Leitlinien & Arzneimittelsicherheit

HOS-288747 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile Serious adverse reactions occurred in 59% of patients who received Enrylaze in a clinical trial. The most frequent serious adverse reactions were febrile neutropenia (29%), pyrexia (10%), vomiting (8%), sepsis (7%), medicinal product hypersensitivity (6%), nausea (6%), and pancreatitis (5%). The most common adverse reactions were anaemia (52%), vomiting (49%), thrombocytopenia (42%), neutropenia (41%), nausea (38%), febrile neutropenia (32%), fatigue (32%), pyrexia (32%), decreased appetite (29%), transaminase increased (29%), abdominal pain (27%), white blood cell count decreased (27%), headache (25%), diarrhoea (22%), and lymphocyte count decreased (20%). 6 Tabulated list of adverse reactions Adverse reactions reported in clinical trial are listed in Table 1 by system organ class and by frequency. The frequencies identified are from patients (n=228) who received 6 doses of Enrylaze, along with a multi-agent chemotherapeutic regimen. Certain adverse reactions listed below, such as reactions resulting from bone marrow suppression, and infections, are known to be associated with multi-agent chemotherapeutic regimens, and the contributory role of Enrylaze is not clear. In individual cases of adverse reactions, other medicinal products of the regimen may have contributed. 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions in patients receiving Enrylaze with multi-agent chemotherapy (Study JZP458-201) System organ class Frequency Adverse reaction Infections and infestations Common Sepsis Blood and lymphatic system Very common Anaemia, Thrombocytopenia, disorders Neutropenia, Febrile neutropenia Immune system disorders Very common Drug hypersensitivity Common Anaphylactic reaction, Hypersensitivity M

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HOS-288743 · has-contraindication-information · PDF-Seite 4

• History of severe hypersensitivity reactions to the active substance • Hypersensitivity to any of the excipients listed in section 6.1 • Severe pancreatitis • History of severe pancreatitis during previous asparaginase therapy • Severe thrombosis during previous asparaginase therapy • Severe haemorrhagic events during previous asparaginase therapy

HOS-288742 · has-indication-information · PDF-Seite 2

Enrylaze is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LBL) in adult and paediatric patients (1 month and older) who developed hypersensitivity or silent inactivation to E. coli-derived asparaginase.

HOS-288745 · has-interaction-information · PDF-Seite 5

No interaction studies have been performed. General The possibility of interactions with medicinal products whose pharmacokinetics or pharmacodynamics are affected by asparaginase-induced changes in the liver function or plasma protein levels should be taken into account when administering asparaginase. Asparaginase may increase toxicity of other medicinal products through its effect on liver function. Vincristine Administration of asparaginase concurrently or immediately before vincristine may be associated with increased toxicity of vincristine. Asparaginase inhibits hepatic clearance of vincristine. 5 Methotrexate, cytarabine Non-clinical data indicates that prior or concurrent administration of L-asparaginase attenuates the effect of methotrexate and cytarabine. Administration of L-asparaginase after methotrexate or cytarabine results in a synergistic effect. However, the clinical effect of sequence-dependent L-asparaginase administration on the efficacy of methotrexate and cytarabine is unknown. Glucocorticoids Administration of asparaginase with or immediately before glucocorticoids (e.g. prednisone) may change coagulation parameters, such as a decrease in fibrinogen and antithrombin III levels.

HOS-288746 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential/Contraception in males and females Men and women should use contraception during treatment with Enrylaze containing chemotherapy. Because the time period following treatment with asparaginase when it is safe to become pregnant or father a child is unknown, effective contraception should be used in men and women for at least 3 months after discontinuation. Since an indirect interaction between oral contraceptives and Enrylaze cannot be ruled out, patients of childbearing potential should use effective non-hormonal contraceptive methods while undergoing treatment (see section 4.4). Pregnancy There are no data on the use of recombinant crisantaspase in pregnant women. Based on studies with Erwinia chrysanthemi L-asparaginase in pregnant animals, recombinant crisantaspase can cause embryonic and foetal harm when administered to a pregnant woman (see section 5.3). Women of childbearing potential should undergo pregnancy testing before initiation of Enrylaze. Enrylaze should not be used during pregnancy, unless the clinical condition of the woman requires treatment and justifies the potential risk to the foetus. If the medicinal product is used during pregnancy, or if the patient becomes pregnant while receiving Enrylaze, the woman should be informed of the potential hazard to the foetus. Breast-feeding It is not known whether recombinant crisantaspase is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding infants/children, mothers should be advised not to breast-feed during Enrylaze therapy and for a period of two weeks after the last dose. Fertility No human data on the effect of recombinant crisantaspase on fertility are available. In a fertility and early embryonic development study in rats with Erwinia chrysanthemi crisantaspase, there were no effect on female or male fertility (margins of human exposure < 1) (see section 5.3).

HOS-288744 · 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. Clinical monitoring Asparaginase activity SAA varies substantially between patients, when treatment is administered intravenously. The optimal SAA level is ≥ 0.1 U/mL; if this is not observed the dosing schedule should be individually adapted. When administering Enrylaze intravenously on a Monday/Wednesday/Friday schedule, trough SAA levels should be measured 72 hours after the Friday dose and prior to the following Monday administration. If SAA levels ≥ 0.1 U/mL are not observed, administration of intramuscular Enrylaze or switching to a 48-hour dosing interval (intravenous or intramuscular) should be considered. If SAA levels are monitored at 48-hour intervals of intravenous Enrylaze administration and SAA levels ≥ 0.1 U/mL are not observed, administration intramuscularly should be considered (see section 4.2). Hypersensitivity reactions Grade 3 and 4 hypersensitivity reactions after the use of Enrylaze have occurred in patients during clinical trials (see sections 4.3 and 4.8). Hypersensitivity reactions may occur more frequently when treatment is administered intravenously in comparison to when treatment is administered intramuscularly. Because of the risk of serious allergic reactions, Enrylaze should be administered in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. Enrylaze should be discontinued in patients with severe hypersensitivity reactions (see section 4.3). Pancreatitis Pancreatitis has been reported in patients treated with Enrylaze in clinical trials (see section 4.8). Patients with symptoms compatible with pancreatitis should be evaluated to establish a diagnosis. Enrylaze should be discontinued in patients that develop necrotising or haemorrhagic pancreatitis. In the case of elevations in lipase or amylase > 2 times the ULN or symptomatic pancreatitis, Enrylaze should be withheld until the ULN and symptoms subside. After resolution of pancreatitis, treatment with Enrylaze may be resumed. Glucose intolerance Cases of glucose intolerance have been reported in patients receiving Enrylaze in clinical trials (see section 4.8). Glucose levels in patients should be monitored at baseline and periodically during treatment. Insulin therapy should be administered as necessary in patients with hyperglycaemia.

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