Yondelis · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094680 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Most patients treated with Yondelis can be expected to have adverse reactions of any grade (91% in monotherapy and 99.4% 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 0.6% 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. 8  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 table below 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). System Organ Very Common Common Uncommon Rare Class Infections and Neutropenic infection Sepsis Septic shock Infestations Blood and Neutropenia Febrile neutropenia Lymphatic System Thrombocytopenia Disorders Anaemia Leukopenia Immune system Hypersensitivity disorders Metabolism and Decreased appetite Dehydration Nutrition Disorders Hypokalaemia Psychiatric Insomnia Disorders Nervous System Headache Dizziness Disorders Dysgeusia Peripheral sensory

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HOS-094676 · has-contraindication-information · PDF-Seite 5

- Hypersensitivity to trabectedin or to any of the excipients listed in section 6.1 - Concurrent serious or uncontrolled infection - Breast-feeding (see section 4.6) - Combination with yellow fever vaccine (see section 4.4)

HOS-094675 · has-indication-information · PDF-Seite 2

Yondelis is indicated for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. Yondelis in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer. 2

HOS-094678 · has-interaction-information · PDF-Seite 7

Effects of other substances on trabectedin Interaction studies have only been performed in adults. Since trabectedin is metabolised mainly by CYP3A4, the concentrations of trabectedin in plasma are likely to be increased in patients who are co-administered drugs that potently inhibit the activity of this isoenzyme. Similarly, the co-administration of trabectedin with potent inducers of CPY3A4 may increase the metabolic clearance of trabectedin. Two in vivo drug-drug interaction phase 1 studies have confirmed trends toward increased and decreased trabectedin exposures when administered with ketoconazole and rifampicin, respectively. When ketoconazole was co-administered with trabectedin, the plasma exposure of trabectedin was increased by approximately 21% for Cmax and 66% for AUC, but no new safety concerns were identified. Close monitoring of toxicities is required in patients receiving trabectedin in combination with potent CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) and such combinations should be avoided if possible. If such combinations are needed, appropriate dose adjustments should be applied in the event of toxicities (see sections 4.2 and 4.4). When rifampicin was co-administered with trabectedin, it resulted in reduced plasma exposure of trabectedin by approximately 22% for Cmax and 31% for AUC. Therefore, the concomitant use of trabectedin with strong CYP3A4 inducers (e.g., rifampicin, phenobarbital, Saint John’s Wort) should be avoided if possible (see section 4.4). Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of the medicinal product (see section 4.4). Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or 7 elimination. The relevance of this interaction e.g. central nervous system (CNS) toxicity has not been established. Caution should be taken in such situations.

HOS-094679 · has-pregnancy-information · PDF-Seite 8

Pregnancy No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. Trabectedin crossed the placenta when administered to pregnant rats. Trabectedin should not be used during pregnancy. If pregnancy occurs during treatment, the patient must be informed of the potential risk to the foetus (see section 5.3) and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns. Women of childbearing potential Women of childbearing potential must use highly effective contraception during treatment and 8 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section 5.3). If pregnancy occurs during treatment the possibility of genetic counselling should be considered. Breast-feeding It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breast-feeding is contraindicated during treatment and 3 months thereafter (see section 4.3). Fertility Men in fertile age must use highly effective contraception during treatment and 5 months after treatment (see section 4.4). Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Yondelis. Genetic counselling is also recommended for patients wishing to have children after therapy.

HOS-094677 · has-warning-information · PDF-Seite 5

Hepatic impairment Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since the systemic exposure to trabectedin is on average approximately doubled (see section 5.2) due to hepatic impairment and therefore the risk of toxicities might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated serum bilirubin levels must not be treated with trabectedin (see section 4.2). Renal impairment Creatinine clearance must be monitored prior to and during treatment. Yondelis monotherapy and combination regimens must not be used in patients with creatinine clearance < 30 ml/min and < 60 ml/min respectively (see section 4.2). Neutropenia and thrombocytopenia Grades 3 or 4 neutropenia and thrombocytopenia associated with Yondelis therapy have been very commonly reported. A full blood cell count including differential and platelet count must be performed at baseline, weekly for the first two cycles and then once between cycles (see section 4.2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately. Yondelis should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 and platelets count of less than 100,000 cells/mm3. If severe neutropenia (ANC < 500 cells/mm3) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended (see section 4.2). Nausea and vomiting Anti-emetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients (see section 4.2). Rhabdomyolysis and severe CPK elevations (> 5 x ULN) Trabectedin must not be used in patients with CPK > 2.5 x ULN (see section 4.2). Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test 5 abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with Yondelis should be discontinued until the patient fully recovers. Caution should be taken if med

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