Calquence · 4.6 Fertility, pregnancy and lactation · 2

HOS-099455 · has-adverse-reaction-information · PDF-Seite 49

Summary of the safety profile Calquence monotherapy Of the 1 478 patients treated with Calquence monotherapy, the most common (≥ 20%) adverse drug reactions (ADRs) of any grade were infection, diarrhoea, headache, musculoskeletal pain, bruising, cough, arthralgia, fatigue, nausea and rash. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were infection, leukopenia, neutropenia, anaemia, second primary malignancy, and thrombocytopenia. Calquence in combination with obinutuzumab Of the 223 patients treated with Calquence in combination with obinutuzumab, the most common (≥ 20%) ADRs of any grade were infection, musculoskeletal pain, diarrhoea, headache, leukopenia, neutropenia, cough, fatigue, arthralgia, nausea, dizziness, and constipation. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were leukopenia, neutropenia, infection, thrombocytopenia and anaemia. Calquence in combination with venetoclax Of the 291 patients treated with Calquence in combination with venetoclax, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea and musculoskeletal pain. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reaction was neutropenia. Calquence in combination with venetoclax and obinutuzumab Of the 284 patients treated with Calquence in combination with venetoclax and obinutuzumab, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea, nausea and musculoskeletal pain. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia and thrombocytopenia. Calquence in combination with bendamustine and rituximab Of the 297 patients treated with Calquence in combination with bendamustine and rituximab, the most common (≥ 20%) ADRs of any grade were neutropenia, nausea, rash, diarrhoea, musculoskeletal pain, 49 headache, fatigue, vomiting, constipation, anaemia and thrombocytopenia. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia, rash, thrombocytopenia, anaemia, pneumonia, second primary malignancies, hypertension and second primary malignancies excluding non-melanoma skin. Tabulated list of adverse reactions The below tables present adverse drug reactions (ADRs) identified in clinical studies with patients receiving Calquence monotherapy or combination therapy for haematological malignancies. The median duration of

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HOS-099449 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile Calquence monotherapy Of the 1 478 patients treated with Calquence monotherapy, the most common (≥ 20%) adverse drug reactions (ADRs) of any grade were infection, diarrhoea, headache, musculoskeletal pain, bruising, cough, arthralgia, fatigue, nausea and rash. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were infection, leukopenia, neutropenia, anaemia, second primary malignancy, and thrombocytopenia. Calquence in combination with obinutuzumab Of the 223 patients treated with Calquence in combination with obinutuzumab, the most common (≥ 20%) ADRs of any grade were infection, musculoskeletal pain, diarrhoea, headache, leukopenia, neutropenia, cough, fatigue, arthralgia, nausea, dizziness, and constipation. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were leukopenia, neutropenia, infection, thrombocytopenia and anaemia. Calquence in combination with venetoclax Of the 291 patients treated with Calquence in combination with venetoclax, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea and musculoskeletal pain. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reaction was neutropenia. Calquence in combination with venetoclax and obinutuzumab Of the 284 patients treated with Calquence in combination with venetoclax and obinutuzumab, the most common (≥ 20%) ADRs of any grade were infections, neutropenia, headache, bruising, diarrhoea, nausea 11 and musculoskeletal pain. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia and thrombocytopenia. Calquence in combination with bendamustine and rituximab Of the 297 patients treated with Calquence in combination with bendamustine and rituximab, the most common (≥ 20%) ADRs of any grade were neutropenia, nausea, rash, diarrhoea, musculoskeletal pain, headache, fatigue, vomiting, constipation, anaemia and thrombocytopenia. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia, rash, thrombocytopenia, anaemia, pneumonia, second primary malignancies, hypertension and second primary malignancies excluding non-melanoma skin. Tabulated list of adverse reactions The below tables present adverse drug reactions (ADRs) identified in clinical studies with patients receiving Calquence monotherapy or combination therapy for haematological malignancies. The median duration o

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HOS-099445 · has-contraindication-information · PDF-Seite 7

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

HOS-099451 · has-contraindication-information · PDF-Seite 45

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

HOS-099444 · has-indication-information · PDF-Seite 2

Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence in combination with venetoclax with or without obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy. Calquence in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stem cell transplant (ASCT). Calquence as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) not previously treated with a BTK inhibitor.

HOS-099450 · has-indication-information · PDF-Seite 40

Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence in combination with venetoclax with or without obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy. Calquence in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stem cell transplant (ASCT). Calquence as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) not previously treated with a BTK inhibitor.

HOS-099453 · has-interaction-information · PDF-Seite 47

Acalabrutinib and its active metabolite are primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4), and both substances are substrates for P-gp and breast cancer resistance protein (BCRP). Active substances that may increase acalabrutinib plasma concentrations CYP3A/P-gp inhibitors Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively. Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (see section 4.2). Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mg isavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib Cmax and AUC by 1.4-fold to 2-fold while the active metabolite ACP-5862 Cmax and AUC was decreased by 0.65-fold to 0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2). Active substances that may decrease acalabrutinib plasma concentrations CYP3A inducers Co-administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreased acalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively. Concomitant use with strong inducers of CYP3A activity (e.g., phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant treatment with St. John’s wort, which may unpredictably decrease acalabrutinib plasma concentrations, should be avoided. Gastric acid reducing medicinal products No clinically significant differences in acalabrutinib pharmacokinetics were observed when a 100 mg acalabrutinib tablet was used concomitantly with a proton pump inhibitor (rabeprazole 20 mg twice daily for 3 days). Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump 47 inhibitors, H2-receptor antagonists, antacids), unlike acalabrutinib capsules which show impaired uptake when given with acid reducing agents. Active substances whose plasma concentrations may be altered by Calquence CYP3A substrates Based on in vitr

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HOS-099447 · has-interaction-information · PDF-Seite 9

Acalabrutinib and its active metabolite are primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4), and both substances are substrates for P-gp and breast cancer resistance protein (BCRP). Active substances that may increase acalabrutinib plasma concentrations CYP3A/P-gp inhibitors Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively. Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (see section 4.2). Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mg isavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib Cmax and AUC by 1.4-fold to 2-fold while the active metabolite ACP-5862 Cmax and AUC was decreased by 0.65-fold to 0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2). Active substances that may decrease acalabrutinib plasma concentrations CYP3A inducers Co--administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreased acalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively. Concomitant use with strong inducers of CYP3A activity (e.g., phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant treatment with St. John’s wort, which may unpredictably decrease acalabrutinib plasma concentrations, should be avoided. Gastric acid reducing medicinal products Acalabrutinib solubility decreases with increasing pH. Co-administration of acalabrutinib with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43%. 9 If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate), or an H2-receptor antagonist (e.g., ranitidine or famotidine). For use with antacids, the interval between taking the medicinal products should be at least 2

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HOS-099454 · has-pregnancy-information · PDF-Seite 48

Women of childbearing potential Women of childbearing potential should be advised to avoid becoming pregnant while receiving Calquence. Pregnancy There are no or limited amount of data from the use of acalabrutinib in pregnant women. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy. Dystocia (difficult or prolonged labour) was observed in the rat and administration to pregnant rabbits was associated with reduced foetal growth (see section 5.3). Calquence should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib. Breast-feeding It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed child or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the breast-fed child cannot be excluded. Breast-feeding 48 mothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving the last dose. Fertility There are no data on the effect of Calquence on human fertility. In a non-clinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed (see section 5.3).

HOS-099448 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential Women of childbearing potential should be advised to avoid becoming pregnant while receiving Calquence. Pregnancy There are no or limited amount of data from the use of acalabrutinib in pregnant women. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy. Dystocia (difficult or prolonged labour) was observed in the rat and administration to pregnant rabbits was associated with reduced foetal growth (see section 5.3). Calquence should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib. 10 Breast-feeding It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed child or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the breast-fed child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving the last dose. Fertility There are no data on the effect of Calquence on human fertility. In a non-clinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed (see section 5.3).

HOS-099452 · has-warning-information · PDF-Seite 45

Haemorrhage Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcome, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These events have occurred in patients both with and without thrombocytopenia. Overall, the bleeding events were less severe events including bruising and petechiae (see section 4.8). The mechanism for the bleeding events is not well understood. Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Caution should be used with antithrombotic agents and additional monitoring considered for signs of bleeding when concomitant use is medically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantly with Calquence. Consider the benefit-risk of withholding Calquence for at least 3 days pre- and post-surgery. Infections Serious infections (bacterial, viral or fungal), including fatal events, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These infections predominantly occurred in the absence of neutropenia, with neutropenic infection reported in 10.1% of patients receiving monotherapy and 26.8% in patients receiving combination therapy. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred (see section 4.8). Viral reactivation Cases of hepatitis B reactivation have been reported in patients receiving Calquence. Hepatitis B virus (HBV) status should be established before initiating treatment with Calquence. If patients have positive hepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of Calquence within the context of a prior or concomitant immunosuppressive therapy. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, then appropriate diagnostic evaluations should be undertaken and treatment with Calquence should be suspended unti

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HOS-099446 · has-warning-information · PDF-Seite 7

Haemorrhage Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcome, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These events have occurred in patients both with and without thrombocytopenia. Overall, the bleeding events were less severe events including bruising and petechiae (see section 4.8). The mechanism for the bleeding events is not well understood. Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Caution should be used with antithrombotic agents and additional monitoring considered for signs of bleeding when concomitant use is medically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantly with Calquence. Consider the benefit-risk of withholding Calquence for at least 3 days pre- and post-surgery. Infections Serious infections (bacterial, viral or fungal), including fatal events, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with other medicinal products. These infections predominantly occurred in the absence of neutropenia, with neutropenic infection reported in 10.1% of patients receiving monotherapy and 26.8% in patients receiving combination therapy. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred (see section 4.8). Viral reactivation Cases of hepatitis B reactivation have been reported in patients receiving Calquence. Hepatitis B virus (HBV) status should be established before initiating treatment with Calquence. If patients have positive hepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of Calquence within the context of a prior or concomitant immunosuppressive therapy. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, then appropriate 7 diagnostic evaluations should be underta

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