Brukinsa · 4.8 Undesirable effects · 2

HOS-099045 · has-adverse-reaction-information · PDF-Seite 34

Summary of the safety profile Zanubrutinib monotherapy The most commonly occurring adverse reactions (≥20%) of zanubrutinib monotherapy were upper respiratory tract infection § (36%), bruising§ (32%), haemorrhage/haematoma§ (30%), neutropenia§ ( 30%), musculoskeletal pain § (27%), rash § (25%), pneumonia§ (24%), diarrhoea (21%) and cough § (21%) (Table 3). The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib monotherapy were neutropenia§ (21%), pneumonia§ (14%), hypertension § (8%), thrombocytopenia§ (6%), anaemia (6%) and haemorrhage /haematoma§ (4%). Of the 1550 patients treated with zanubrutinib, 4.8% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (2.6%). Adverse reactions leading to dose reduction occurred in 5.0% of patients. 34 Zanubrutinib in combination with obinutuzumab The most commonly occurring adverse reactions (≥20%) of zanubrutinib in combination with obinutuzumab were thrombocytopenia§ (37%), neutropenia§ (31%) and fatigue§ (27%) (Table 4). The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib in combination with obinutuzumab were neutropenia§ (25%), thrombocytopenia§ (16%), pneumonia§ (15%) and anaemia (5%). Of the 143 patients treated with zanubrutinib in combination with obinutuzumab, 4.9% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (4.2%). Adverse reactions leading to dose reduction occurred in 7.0% of patients. Platelet count decreased† (based on laboratory values) was observed in 65% (all grade) and 12% (grade 3 or 4) patients receiving zanubrutinib in combination with obinutuzumab compared to 43% (all grade) and 11% (grade 3 or 4) in patients receiving obinutuzumab. All grade and grade 3 or 4 platelet counts decreased were reported for 39% and 7.8% patients who received zanubrutinib monotherapy. Tabulated list of adverse reactions The safety profile of zanubrutinib monotherapy is based on pooled data from 1 550 patients with B- cell malignancies, including patients with chronic lymphocytic leukaemia (N = 938), Waldenström macroglobulinemia (N = 249), mantle cell lymphoma (N = 140), marginal zone lymphoma (N = 93), follicular lymphoma (N = 59) and other types of B-cell malignancies (N = 71), treated with BRUKINSA in clinical studies

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HOS-099039 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Zanubrutinib monotherapy The most commonly occurring adverse reactions (≥20%) of zanubrutinib monotherapy were upper respiratory tract infection § (36%), bruising§ (32%), haemorrhage/haematoma§ (30%), neutropenia§ (30%), musculoskeletal pain § (27%), rash § (25%), pneumonia§ (24%), diarrhoea (21%) and cough § (21%) (Table 3). The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib monotherapy were neutropenia§ (21%), pneumonia§ (14%), hypertension § (8%), thrombocytopenia§ (6%), anaemia (6%) and haemorrhage /haematoma§ (4%). Of the 1550 patients treated with zanubrutinib, 4.8% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (2.6%). Adverse reactions leading to dose reduction occurred in 5.0% of patients. Zanubrutinib in combination with obinutuzumab The most commonly occurring adverse reactions (≥20%) of zanubrutinib in combination with obinutuzumab were thrombocytopenia§ (37%), neutropenia§ (31%) and fatigue§ (27%) (Table 4). 8 The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib in combination with obinutuzumab were neutropenia§ (25%), thrombocytopenia§ (16%), pneumonia§ (15%) and anaemia (5%). Of the 143 patients treated with zanubrutinib in combination with obinutuzumab, 4.9% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (4.2%). Adverse reactions leading to dose reduction occurred in 7.0% of patients. Platelet count decreased† (based on laboratory values) was observed in 65% (all grade) and 12% (grade 3 or 4) patients receiving zanubrutinib in combination with obinutuzumab compared to 43% (all grade) and 11% (grade 3 or 4) in patients receiving obinutuzumab. All grade and grade 3 or 4 platelet counts decreased were reported for 39% and 7.8% patients who received zanubrutinib monotherapy. Tabulated list of adverse reactions The safety profile of zanubrutinib monotherapy is based on pooled data from 1 550 patients with B- cell malignancies, including patients with chronic lymphocytic leukaemia (N = 938), Waldenström macroglobulinemia (N = 249), mantle cell lymphoma (N = 140), marginal zone lymphoma (N = 93), follicular lymphoma (N = 59) and other types of B-cell malignancies (N = 71), treated with BRUKINSA in clinical studies w

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HOS-099035 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099041 · has-contraindication-information · PDF-Seite 31

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099040 · has-indication-information · PDF-Seite 28

BRUKINSA as monotherapy is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy. BRUKINSA as monotherapy is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based therapy. BRUKINSA as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL). BRUKINSA in combination with obinutuzumab is indicated for the treatment of adult patients with refractory or relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

HOS-099034 · has-indication-information · PDF-Seite 2

BRUKINSA as monotherapy is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy. BRUKINSA as monotherapy is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based therapy. BRUKINSA as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL). BRUKINSA in combination with obinutuzumab is indicated for the treatment of adult patients with refractory or relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

HOS-099043 · has-interaction-information · PDF-Seite 32

Zanubrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A). Agents that may increase zanubrutinib plasma concentrations Concomitant use of BRUKINSA and medicinal products that strongly or moderately inhibit CYP3A can increase zanubrutinib exposure. Strong CYP3A inhibitors The coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) in healthy volunteers increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold. The coadministration of multiple doses of strong CYP3A inhibitors voriconazole and clarithromycin in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 3.30-fold and 1.92-fold for dose- normalized AUC0-24h and 3.29-fold and 2.01-fold for dose-normalized Cmax, respectively. If a strong CYP3A inhibitor must be used (e.g., voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir), reduce the BRUKINSA dose to 80 mg (one- half tablet) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2). Moderate CYP3A inhibitors The coadministration of multiple doses of moderate CYP3A inhibitors fluconazole and diltiazem in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 1.88-fold and 1.62- fold for dose-normalized AUC0-24h and 1.81-fold and 1.62-fold for dose-normalized Cmax, respectively. If a moderate CYP3A inhibitor must be used (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges), reduce 32 the BRUKINSA dose to 160 mg (one tablet) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2). Mild CYP3A inhibitors Simulations using fasted conditions suggested that the mild CYP3A inhibitors (e.g., cyclosporine and fluvoxamine) may increase the AUC of zanubrutinib by <1.5-fold. No dose adjustment is required in combination with mild inhibitors. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed. Agents that may decrease zanubrutinib plasma concentrations Concomitant use of zanubrutinib and strong or moderate inducers of CYP3A can decrease zanubrutinib plasma concentrations. CYP3A inducers C

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HOS-099037 · has-interaction-information · PDF-Seite 6

Zanubrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A). Agents that may increase zanubrutinib plasma concentrations Concomitant use of BRUKINSA and medicinal products that strongly or moderately inhibit CYP3A can increase zanubrutinib exposure. Strong CYP3A inhibitors The coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) in healthy volunteers increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold. The coadministration of multiple doses of strong CYP3A inhibitors voriconazole and clarithromycin in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 3.30-fold and 1.92-fold for dose- normalized AUC0-24h and 3.29-fold and 2.01-fold for dose-normalized Cmax, respectively. If a strong CYP3A inhibitor must be used (e.g., voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir), reduce the BRUKINSA dose to 80 mg (one capsule) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2). Moderate CYP3A inhibitors The coadministration of multiple doses of moderate CYP3A inhibitors fluconazole and diltiazem in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 1.88-fold and 1.62- fold for dose-normalized AUC0-24h and 1.81-fold and 1.62-fold for dose-normalized Cmax, respectively. If a moderate CYP3A inhibitor must be used (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges), the BRUKINSA dose should be reduced to 160 mg (two capsules) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2). 6 Mild CYP3A inhibitors Simulations using fasted conditions suggested that the mild CYP3A inhibitors (e.g., cyclosporine and fluvoxamine) may increase the AUC of zanubrutinib by <1.5-fold. No dose adjustment is required in combination with mild inhibitors. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed. Agents that may decrease zanubrutinib plasma concentrations Concomitant use of zanubrutinib and strong or moderate inducers of CYP3A can decrease zanubrutinib plasma concentrations. CYP3A indu

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HOS-099038 · has-pregnancy-information · PDF-Seite 7

7 Women of childbearing potential/Contraception in females Based on findings in animals, BRUKINSA may cause foetal harm when administered to pregnant women (see section 5.3). Women should avoid becoming pregnant while taking BRUKINSA and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking BRUKINSA and for up to 1 month after stopping treatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy. Pregnancy BRUKINSA should not be used during pregnancy. There are no data from the use of zanubrutinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Breast-feeding It is not known whether zanubrutinib or its metabolites are excreted in human milk and no non- clinical studies were conducted. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with BRUKINSA. Fertility No effect on male or female fertility was noted in rats but morphological abnormalities in sperm and increased post-implantation loss were noted at 300 mg/kg/day (see section 5.3).

HOS-099044 · has-pregnancy-information · PDF-Seite 34

Women of childbearing potential/Contraception in females Based on findings in animals, BRUKINSA may cause foetal harm when administered to pregnant women (see section 5.3). Women should avoid becoming pregnant while taking BRUKINSA and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking BRUKINSA and for up to 1 month after stopping treatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy. Pregnancy BRUKINSA should not be used during pregnancy. There are no data from the use of zanubrutinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Breast-feeding It is not known whether zanubrutinib or its metabolites are excreted in human milk and no non- clinical studies were conducted. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with BRUKINSA. Fertility No effect on male or female fertility was noted in rats but morphological abnormalities in sperm and increased post-implantation loss were noted at 300 mg/kg/day (see section 5.3).

HOS-099036 · has-warning-information · PDF-Seite 5

Haemorrhage Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA. Grade 3 or higher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax have been reported in patients (see section 4.8). Bleeding events of any grade including purpura and petechiae occurred in patients with haematological malignancies. The mechanism for the bleeding events is not well understood. BRUKINSA may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Dose modification may be necessary for Grade 3 or greater adverse reactions as recommended (see section 4.2). Warfarin or other vitamin K antagonists should not be administered concomitantly with BRUKINSA. Patients should be monitored for signs and symptoms of bleeding and complete blood counts should be monitored. The risks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSA should be considered. The benefit-risk of withholding zanubrutinib for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding should be considered. Infections Fatal and non-fatal infections (including bacterial, viral, fungal infections, or sepsis) and opportunistic infections (e.g., herpes viral, cryptococcal, aspergillus and pneumocystis jiroveci infections) have occurred in patients treated with BRUKINSA. Grade 3 or higher infections occurred in patients (see section 4.8). The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have also occurred. Before initiating treatment with BRUKINSA, patients’ HBV status should be established. Consultation with a liver disease expert physician is recommended for patients who test positive for HBV or have positive hepatitis B serology, before initiating treatment. Patients should be monitored and managed according to the medical standards to prevent hepatitis B reactivation. Consider prophylaxis according to standard of care in patients who are at increased risk for infections. Patients should be monitored for signs and symptoms of infection and treat appropriately. Cytopenia Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anaemia based on laboratory measurements were reported in patients treated with BRUKINSA (see section 4.8). Complete blood counts should be monitored monthly during tr

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HOS-099042 · has-warning-information · PDF-Seite 31

Haemorrhage Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA. Grade 3 or higher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax have been reported in patients (see section 4.8). Bleeding events of any grade including purpura and petechiae occurred in patients with haematological malignancies. The mechanism for the bleeding events is not well understood. BRUKINSA may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Dose modification may be necessary for Grade 3 or greater adverse reactions as recommended (see section 4.2). Warfarin or other vitamin K antagonists should not be administered concomitantly with BRUKINSA. Patients should be monitored for signs and symptoms of bleeding and monitor complete blood counts. The risks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSA should be considered. The benefit-risk of withholding zanubrutinib for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding should be considered. Infections Fatal and non-fatal infections (including bacterial, viral, fungal infections, or sepsis) and opportunistic infections (e.g., herpes viral, cryptococcal, aspergillus and pneumocystis jiroveci infections) have occurred in patients treated with BRUKINSA. Grade 3 or higher infections occurred in patients (see section 4.8). The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have also occurred. Before initiating treatment with BRUKINSA, patients’ HBV status should be established. Consultation with a liver disease expert physician is recommended for patients who test positive for HBV or have positive hepatitis B serology, before initiating treatment. Patients should be monitored and managed according to the medical standards to prevent hepatitis B reactivation. Prophylaxis according to standard of care in patients who are at increased risk for infections should be considered. Patients should be monitored for signs and symptoms of infection and treat appropriately. Cytopenia Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anaemia based on laboratory measurements were reported in patients treated with BRUKINSA (see section 4.8). Complete blood counts should be monitored monthly during tr

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