damage. Should extravasation occur, it should not be administered by direct injection into a peripheral vein (see section 4.2). Hepatic veno-occlusive disease is a major complication that can occur during treatment with melphalan. Monitoring Since melphalan is a potent myelosuppressive agent, it is essential that careful attention is paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia or irreversible bone marrow failure. Cytopenia may continue to fall after treatment is stopped. So, at the first sign of an abnormally, large fall in leukocyte or severe thrombocytopenia, treatment should be temporarily interrupted. PHELINUN should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity. It is recommended to ensure patients’ adequate hydration and forced diuresis and the prophylactic administration of anti-infective agents (bacterial fungal, viral). The administration of blood products should be considered if required. It is recommended to monitor the general and renal status of patients receiving high-doses of PHELINUN. The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of PHELINUN in association with autologous bone marrow 5 transplantation. Cyclophosphamide pre-treatment appears to reduce the severity of gastrointestinal damage induced by high-dose PHELINUN and the literature should be consulted for details. Mutagenicity Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the medicinal product. Carcinogenicity Acute myeloide leukemia (AML) and myelodysplastic syndromes. Melphalan has been reported to be leukaemogenic (acute leukemia and myelodysplastic syndromes). There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer. The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan, in particular when used in combination with thalidomide or lenalidomide and prednisone, as it has been determined that these combinations increase the leukaemogenic risk. Before,

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