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

HOS-097199 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile In clinical studies of subjects with hematologic malignancies who received idelalisib, the most frequently reported adverse reactions were: infections (70%), neutropenia (55%), transaminases increased (53%), diarrhoea (48%), triglycerides increased (47%), pyrexia (36%), rash (30%) and lymphocytosis (21%). The most frequently reported severe adverse reactions (≥ Grade 3) were: infections (39%), neutropenia (33%), diarrhoea/colitis (22%), transaminases increased (15%) and lymphocytosis (13%). Tabulated list of adverse reactions Assessment of adverse reactions is based on two Phase 3 studies (study 312-0116 and study 312-0119) and six Phase 1 and 2 studies. Study 312-0116 was a randomised, double-blind, placebo-controlled study in which 110 subjects with previously treated CLL received idelalisib + rituximab. In addition, 86 subjects from this study who were randomised to receive placebo + rituximab went on to receive idelalisib as a single agent in an extension study (study 312-0117). Study 312-0119 was a randomised, controlled, open-label study in which 173 subjects with previously treated CLL received idelalisib + ofatumumab. The Phase 1 and 2 studies assessed the safety of idelalisib in a total of 536 subjects with haematologic malignancies, including 400 subjects who received idelalisib (any dose) as a single agent 11 and 136 subjects who received idelalisib in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab). The adverse drug reactions reported with idelalisib alone or in combination with anti-CD20 monoclonal antibodies (rituximab or ofatumumab) are provided in Table 2. Adverse reactions are listed by system organ class and frequency. Frequencies are defined as follows: 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 available data). Table 2: Adverse drug reactions reported in clinical studies in subjects with haematologic malignancies receiving idelalisib and post-marketing. Reaction Any grade Grade ≥ 3 Infections and infestations Infections (including Very common Very common Pneumocystis jirovecii pneumonia and CMV)* Blood and lymphatic system disorders Neutropenia Very common

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HOS-097195 · has-contraindication-information · PDF-Seite 4

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

HOS-097194 · has-indication-information · PDF-Seite 2

Zydelig is indicated in combination with rituximab for the treatment of adult patients with chronic lymphocytic leukaemia (CLL): • who have received at least one prior therapy (see section 4.4), or • as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies (see section 4.4). Zydelig is indicated as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment (see section 4.4).

HOS-097197 · has-interaction-information · PDF-Seite 6

Idelalisib is metabolised primarily via aldehyde oxidase, and to a lesser extent via CYP3A and glucuronidation (UGT1A4). Its primary metabolite is GS-563117, which is not pharmacologically active. Idelalisib and GS-563117 are substrates of P-gp and BCRP. 6 Effect of other medicinal products on idelalisib pharmacokinetics CYP3A inducers A clinical drug interaction study found that co-administration of a single dose of 150 mg idelalisib with rifampicin (a strong CYP3A inducer) resulted in a ~75% reduction in idelalisib AUCinf. Co-administration of Zydelig with moderate or strong CYP3A inducers such as rifampicin, phenytoin, St. John’s wort, or carbamazepine should be avoided as this may result in decreased efficacy. CYP3A/P-gp inhibitors A clinical drug interaction study found that co-administration of a single dose of 400 mg idelalisib with 400 mg once daily ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) resulted in a 26% increase in Cmax and a 79% increase in AUCinf of idelalisib. No initial dose adjustment of idelalisib is considered necessary when administered with CYP3A/P-gp inhibitors, but an intensified monitoring of adverse reactions is recommended. Effect of idelalisib on the pharmacokinetics of other medicinal products CYP3A substrates The primary metabolite of idelalisib, GS-563117, is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administration of idelalisib with midazolam (a sensitive CYP3A substrate) resulted in a ~140% increase in Cmax and a ~440% increase in AUCinf of midazolam due to the CYP3A inhibition by GS-563117. Co-administration of idelalisib with CYP3A substrates may increase their systemic exposures and increase or prolong their therapeutic activity and adverse reactions. In vitro, the CYP3A4 inhibition was irreversible, and return to normal enzyme activity is therefore expected to take several days after stopping idelalisib administration. Potential interactions between idelalisib and co-administered medicinal products that are CYP3A substrates are listed in Table 1 (increase is indicated as “↑”). This list is not exhaustive and is intended to serve as guidance only. In general, the SmPC for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors (see section 4.4). Table 1: Interactions between idelalisib and other medicinal products that are CYP3A substrates Medicinal product Expe

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HOS-097198 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential / contraception Based on findings in animals, idelalisib may cause foetal harm. Women should avoid becoming pregnant while taking Zydelig, and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraception while taking Zydelig and for 1 month after stopping treatment. It is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method as a second form of contraception. Pregnancy There are no or limited amount of data from the use of idelalisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Zydelig is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is not known whether idelalisib and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Zydelig. Fertility No human data on the effect of idelalisib on fertility are available. Animal studies indicate the potential for harmful effects of idelalisib on fertility and foetal development (see section 5.3).

HOS-097196 · has-warning-information · PDF-Seite 4

Serious infections Treatment with Zydelig should not be initiated in patients with any evidence of ongoing systemic bacterial, fungal, or viral infection. Serious and fatal infections have occurred with idelalisib, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV). Prophylaxis for PJP should therefore be administered to all patients throughout idelalisib treatment, and for a period of 2 to 6 months after discontinuation. The duration of post-treatment prophylaxis should be based on clinical judgment and may take into account a patient’s risk factors such as concomitant corticosteroid treatment and prolonged neutropenia (see section 4.8). Patients should be monitored for respiratory signs and symptoms throughout treatment. Patients should be advised to report new respiratory symptoms promptly. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with positive CMV serology at the start of treatment with idelalisib or with other evidence of a history of CMV infection. Patients with CMV viraemia without associated clinical signs of CMV infection should be carefully monitored. For patients with evidence of CMV viraemia and clinical signs of CMV infection, consideration should be given to interrupting idelalisib until the infection has resolved. If the benefits of resuming idelalisib are judged to outweigh the risks, consideration should be given to administering pre-emptive CMV therapy. 4 Cases of progressive multifocal leukoencephalopathy (PML) have been reported following the use of idelalisib within the context of prior or concomitant immunosuppressive therapies that have been associated with PML. 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 suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC viral DNA and repeat neurological assessments should be considered. Neutropenia Treatment-emergent Grade 3 or 4 neutropenia, including febrile neutropenia, have occurred in patients treated with idelalisib. Blood counts should be monitored in all patients at least e

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