Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of 569 patients treated up to April 2007 with the recommended treatment regimen in several cancer types including soft tissue sarcoma, breast cancer, osteosarcoma, ovarian cancer, gastrointestinal stroma tumor (GIST), melanoma and renal carcinoma.
Approximately 91% of patients can be expected to have adverse reactions of any grade. Around 40% of patients are expected to have adverse reactions of grade 3 or 4 severity. The most common adverse reactions of any severity grade were nausea, fatigue, vomiting, anorexia, neutropenia and increases in AST/ALT.
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 failure and rhabdomyolysis.
The following information displays the adverse reactions reported in ≥1% of patients according to the standard MEdDRA system organ class. Both adverse reactions and laboratory values have been used to provide frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.
Treatment Emergent Drug-Related Adverse Events Reported in ≥1% of Patients in Clinical Trials at the Recommended Regimen (1.5 mg/m2, 24-hr infusion every 3 weeks): Investigations:
Increased blood creatinine*
(31%), increased blood creatine phosphokinase*
(26%), decreased blood albumin*
(55%), decreased weight (6%).
Blood and Lymphatic System Disorders:
Anaemia* (97%), leukopenia*
(79%), thrombocytopenia* (49%), febrile neutropenia (2%).
Nervous System Disorders:
Headache (11%), dysgeusia (4%), peripheral sensory neuropathy (2%), dizziness (2%), paraesthesia(2%).
Respiratory, Thoracic and Mediastinal Disorders:
Dyspnoea (5%), cough (1%).
Nausea (63%), vomiting (39%), constipation (16%), diarrhea (10%), stomatitis (6%), abdominal pain (5%), dyspepsia (3%), upper abdominal pain (2%).
Skin and Subcutaneous Tissue Disorders:
Musculoskeletal and Connective Tissue Disorders:
Myalgia (5%), arthralgia (2%), back pain (1%).
Metabolism and Nutrition Disorders:
Anorexia (20%), dehydration (2%), decreased appetite (1%), hypokalemia (1%).
Infections and Infestations:
Flushing (2%), hypotension (2%).
General Disorders and Administration Site Conditions:
Fatigue (55%), asthenia (11%), pyrexia (6%), edema (2%), peripheral edema (2%), injection site reaction (2%).
Increased ALT (95%), increased AST (94%), increased GGT (84%), increased blood alkaline phosphatase (60%), hyperbilirubinemia (24%).
Based on laboratory measurements.
Most Frequent Adverse Reactions: Blood and Lymphatic Disorders: Neutropenia:
Neutropenia occurred in 79% of patients. Grades 3 and 4 neutropenia occurred in 27% and 24% of patients, respectively. Neutropenia followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection.
Grades 3 and 4 thrombocytopenia occurred in 18% and 3% of patients, respectively. Bleeding events associated to thrombocytopenia occurred in <1% patients.
Anaemia: Anaemia occurred in 97% of patients although 52% of patients were anaemic at baseline. Grades 3 and 4 anaemia occurred in 13% and 4% of patients, respectively.
Hepatobiliary Disorders: AST/ALT Increases:
Transient grade 3 increases of AST and ALT were observed in 38% and 44% of the patients and grade 4 elevations in 3% and 7% of the patients, respectively. 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 and <2% of cycles had recovery times longer than 25 days. Increased ALT and AST did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.
Grades 1-2 bilirubin increases were observed in 23% of the patients. Grade 3 hyperbilirubinemia occurred in 1% of patients. Bilirubin peaks approximately a week after onset and resolves approximately 2 weeks after onset.
Clinical manifestations of severe hepatic injury were uncommon with a <1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in <1% of patients.
Other Adverse Reactions: Nausea, Vomiting, Diarrhoea and Constipation:
Nausea and vomiting were reported in 63% and 39% of patients, respectively. Grade 3-4 nausea and vomiting were reported in 6% and 7% of patients, respectively. Grade 3-4 diarrhoea and constipation were reported in <1% of patients.
Grade 3-4 mucositis was reported in <1% of the patients.
Grade 3-4 fatigue/asthenia occurred in 9% and 1% of patients, respectively.
Grade 3-4 anorexia occurred in <1% of the patients.
Creatine Phosphokinase (CPK) Elevations and Rhabdomyolysis:
CPK elevations of any grade were observed in 26% of patients. Grade 3 or 4 increases of CPK were observed in 4% of patients. CPK increases in association with rhabdomyolysis were reported in <1% of patients.
Grade 3-4 dyspnoea reported as trabectedin-related occurred in 2% of the patients.
Alopecia was reported in approximately 3% of all patients, of which the majority was grade 1 alopecia.