Evoltra · 4.8 Undesirable effects · 1

HOS-094096 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Nearly all patients (98%) experienced at least one adverse event considered by the study investigator to be related to clofarabine. Those most frequently reported were nausea (61% of patients), vomiting (59%), febrile neutropaenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%), pyrexia (19%), palmar-plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), mucosal inflammation (11%), and flushing (11%). Sixty-eight patients (59%) experienced at least one serious clofarabine-related adverse event. One patient discontinued treatment due to grade 4 hyperbilirubinaemia considered as related to clofarabine after receiving 52 mg/m2/day clofarabine. Three patients died of adverse events considered by the study investigator to be related to treatment with clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leak syndrome; one patient from VRE sepsis and multi-organ failure; and one patient from septic shock and multi-organ failure. Tabulated list of adverse reactions The information provided is based on data generated from clinical trials in which 115 patients (> 1 and ≤ 21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of clofarabine at the recommended dose of 52 mg/m2 daily x 5. Adverse reactions are listed by system organ class and frequency (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) and very rare (< 1/10,000)) in the table below. Adverse reactions reported during the post-marketing period are also included in the table under the frequency category “not known” (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Patients with advanced stages of ALL or AML may have confounding medical conditions that make causality of adverse events difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the co-administration of numerous medicinal products. Adverse reactions considered to be related to clofarabine reported at frequencies ≥ 1/1,000 (i.e. in > 1/115 patients) in clinical trials and post-marketing Infections and infestations Common: Septic shock*, sepsis, bacteraemia,

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HOS-094092 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use in patients with severe renal insufficiency or severe hepatic impairment. Breast-feeding (see section 4.6).

HOS-094091 · has-indication-information · PDF-Seite 2

Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response. Safety and efficacy have been assessed in studies of patients ≤ 21 years old at initial diagnosis (see section 5.1).

HOS-094094 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed. However, there are no known clinically significant interactions with other medicinal products or laboratory tests. Clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system. Therefore, it is unlikely to interact with active substances which inhibit or induce cytochrome P450 enzymes. In addition, clofarabine is unlikely to inhibit any of the major 5 human CYP isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) or to induce 2 of these isoforms (1A2 and 3A4) at the plasma concentrations achieved following intravenous infusion of 52 mg/m2/day. As a result, it is not expected to affect the metabolism of active substances which are known substrates for these enzymes. 6 Clofarabine is predominately excreted via the kidneys. Thus, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period (see sections 4.4, 4.8 and 5.2). The liver is a potential target organ for toxicity. Thus, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.4 and 4.8). Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.4 and 4.8).

HOS-094095 · has-pregnancy-information · PDF-Seite 7

Contraception in men and women Due to the genotoxic risk of clofarabine (see section 5.3), women of childbearing potential must use effective methods of contraception during treatment with clofarabine and for 6 months following completion of treatment. Men should use effective methods of contraception and be advised to not father a child while receiving clofarabine, and for 3 months following completion of treatment. Pregnancy There are no data on the use of clofarabine in pregnant women. Studies in animals have shown reproductive toxicity including teratogenicity (see section 5.3). Clofarabine may cause serious birth defects when administered during pregnancy. Therefore, Evoltra should not be used during pregnancy, especially not during the first trimester, unless clearly necessary (i.e. only if the potential benefit to the mother outweighs the risk to the foetus). If a patient becomes pregnant during treatment with clofarabine, they should be informed of the possible hazard to the foetus. Breast-feeding It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretion of clofarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and within 2 weeks after completion of treatment with Evoltra (see section 4.3). Fertility Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, and toxicities on female reproductive organs have been observed in mice (see section 5.3). As the effect of clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with patients as appropriate.

HOS-094093 · has-warning-information · PDF-Seite 4

Evoltra is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions (see section 4.8). The following parameters should be closely monitored in patients undergoing treatment with clofarabine: • Complete blood and platelet counts should be obtained at regular intervals, more frequently in patients who develop cytopaenias. • Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine should be discontinued immediately if substantial increases in creatinine, liver enzymes and/or bilirubin are observed. • Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the 5 day clofarabine administration period. Blood and lymphatic disorders Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose- dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopaenia have been observed in patients treated with clofarabine. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of the cases were associated with thrombocytopaenia (see section 4.8). In addition, at initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromised condition of these patients and prolonged neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be monitored for signs and symptoms of infection and treated promptly. Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis, have been reported during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, 4 perforation or sepsis complications and may be associated with fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of enterocolitis. Skin and subcutaneous tissue disorders Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported (see section 4.8). Clofarabine must be discontinued for exfoliative or bullous ras

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