Leitlinien & Arzneimittelsicherheit

HOS-100180 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Of the 1 153 patients treated with Jaypirca, the most common adverse reactions of any grade (in ≥20 % of patients) were neutropenia (27.4 %) and haemorrhage (20.4 %). The most common severe (Grade ≥ 3) adverse reactions (in ≥5 % of patients) were neutropenia (22.8 %), anaemia (9.0 %), pneumonia (8.8 %), and thrombocytopenia (7.2 %). The frequency of treatment discontinuations due to adverse reactions was 3.3 % and the most common adverse reaction leading to treatment discontinuation was pneumonia (0.8 %). The frequency of dose reductions due to adverse reactions was 4.3 % and the most common adverse reaction leading to dose reduction was neutropenia (2.4 %). Serious adverse reactions associated with Jaypirca have occurred in 18.0 % of patients and the most common serious adverse reactions (in ≥1 % of patients) were pneumonia (8.2 %), haemorrhage (2.9 %), neutropenia (2.6 %), anaemia (2.4 %), atrial fibrillation/atrial flutter (1.1 %) and urinary tract infection (1.0 %). Fatal adverse reactions have been observed in 0.7 % of patients for pneumonia, in 0.3 % of patients for haemorrhage and in 0.1 % of patients for urinary tract infection. Tabulated list of adverse reactions Table 1 lists the adverse drug reactions (ADRs) associated with Jaypirca used as a monotherapy from clinical study data and post-marketing experience. The ADRs identified from clinical trials are based on pooled data from 1 153 patients treated with Jaypirca monotherapy 200 mg QD starting dose with no dose escalation in a phase 1/2 clinical study, and from patients treated with Jaypirca monotherapy 200 mg QD in phase 3 studies. Patients were treated for MCL, chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and other non-Hodgkin lymphoma (NHL). Patients were exposed to Jaypirca for a median duration of 18 months. ADRs are listed below by MedDRA body system organ class. Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Table 1: ADRs of patients treated with Jaypircaa System organ class ADR Frequency category (%) Grade ≥ 3c (MedDRA) (All grades)

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HOS-100176 · has-contraindication-information · PDF-Seite 4

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

HOS-100175 · has-indication-information · PDF-Seite 2

Jaypirca as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have been previously treated with a Bruton’s tyrosine kinase (BTK) inhibitor. Jaypirca as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL). 2

HOS-100178 · has-interaction-information · PDF-Seite 5

Pirtobrutinib is primarily metabolised by CYP3A4, UGT1A8, and UGT1A9. Effects of other medicinal products on the pharmacokinetics of pirtobrutinib CYP3A inhibitors In a clinical study, itraconazole, a strong CYP3A4 inhibitor, increased the AUC of pirtobrutinib by 48 % and did not change Cmax of pirtobrutinib. This increase in pirtobrutinib exposure is not clinically meaningful. Therefore, no dose adjustment of Jaypirca is necessary with CYP3A inhibitors. CYP3A inducers In a clinical study, rifampin, a strong CYP3A inducer, decreased the AUC and Cmax of pirtobrutinib by 71 % and 42 %, respectively. Though this decrease in pirtobrutinib exposure is not expected to be clinically meaningful, if possible avoid strong CYP3A inducers (e.g. rifampicin, carbamazepine, phenytoin). Coadministration with medicinal products that are proton pump inhibitors No clinically significant differences in pirtobrutinib pharmacokinetics were observed when administered concomitantly with omeprazole, a proton pump inhibitor. Effects of pirtobrutinib on the pharmacokinetics of other medicinal products (increase in plasma concentration) CYP2C8 substrates Pirtobrutinib is a moderate inhibitor of CYP2C8. Pirtobrutinib increased the AUC and Cmax of repaglinide (a substrate of CYP2C8) by 130 % and 98 %, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of CYP2C8 substrates, caution is advised when co-administering with CYP2C8 substrates (e.g. repaglinide, dasabuvir, selexipag, rosiglitazone, pioglitazone, and montelukast). BCRP substrates Pirtobrutinib is a moderate inhibitor of BCRP. Pirtobrutinib increased the AUC and Cmax of rosuvastatin (a BCRP substrate) by 140 % and 146 %, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of BCRP substrates, caution is advised when co-administering BCRP substrates (e.g. rosuvastatin). If co-administration with narrow therapeutic index BCRP substrates (e.g. high dose methotrexate, mitoxantrone) cannot be avoided, close clinical monitoring should be considered. 5 P-gp substrates Pirtobrutinib is a weak inhibitor of P-gp. Pirtobrutinib increased the AUC and Cmax of digoxin (a P-gp substrate) by 35 % and 55 %, respectively. Therefore, pirtobrutinib can increase the plasma concentrations of P-gp substrates. If co-administration with narrow therapeutic index P-gp substrates (e.g dabigatran etexilate and digoxin) cannot be avoide

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HOS-100179 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential/Contraception in males and females Based on findings in animals and the genotoxicity of pirtobrutinib (see section 5.3), pirtobrutinib can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should use an effective method of contraception during treatment and for 5 weeks after the last dose of Jaypirca. Men are advised to use an effective method of contraception and not father a child during treatment and for 3 months after the last dose of Jaypirca (see section 4.4). Pregnancy There are no data from the use of Jaypirca in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Jaypirca should not be used during pregnancy. Breast-feeding It is unknown whether pirtobrutinib is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Jaypirca and for one week after the last dose of Jaypirca. Fertility There are no data on the effect of pirtobrutinib on human fertility.

HOS-100177 · has-warning-information · PDF-Seite 4

Infections Serious infections, including fatal cases, have occurred in patients treated with Jaypirca. The most frequently reported Grade 3 or higher infections were pneumonia, COVID-19 pneumonia, COVID-19, and sepsis. Prophylactic antimicrobial therapy should be considered in patients who are at increased risk for opportunistic infections. Based on the grade of infection and whether it occurs with neutropenia, dose interruption may be required (see section 4.2). Haemorrhage Bleeding events, including fatal cases, have occurred in patients treated with Jaypirca, with and without thrombocytopenia. Major bleeding events of Grade 3 or higher, including gastrointestinal bleeding and intracranial haemorrhage have been observed. Patients should be monitored for signs and symptoms of bleeding. Patients receiving anticoagulant or antiplatelet agents may be at increased risk of haemorrhage. The risks and benefits of anticoagulant or antiplatelet therapy should be considered when co-administered with Jaypirca and consider additional monitoring for signs of bleeding. The use of Jaypirca has not been studied with warfarin or other vitamin K antagonists. Dose interruption may be required for Grade 3 or 4 bleeding events (see section 4.2). The benefit-risk of withholding Jaypirca for 3 to 5 days pre- and post-surgery should be considered depending upon the type of surgery and risk of bleeding. Cytopenias Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia occurred in patients treated with Jaypirca. Complete blood counts should be monitored in patients during treatment as medically indicated. Based on the grade of cytopenia, dose interruption may be required (see section 4.2). Atrial fibrillation/ flutter Atrial fibrillation and atrial flutter have been observed in patients treated with Jaypirca, particularly in patients with a history of atrial fibrillation and/or multiple cardiovascular comorbidities. Signs and symptoms of atrial fibrillation and atrial flutter should be monitored in patients; obtain an electrocardiogram as medically indicated. Based on the grade of atrial fibrillation/atrial flutter, dose interruption may be required (see section 4.2). Second primary malignancies Second primary malignancies have commonly occurred in patients treated with Jaypirca, with the most frequent types being non-melanoma skin cancers. Patients should be monitored for the appearance of skin cancers and advise protection from sun exposure. Tumo

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