Onivyde Adverse Reactions

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. 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, considered 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 permanent treatment discontinuation were 11% for the ONIVYDE pegylated liposomal +5-FU/LV.
The most frequently reported adverse reactions leading to discontinuation were infection and diarrhoea for ONIVYDE pegylated liposomal +5-FU/LV arm.
Tabulated list of adverse reactions: The adverse reactions described as follows are derived from studies data and post marketing experience of ONIVYDE pegylated liposomal.
The adverse reactions that may occur during treatment with ONIVYDE pegylated liposomal are summarised as follows and are presented by system organ class and frequency category (Table 7). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness. Frequencies categories used for adverse reactions are: 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 not known (cannot be estimated from the available data). (See Table 7.)

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Description of selected adverse reactions: Myelosuppression: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: Fatal events were febrile neutropenia or pancytopenia, each occurred in 0.3% of patients receiving NALIRIFOX arm.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: Myelosuppression (neutropenia/leukopenia, thrombocytopenia and, anaemia) was more common in the ONIVYDE pegylated liposomal +5-FU/LV arm compared to the 5-FU/LV control arm.
Neutropenia/leukopenia: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: Grade 3 or 4 leukopenia occurred in 0.8% of patients receiving NALIRIFOX.
In NAPOLI-3, where ONIVYDE pegylated liposomal plus oxaliplatin/5-FU/LV (NALIRIFOX) was compared to gemcitabine plus nab-paclitaxel (Gem+NabP), safety data showed a higher incidence of neutropenia reported in the Gem+NabP arm. Grade 3 or 4 neutropenia, neutrophil count decreased and febrile neutropenia occurred in 14.1%, 9.7% and 1.9% (respectively) in patients receiving NALIRIFOX.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: Neutropenia/leukopenia was the most notable important haematological toxicity. Grade 3 or higher neutropenia occurred more frequently in patients treated with ONIVYDE pegylated liposomal +5-FU/LV (27.4%) compared to patients treated with 5-FU/LV (1.5%). Neutropenic fever/sepsis appeared more frequently in the ONIVYDE pegylated liposomal +5-FU/LV combination arm [in 4 patients (3.4%)] compared to 5-FU/LV control arm [in 1 patient (0.7%)].
The median time to nadir for ≥ Grade 3 neutropenia is 23 (range 8-104) days post first dose of treatment with ONIVYDE pegylated liposomal.
Thrombocytopenia: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: Grade 3 or 4 thrombocytopenia occurred in 0.5% of patients receiving NALIRIFOX.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: Grade 3 or higher thrombocytopenia occurred in 2.6% of patients treated with ONIVYDE pegylated liposomal +5-FU/LV and 0% in patients treated with 5-FU/LV.
Anaemia: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: Grade 3 or 4 anaemia occurred in 7.3% of patients receiving NALIRIFOX.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: Grade 3 or higher anaemia occurred in 10.3% of patients treated with ONIVYDE pegylated liposomal +5-FU/LV and in 6.7% of patients treated with 5-FU/LV.
Acute renal failure: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: In NAPOLI-3, renal impairment occurred in 0.3% of patients and was of Grade 3 or 4, renal failure occurred with Grade 1 to 4 in 0.5% of patients, among them 0.3% was Grade 3 or 4, acute kidney injury occurred with Grade 1 to 4 in 1.1% of patients, among them 0.8% were of Grade 3 or 4 in patients receiving NALIRIFOX. Blood creatinine increased occurred with all Grade 1 to 4 in 1.4% of patients, among them, 0.3% was Grade 3 or 4, creatinine renal clearance decreased occurred with Grade 1 or 2 in 0.3% of patients receiving NALIRIFOX. There was one case (0.3%) of renal failure with a fatal outcome in the NALIRIFOX arm.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: In NAPOLI-1, renal impairment and acute renal failure have been identified, usually in patients who become volume depleted from nausea/vomiting and/or diarrhoea. Acute renal failure was reported in 6 of 117 patients (5.1%) in the ONIVYDE pegylated liposomal +5-FU/LV arm.
Diarrhoea and related adverse reactions: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: In NAPOLI-3, safety data showed a higher incidence of diarrhoea reported in the NALIRIFOX arm for all grades and for grade 3 or 4. Grade 1 to 4 diarrhoea occurred in 64.3% of patients and Grade 3 or 4 diarrhoea occurred in 19.5% of patients receiving NALIRIFOX arm. Cholinergic reaction manifestations such as rhinitis, rhinorrhoea, salivary hypersecretion, flushing, hot flush and lacrimation increased, were reported in patients receiving NALIRIFOX.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: In NAPOLI-1, Grade 3 or Grade 4 diarrhoea occurred 12.8% receiving ONIVYDE pegylated liposomal +5-FU/LV. For patients experiencing late diarrhoea, the median time to late diarrhoea onset was 8 days from the previous dose of ONIVYDE pegylated liposomal. Early onset diarrhoea, typically appearing ≤ 24 hours after dose administration, can occur and is usually transient. Early onset diarrhoea may also be accompanied by cholinergic symptoms that can include rhinitis, increased salivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis that can induce abdominal cramping. Early diarrhoea onset occurred in 29.9% and cholinergic events occurred in 3.4% receiving ONIVYDE pegylated liposomal +5-FU/LV.
Infusion reaction: ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: In NAPOLI-3, Infusion related reaction occurred in 1.4% of patients receiving NALIRIFOX. All of them were mild or moderate (Grade 1 and 2).
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: In NAPOLI-1, acute infusion reactions were reported in 6.8% in the ONIVYDE pegylated liposomal +5-FU/LV arm.
Other special populations: Elderly: Overall, no major clinical differences in safety were reported between patients ≥65 years and patients <65 years.
ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: In NAPOLI-3, the median age was 65 years (range from 20 to 85), 50.1% of patients were at least 65 years of age with 6.9% of patients of 75 years or older. The safety data by age groups, were in line with the data of NALIRIFOX arm in the whole population.
ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin: In NAPOLI-1, a higher frequency of discontinuation was noted for patients between ≥65 years and <65 years treated with ONIVYDE pegylated liposomal +5-FU/LV (14.8% vs 7.9% respectively) and in some cases the adverse reactions did not resolve. Grade 3 or higher and serious treatment emergent adverse reactions were more frequent in patients <65 years (84.1% and 50.8%) compared to patients ≥65 years (68.5% and 44.4%). Conversely, patients >75 years (n=12) experienced more frequent serious adverse reactions, dose delay, dose reduction and discontinuation compared to patients ≤75 years (n=105) when treated with ONIVYDE pegylated liposomal +5-FU/LV in the pancreatic adenocarcinoma study.
Asian population: In NAPOLI-1, compared to Caucasians, Asian patients were observed with a lower incidence of diarrhoea [14 (19.2%) out of 73 Caucasians had a ≥ Grade 3 diarrhoea, and 1 out of 33 (3.3%) Asians had a ≥ Grade 3 diarrhoea], but a higher incidence and higher severity of neutropenia. In patients receiving ONIVYDE pegylated liposomal +5-FU/LV, the incidence of ≥ Grade 3 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to Caucasian patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of Caucasian patients. This is consistent with the population pharmacokinetic analysis that showed a lower exposure to irinotecan and a higher exposure to its active metabolite SN-38 in Asians than in Caucasians.
Patients with hepatic impairment: In clinical studies of non-liposomal irinotecan administered on a weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dl) had a significantly greater likelihood of experiencing first cycle Grade 3 or Grade 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dl.
Patients with UGT1A1 allele: Individuals who are 7/7 homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from non-liposomal irinotecan. In NAPOLI-1, the frequency of ≥ Grade 3 neutropenia in these patients [2 of 7 (28.6%)] was similar to the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of ONIVYDE pegylated liposomal of 70 mg/m² [30 of 110 (27.3%)] (see Pharmacology: Pharmacodynamics under Actions). This observation was not evaluated in NAPOLI-3.
Underweight patients (body mass index <18.5 kg/m²): In NAPOLI-1, 5 of 8 underweight patients experienced a grade 3 or 4 adverse reaction, mostly myelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dose reduction or dose discontinuation (see Precautions). This observation was not evaluated in NAPOLI-3.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.