Venclyxto

HOS-097681 · has-adverse-reaction-information · PDF-Seite 14

Summary of safety profile Chronic lymphocytic leukaemia The overall safety profile of Venclyxto is based on data from 1187 patients with CLL treated in clinical studies with venetoclax in combination with obinutuzumab, ibrutinib, or rituximab, or as monotherapy. The safety analysis included patients from three phase 3 studies (CLL14, GLOW, and MURANO), three phase 2 studies (CAPTIVATE, M13-982, and M14-032), and one phase 1 study (M12-175). CLL14 was a randomised, controlled study in which 212 patients with previously untreated CLL and comorbidities received venetoclax in combination with obinutuzumab. GLOW was an open-label randomised study in which 106 patients with previously untreated CLL received venetoclax in combination with ibrutinib. MURANO was a randomised, controlled study in which 194 patients with previously treated CLL received venetoclax in combination with rituximab. CAPTIVATE was a multicentre, 2-cohort study in which 323 patients with previously untreated CLL received venetoclax in combination with ibrutinib. In the M13-982, M14-032 and M12-175 studies, 352 patients with previously treated CLL, which included 212 patients with 17p deletion and 146 patients who had failed a B-cell receptor pathway inhibitor were treated with venetoclax monotherapy (see section 5.1). The most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab, ibrutinib, or rituximab were diarrhoea, neutropenia, nausea, upper respiratory tract infection, fatigue and vomiting. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection. 14 The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax in combination with obinutuzumab, ibrutinib, or rituximab were pneumonia, febrile neutropenia, sepsis, neutropenia, anaemia, diarrhoea and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and febrile neutropenia. The safety of venetoclax in combination with acalabrutinib with or without obinutuzumab was assessed in AMPLIFY, a randomised, controlled study of 575 patients with previously untreated CLL without del (17p) or TP53 mutation. Of the 291 patients treated with venetoclax in combination with acalabrutinib, the most commonly

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HOS-097677 · has-contraindication-information · PDF-Seite 10

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. In patients with CLL, concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase (see sections 4.2 and 4.5). In all patients, concomitant use of preparations containing St. John’s wort (see sections 4.4 and 4.5).

HOS-097676 · has-indication-information · PDF-Seite 2

Venclyxto is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL): • in combination with acalabrutinib with or without obinutuzumab • in combination with obinutuzumab (see section 5.1) • in combination with ibrutinib Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy. Venclyxto monotherapy is indicated for the treatment of CLL: • in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or • in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor. 2 Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

HOS-097679 · has-interaction-information · PDF-Seite 12

Venetoclax is predominantly metabolised by CYP3A. Agents that may alter venetoclax plasma concentrations CYP3A inhibitors Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days in 11 patients increased venetoclax Cmax to 2.3-fold and AUC to 6.4-fold. Co-administration of 50 mg once daily ritonavir, a strong CYP3A and P-gp inhibitor, for 14 days in 6 healthy subjects increased venetoclax Cmax to 2.4-fold and AUC by 7.9-fold. Compared with venetoclax 400 mg administered alone, co-administration of 300 mg posaconazole, a strong CYP3A and P-gp inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients increased venetoclax Cmax to 1.6-fold and 1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively. Co-administration of venetoclax with other strong CYP3A4 inhibitors is predicted to increase venetoclax AUC by on average 5.8- to 7.8-fold. For patients requiring concomitant use of venetoclax with strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil), venetoclax dosing should be administered according to Table 7. Patients should be monitored more closely for signs of toxicities and the dose may need to be further adjusted. The venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor (see section 4.2). Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A. P-gp and BCRP inhibitors Venetoclax is a substrate for P-gp and BCRP. Co-administration of a 600 mg single dose of rifampicin, a P-gp inhibitor, in 11 healthy subjects increased venetoclax Cmax by 106% and AUC by 78%. Concomitant use of venetoclax with P-gp and BCRP inhibitors at initiation and during the dose-titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of toxicities (see section 4.4). Ibrutinib In studies of ibrutinib (420 mg) in combination with venetoclax (400 mg) in CLL patients, an increase in venetoclax exposure (approximately 1.8-fold based on AUC) was observed compared with monotherapy data for venetoclax. CYP3A inducers Co-administration of 600 mg once daily rifampicin, a strong CYP3A inducer, for 13 days in 10 healthy su

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HOS-097680 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential/Contraception in females Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking venetoclax and for 30 days after stopping treatment. It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. 13 Pregnancy Based on embryo-foetal toxicity studies in animals (see section 5.3), venetoclax may harm the foetus when administered to pregnant women. There are no adequate and well-controlled data from the use of venetoclax in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Venetoclax is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception. Breast-feeding It is unknown whether venetoclax or its metabolites are excreted in human milk. A risk to the breast-feeding child cannot be excluded. Breast-feeding should be discontinued during treatment with Venclyxto. Fertility No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity in dogs at clinically relevant exposures, male fertility may be compromised by treatment with venetoclax (see section 5.3). Before starting treatment, counselling on sperm storage may be considered in some male patients.

HOS-097678 · has-warning-information · PDF-Seite 10

Tumour lysis syndrome Tumour lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax (see section 4.8). 10 Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose increase. During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax. Information described in section 4.2, including risk assessment, prophylactic measures, dose-titration and modification schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden, and splenomegaly in CLL. All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. Blood chemistries should be monitored, and abnormalities managed promptly. More intensive measures (intravenous hydration, frequent monitoring, hospitalisation) should be employed as overall risk increases. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed (see Table 4 and Table 5). The instructions for “Prevention of tumour lysis syndrome (TLS)” should be followed (see section 4.2). Concomitant use of this medicinal product with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation and during the dose-titration phase (see sections 4.2 and 4.3). Also, inhibitors of P-gp or BCRP may increase venetoclax exposure (see section 4.5). Neutropenia and infections In patients with CLL, grade 3 or 4 neutropenia has been reported in patients treated with venetoclax in combination studies and in monotherapy studies (see section 4.8). In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. The neutrophil counts can worsen with venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reducti

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