Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile:
Most patients treated with Yondelis 1mg can be expected to have adverse reactions of any grade (91%) and less than one third serious adverse reactions of grade 3 or 4 severity (10%). The most common adverse reactions of any severity grade were neutropenia, nausea, vomiting, increases in AST/ALT, anemia, fatigue, thrombocytopenia, anorexia and diarrhea.

Fatal adverse reactions have occurred in 1.9% of patients .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 1mg is based on adverse reactions reported in clinical trials, post- authorisation safety studies and spontaneous reporting.

The table below displays the adverse reactions reported in patients with soft tissue sarcoma and that were treated with Yondelis 1mg recommended regimen. Both adverse reactions and laboratory values have been used to provide frequencies.

The frequencies of the adverse reactions reported below are classified as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).


System Organ       Adverse reactions reported in ≥ 1% of patients with soft tissue Class         sarcoma in clinical trials.
Infections and      Very Common
Infestations        Neutropenic infection
Common
Sepsis
Uncommon
Septic shock
Blood and           Very Common
Lymphatic           Neutropenia, Thrombocytopenia, Anaemia, Leukopenia System              Common
Disorders           Febrile neutropenia
Immune             Common system             Hypersensitivity disorders

Metabolism and     Very Common
Nutrition          Decreased appetite
Disorders          Common
Dehydration, Hypokalaemia

Psychiatric         Very Common
Disorders          Insomnia
Nervous            Very Common
System             Headache
Disorders          Common
Peripheral sensory neuropathy, Dysgeusia, Dizziness
Vascular           Common
Disorders          Hypotension, Flushing
Uncommon
Capillary leak syndrome
Respiratory,       Very Common
Thoracic and       Dyspnoea, Cough
Mediastinal        Uncommon
Disorders          Pulmonary oedema
Gastrointestinal   Very Common disorders          Vomiting, Nausea, Constipation, Abdominal pain, Diarrhoea, Stomatitis Common
Dyspepsia
Hepatobiliary      Very Common
Disorders          Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood bilirubin increased.
Common
Gamma-glutamyltransferase increased
Rare
Hepatic failure

Skin and           Very Common
Subcutaneous        Palmar-plantar, erythrodysaesthesia
Tissue             Common
Disorders          Rash, Alopecia
Musculoskeletal    Very Common and Connective     Arthralgia, Back pain, Blood creatine, phosphokinase increased Tissue             Common
Disorders          Myalgia
Uncommon
Rhabdomyolysis
General            Very Common
Disorders and      Fatigue, Pyrexia, Oedema
Administration     Common
Site Conditions    Injection site reaction
Uncommon
Extravasation Soft tissue necrosis
 Investigations     Very Common
Blood creatinine increased, Blood albumin decreased
Common
Weight decreased


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%. 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. The percentages of patients anaemic at baseline were 46% and 35% respectively. The analysis per cycle 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 section 4.4). 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.

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 section 4.4).

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.