Onivyde Adverse Reactions

Summary of the safety profile: The safety profile is based on the NAPOLI-1 clinical study. The following adverse reactions, considered to be possibly or probably related to the administration of ONIVYDE pegylated liposomal, were reported in 264 patients with metastatic adenocarcinoma of the pancreas, 147 of whom received ONIVYDE pegylated liposomal monotherapy (100 mg/m²) and 117 received ONIVYDE pegylated liposomal (70 mg/m²) in combination with 5-FU/LV.
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 arm and 12% for the monotherapy arm.
The most frequently reported adverse reactions leading to discontinuation were infection and diarrhoea for ONIVYDE pegylated liposomal +5-FU/LV arm, and vomiting and diarrhoea for the monotherapy arm.
Tabulated list of adverse reactions: The adverse reactions described as follows are derived from study 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 5). 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 5.)

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Description of selected adverse reactions: The following adverse reactions were observed in the NAPOLI-1 clinical study: Myelosuppression: 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: 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%)].
Thrombocytopenia: 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: 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: 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, 10 of 147 (6.8%) in the ONIVYDE pegylated liposomal monotherapy arm and 6 of 134 patients (4.5%) in the 5-FU/LV arm.
Diarrhoea and related adverse reactions: Diarrhoea is a very common adverse reaction leading to colitis, ileus, gastroenteritis, fatigue, dehydration, weight loss, renal toxicities, hyponatraemia, and hypokalaemia. Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhoea. In the clinical study Grade 3 or Grade 4 diarrhoea occurred in 15 out of 117 patients (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. In the clinical study, early diarrhoea onset occurred in 35 patients (29.9%) and cholinergic events occurred in 4 patients (3.4%) receiving ONIVYDE pegylated liposomal +5-FU/LV.
Withhold ONIVYDE pegylated liposomal for Grade 2-4 diarrhoea and initiate treatment for diarrhoea. Following recovery to Grade 1 diarrhoea, resume ONIVYDE pegylated liposomal at a reduced dose (see Dosage & Administration).
Infusion reaction: Acute infusion reactions were reported in 8 of 117 patients (6.8%) in the ONIVYDE pegylated liposomal +5-FU/LV arm, 3 of 147 patients (2.0%) in the ONIVYDE pegylated liposomal monotherapy arm, and 8 of 134 patients (6.0%) in the 5-FU/LV arm.
Other special populations: Elderly: Overall, no major clinical differences in safety or efficacy were reported between patients ≥ 65 years and patients < 65 years, although a higher frequency of discontinuation (14.8% vs 7.9%) was noted in the former group treated with ONIVYDE pegylated liposomal +5-FU/LV in the NAPOLI-1 study 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: 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 prior Whipple procedure: In the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, patients with a prior Whipple procedure had a higher risk of serious infections following treatment with ONIVYDE pegylated liposomal +5-FU/LV [9 of 29 (30%)] compared to 11 of 88 (12.5%) patients with no prior Whipple procedure.
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 the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, 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).
Underweight patients (body mass index < 18.5 kg/m²): In the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, 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).
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.