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 regime in several cancer types including soft tissue sarcoma, breast cancer, osteosarcoma, ovarian cancer, 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, neuutropenia, and increases in AST/ALT.
Fatal adverse reactions have occurred in 1.9% of patients. They were often result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal failure and rhabdomyolysis.
Adverse reactions: The frequencies of the adverse reactions reported below are classified as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1000 to <1/100). The following are 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 seriousness.
Adverse Reactions Reported in ≥1% of Patients in Clinical Trials at the Recommended Regime (1.5 mg/m2
, 24-hr infusion every 3 weeks): Investigations: Very Common: Increased blood creatine phosphokinase, increased blood creatinine; decreased blood albumin. Common: Decreased weight.
Blood and Lymphatic System Disorders: Very Common: Neutropenia, thrombocytopenia, anaemia, leukopenia. Common: Febrile neutropenia.
Nervous System Disorders: Very Common: Headache. Common: Peripheral sensory neuropathy, dysgeusia, dizziness, paraesthesia.
Respiratory, Thoracic and Mediastinal Disorders: Common: Dyspnoea, cough.
GI Disorders: Very Common: Vomiting, nausea, constipation. Common: Diarrhoea, stomatitis, abdominal pain, dyspepsia, upper abdominal pain.
Skin and Subcutaneous Tissue Disorders: Common: Alopecia.
Musculoskeletal and Connective Tissue Disorders: Common: Myalgia, arthralgia, back pain.
Metabolism and Nutrition Disorders: Very Common: Anorexia. Common: Dehydration, decreased appetite, hypokalemia.
Infections and Infestations: Common: Infection.
Vascular Disorders: Common: Hypotension, flushing.
General Disorders and Administration Site Conditions: Very Common: Fatigue, asthenia. Common: Pyrexia, oedema, oedema peripheral, injection site reaction.
Hepatobiliary Disorders: Very Common: Hyperbilirubinemia; increased ALT and AST, γ-glutamyltransferase.
Psychiatric Disorders: Common: Insomnia.
Most Frequent Adverse Reactions: Blood and Lymphatic System Disorders: Neutropenia: Neutropenia occurred in 77% of patients. Grades 3 and 4 neutropenia occurred in 26% and 24% of patients, respectively. The analysis per cycle showed that neutropenia of grade 3 and 4 occurred in approximately 19% and 8% of cycles respectively. Febrile neutropenia occurred in 2% of patients and in <1% of cycles. Neutropenia followed a predictable pattern of rapid onset and reversibility and was rarely associated with fever or infection.
Thrombocytopenia: Grades 3 and 4 thrombocytopenia occurred in 11% and 2% of patients, respectively. The analysis per cycle showed that thrombocytopenia of grade 3 and 4 occurred in approximately 3% and <1% of cycles respectively. Bleeding events associated to thrombocytopenia occurred in <1% of patients.
Anaemia: Anaemia occurred in 93% of patients although 46% of patients were anaemic at baseline. Grades 3 and 4 anaemia occurred in 10% and 3% of patients, respectively. The analysis per cycle showed that anaemia of grade 3 and 4 occurred in approximately 3% and 1% cycles 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 (see Precautions). Grade 3 elevations of AST and ALT occurred in 12% and 20% 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: Grades 1 to 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 38.5% of patients, respectively. Grades 3-4 nausea and vomiting were reported in 6% and 6.5% of patients, respectively. Grades 3-4 diarrhoea and constipation were reported in <1% of patients.
Stomatitis: Grades 3-4 mucositis was reported in <1% of the patients.
Fatigue/Asthenia: Grades 3-4 fatigue/asthenia occurred in 9% and 1% of patients, respectively.
Anorexia: Grades 3-4 anorexia occurred in <1% of the patients.
CPK Elevations and Rhabdomyolysis: CPK elevations of any grade were observed in 26% of patients. Grades 3 or 4 increases of CPK were observed in 4% of patients. CPK increases in association with rhabdomyolysis were reported in <1% of patients.
Dyspnoea: Grades 3-4 dyspnoea reported as trabectedin related occurred in 2% of the patients.
Alopecia: Alopecia was reported in approximately 3% of all patients, of which the majority was grade 1 alopecia.