Onivyde pegylated liposomal (previously Onivyde)

HOS-097721 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX): The following adverse reactions, related to the administration of ONIVYDE pegylated liposomal, were reported in 370 patients treated in combination with oxaliplatin/5-FU/LV, who had not previously received chemotherapy for metastatic adenocarcinoma of the pancreas. The most common adverse reactions (incidence ≥20%) were diarrhoea, nausea, vomiting, decreased appetite, fatigue, asthenia, neutropenia, neutrophil count decreased and anaemia. The most common, severe adverse reactions (≥5% Grade 3 or 4) were diarrhoea, nausea, vomiting, decreased appetite, fatigue, asthenia, neutropenia, neutrophil count decreased, anaemia and hypokalaemia. The most common serious adverse reactions (≥2%) were diarrhoea, nausea, vomiting and dehydration. 11 Adverse reactions seen with ONIVYDE pegylated liposomal which led to its permanent discontinuation occurred in 9.5 % of patients; the most frequent adverse reaction resulting in discontinuation was neutropenia. Dose reductions of ONIVYDE pegylated liposomal due to adverse events (regardless of causality assessment), occurred in 52.4% of patients; the most frequent adverse events requiring dose reduction (≥5%) were diarrhoea, nausea, neutropenia and neutrophil count decreased. ONIVYDE pegylated liposomal was withheld due to adverse events (regardless of causality assessment), in 1.9% of patients; the most frequent adverse events requiring interruption were hypersensitivity and infusion related reactions that occurred in 0.5% of patients. ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: The following adverse reactions, related to the administration of ONIVYDE pegylated liposomal, were reported in 264 patients with metastatic adenocarcinoma of the pancreas treated after disease progression following gemcitabine-based therapy. The most common adverse reactions (incidence ≥ 20%) of ONIVYDE pegylated liposomal +5-FU/LV were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis and pyrexia. The most common serious adverse reactions (≥ 2%) of ONIVYDE pegylated liposomal therapy were diarrhoea, vomiting, febrile neutropenia, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. The rates of adverse reactions leading to pe

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HOS-097717 · has-contraindication-information · PDF-Seite 7

History of severe hypersensitivity to irinotecan or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6).

HOS-097716 · has-indication-information · PDF-Seite 2

ONIVYDE pegylated liposomal is indicated: - in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas, - in combination with 5-FU and LV for the treatment of metastatic adenocarcinoma of the pancreas in adult patients who have progressed following gemcitabine based therapy.

HOS-097719 · has-interaction-information · PDF-Seite 10

Information about drug interactions with ONIVYDE pegylated liposomal is referenced from the published scientific literature for nonliposomal irinotecan. Interaction affecting the use of ONIVYDE pegylated liposomal Strong CYP3A4 inducers Patients receiving concomitant non-liposomal irinotecan and CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine have substantially reduced exposure to irinotecan (AUC reduction by 12% with St John’s wort, 57%-79% with phenytoin, phenobarbital, or carbamazepine) and SN-38 (AUC reduction by 42% with St John’s wort, 36%-92% with phenytoin phenobarbital, or carbamazepine). Therefore, co-administration of ONIVYDE pegylated liposomal with inducers of CYP3A4 may reduce systemic exposure of ONIVYDE pegylated liposomal. Strong CYP3A4 inhibitors and UGT1A1 inhibitors Patients receiving concomitant non-liposomal irinotecan and ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased SN-38 exposure by 109%. Therefore, co-administration of ONIVYDE pegylated liposomal with other inhibitors of CYP3A4 (e.g. grapefruit juice, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) may increase systemic exposure of ONIVYDE pegylated liposomal. Based on the drug interaction of non-liposomal irinotecan and ketoconazole, co-administration of ONIVYDE pegylated liposomal with other inhibitors of UGT1A1 (e.g. atazanavir, gemfibrozil, indinavir, regorafenib) may also increase systemic exposure of ONIVYDE pegylated liposomal. Co-administration of ONIVYDE pegylated liposomal +5-FU/LV does not alter the pharmacokinetics of ONIVYDE pegylated liposomal based on the population pharmacokinetic analysis. Antineoplastic agents (including flucytosine as a prodrug for 5-fluorouracil) Adverse effects of irinotecan, such as myelosuppression, may be exacerbated by other 10 antineoplastic agents having a similar adverse-effect profile. No interaction of ONIVYDE pegylated liposomal with other medicinal products is known.

HOS-097720 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential / contraception in males and females Women of childbearing potential should use effective contraception during ONIVYDE pegylated liposomal treatment and 7 months thereafter. Males should use condoms during ONIVYDE pegylated liposomal treatment and 4 months thereafter. Pregnancy There are no adequate data on the use of ONIVYDE pegylated liposomal in pregnant women. ONIVYDE pegylated liposomal can cause harm to the foetus when administered to the pregnant woman, as the main ingredient irinotecan has been shown to be embryotoxic and teratogenic in animals (see section 5.3). Therefore, based on results from animal studies and the mechanism of action of irinotecan, ONIVYDE pegylated liposomal should not be used during pregnancy unless clearly necessary. If ONIVYDE pegylated liposomal is used during pregnancy or if the patient becomes pregnant while receiving therapy, the patient should be informed about the potential hazard to the foetus. Breast-feeding It is unknown whether ONIVYDE pegylated liposomal or its metabolites are excreted into human milk. Because of the potential for serious adverse reactions of ONIVYDE pegylated liposomal in breast-feeding infants, ONIVYDE pegylated liposomal is contraindicated during breast-feeding (see section 4.3). Patients should not breast-feed until one month after the last dose. Fertility There are no data on the impact of ONIVYDE pegylated liposomal on human fertility. Non-liposomal irinotecan was shown to cause atrophy of male and female reproductive organs after multiple daily irinotecan doses in animals (see section 5.3). Prior to starting the administration of ONIVYDE pegylated liposomal consider advising patients on the preservation of gametes.

HOS-097718 · has-warning-information · PDF-Seite 7

General ONIVYDE pegylated liposomal is a liposomal formulation of irinotecan with different pharmacokinetic properties compared to non-liposomal irinotecan. The dose concentration and strength are different in comparison to non-liposomal irinotecans. ONIVYDE pegylated liposomal is not equivalent to other non-liposomal irinotecan formulations and should not be interchanged. 7 In the limited number of patients with prior exposure to non-liposomal irinotecan, no benefit of ONIVYDE pegylated liposomal has been demonstrated. Myelosuppression/neutropenia Complete blood cell count monitoring is recommended during ONIVYDE pegylated liposomal treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (body temperature > 38°C and neutrophil count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics. Sepsis with neutropenic fever and consequent septic shock with fatal outcome has been observed in patients with metastatic pancreatic adenocarcinoma treated with ONIVYDE pegylated liposomal. In patients who experienced severe haematological events, a dose reduction or treatment discontinuation is recommended (see section 4.2). Patients with severe bone marrow failure should not be treated with ONIVYDE pegylated liposomal. History of prior abdominal radiation increases the risk of severe neutropenia and febrile neutropenia following ONIVYDE pegylated liposomal treatment. Close monitoring of blood counts is recommended, and the use of myeloid growth factors should be considered for patients with a history of abdominal radiation. Caution should be exercised in patients receiving concurrent administration of ONIVYDE pegylated liposomal with irradiation. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with ONIVYDE pegylated liposomal. Immunosuppressive effects and vaccines Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic medicinal products including ONIVYDE pegylated liposomal may result in serious or fatal infections; therefore vaccination with a live vaccine should be avoided. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. Interactions with strong CYP3A4 inducers ONIVYDE pegylated l

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