Yondelis Adverse Reactions

Summary of the safety profile: Most patients treated with Yondelis can be expected to have adverse reactions of any grade (91% in monotherapy and 99% in combination therapy) and less than one-third serious adverse reactions of grade 3 or 4 severity (10% in monotherapy and 25% in combination therapy). The most common adverse reactions of any severity grade were neutropenia, nausea, vomiting, increase in AST/ALT, anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea.
Fatal adverse reactions have occurred in 1.9% and 0.9% of patients treated with the monotherapy and combination regimens, respectively. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.
Tabulated summary of adverse reactions: The following safety profile of Yondelis is based on adverse reactions reported in clinical trials, post-authorisation safety studies and spontaneous reporting.
The following table displays the adverse reactions reported in patients with soft tissue sarcoma and ovarian cancer that were treated with Yondelis recommended regimen in each indication. Both adverse reactions and laboratory values have been used to provide frequencies.
Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000). (See Table 4.)

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In the Yondelis+PLD arm, non-White (mainly Asian) patients had a higher incidence than White patients in grade 3 or 4 adverse reactions (96% versus 87%) and serious adverse reactions (44% versus 23% all grades). The differences were mainly observed in relation with neutropenia (93% versus 66%), anaemia (37% versus 14%) and thrombocytopenia (41% versus 19%). However, the incidences of clinical complications related to haematological toxicity such as severe infections or bleeding, or those leading to death or treatment termination, were similar in both subpopulations.
Description of selected adverse reactions: Most frequent adverse reactions: Blood and lymphatic system disorders: Neutropenia: Neutropenia is the most common haematological toxicity. It followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred at a median of 15 days and recovered within a week. The analysis per cycle performed in patients treated with the monotherapy regimen showed neutropenia of grade 3 and 4 in approximately 19% and 8% of cycles, respectively. In this population, febrile neutropenia occurred in 2% of patients and in <1% of cycles.
Thrombocytopenia: Bleeding events associated to thrombocytopenia occurred in <1% of patients treated with the monotherapy regimen. The analysis per cycle performed in these patients showed thrombocytopenia of grade 3 and 4 in approximately 3% and <1% of cycles, respectively.
Anaemia: Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combination regimens, respectively. The percentages of patients anaemic at baseline were 46% and 35%, respectively. The analysis per cycle performed in patients treated with the monotherapy regimen showed anaemia of grade 3 and 4 in approximately 3% and 1% of cycles, respectively.
Hepatobiliary disorders: AST/ALT increases: The median time to reach the peak values was 5 days for both AST and ALT. Most of the values had decreased to grade 1 or resolved by day 14-15 (see Precautions). The analysis per cycle performed in patients treated with the monotherapy regimen showed grade 3 elevations of AST and ALT in 12% and 20% of cycles, respectively. Grade 4 elevations of AST and ALT occurred in 1% and 2% of cycles, respectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.
Hyperbilirubinemia: Bilirubin peaks approximately a week after onset and resolves approximately two weeks after onset.
Liver function tests predicting severe toxicity (meeting Hy's law) and clinical manifestations of severe hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in less than 1% of patients in both regimens.
Other adverse reactions: Hepatic failure: Rare cases of hepatic failure (including cases with fatal outcomes) have been reported in patients with serious underlying medical conditions treated with trabectedin, both in clinical trials and in post-marketing setting. Some potential risk factors that may have contributed to increased trabectedin toxicity observed in these cases were dose management inconsistent with recommended guidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 substrates or CYP3A4 inhibitors, or lack of dexamethasone prophylaxis.
Capillary Leak Syndrome (CLS): Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes) (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 as per local guideline.