Joenja · 4.1 Therapeutic indications · 1

HOS-100287 · has-adverse-reaction-information · PDF-Seite 6

Summary of safety profile The most commonly reported adverse reactions during leniolisib treatment were headache (32%), vomiting (16%), weight increase (13%), and alopecia (11%). Based on laboratory data from the clinical studies, 33% of patients experienced a decrease in neutrophil counts. Tabulated list of adverse reactions The safety of leniolisib was evaluated in 38 adolescent and adult patients with APDS who participated in the placebo-controlled portion of Study 2201, and an open label safety study. Thirty-seven of 38 patients received leniolisib 70 mg orally twice daily for at least 60 weeks and 84% were exposed for 108 weeks or longer. Median duration of leniolisib treatment was approximately 4 years, and 10 patients had more than 5 years of leniolisib exposure. The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience. Adverse reactions in Table 1 are listed by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), and rare (≥ 1/10 000 to < 1/1 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency. Table 1 Adverse reactions System organ class Adverse reaction Frequency Immune system disorders Hypersensitivity* Not known Nervous system disorders Headache Very common Gastrointestinal disorders Vomiting Very common Dyspepsia Common Skin and subcutaneous tissue disorders Alopecia Very common Atopic dermatitis** Common Rash Common 6  System organ class Adverse reaction Frequency General disorders and administration Fatigue Common site conditions Investigations Weight increased Very common Neu

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HOS-100283 · has-contraindication-information · PDF-Seite 3

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

HOS-100282 · has-indication-information · PDF-Seite 2

Joenja is indicated for the treatment of activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and adolescents 12 years of age and older and weighing 45 kg or more.

HOS-100285 · has-interaction-information · PDF-Seite 4

Medicinal products affecting the pharmacokinetics of leniolisib CYP3A4 inhibitors Leniolisib is cleared primarily through oxidative metabolism (primarily hydroxylation and dealkylation) by CYP isoenzymes (predominantly CYP3A4, 95.4%). In a study of healthy adults, co-administration of leniolisib and itraconazole, a strong CYP3A4 inhibitor, resulted in a 2-fold increase in leniolisib exposure. Concomitant use of leniolisib with strong CYP3A4 inhibitors (e.g., cobicistat, danoprevir, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telithromycin, tipranavir, troleandomycin, 4 voriconazole) should be avoided (see sections 4.4 and 5.2). CYP3A4 inducers No interaction studies have been conducted with leniolisib and strong and moderate CYP3A4 inducers. Concomitant use may result in reduced leniolisib exposure and thus reduced leniolisib efficacy. Therefore, concomitant use of leniolisib with strong and moderate CYP3A4 inducers (e.g., avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampicin, St. John’s Wort, bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided (see section 4.4). BCRP inhibitors Leniolisib is a substrate of BCRP transporters. No interaction studies have been conducted with leniolisib and strong BCRP inhibitors. Concomitant use may result in increased leniolisib exposure, which could lead to an increased risk of adverse effects. Therefore, concomitant use of leniolisib with strong BCRP inhibitors (e.g., curcumin, cyclosporine) should be avoided (see section 4.4). Gastric acid reducing agents Leniolisib exhibits pH-dependent solubility, with lower solubility at higher pH-values. Locally acting antacids (e.g., magnesium-, aluminum-, and calcium-based antacids, sodium bicarbonate) should be taken 2 hours before or 2 hours after leniolisib administration (see sections 4.2 and 4.4). Medicinal products that have their exposure altered by leniolisib OATP1B1, OATP1B3, and BCRP substrates When co-administered, leniolisib increased rosuvastatin exposure 2-fold. Avoid concomitant use of leniolisib with medicinal products that are OATP1B1, OATP1B3, and BCRP substrates (e.g., rosuvastatin, pitavastatin, letermovir). OAT3 substrates Leniolisib is an OAT3 inhibitor and may increase systemic exposure to OAT3 substrates (e.g., adefovir, baricitinib, bumetanide, cefaclor, ceftizoxime,

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HOS-100286 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential/contraception in females Women of childbearing potential should use highly effective methods of contraception during treatment with Joenja and for 1 week after the last dose. Leniolisib can cause foetal harm based on findings from animal studies (see section 5.3). Verify pregnancy status in females of reproductive potential prior to initiating treatment with Joenja. 5 Pregnancy There are no data from the use of leniolisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Joenja is not recommended during pregnancy and in women of childbearing potential not using highly effective methods of contraception. Breast-feeding It is unknown whether leniolisib and its metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of leniolisib in milk (see section 5.3). A risk to breastfed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Joenja. Fertility No human data on the effect of leniolisib on fertility are available. Studies in animals have shown effects on the male reproductive organs (see section 5.3).

HOS-100284 · has-warning-information · PDF-Seite 3

Immune-related adverse events Serious, sometimes fatal, immune-related adverse events such as severe infections, severe cutaneous adverse reactions (SCARs), pneumonitis, severe diarrhoea/colitis, and hepatotoxicity have occurred in patients receiving other phosphoinositide 3-kinase delta (PI3Kδ) inhibitors for the treatment of haematological or solid cancers. These serious events have not been associated with the use of Joenja in APDS patients. Joenja is not approved for treatment of haematological or solid cancers. Combination with CYP3A4 inhibitors Concomitant therapy with a strong cytochrome P450 (CYP)3A4 inhibitor increased leniolisib exposure. Concomitant use of leniolisib with strong CYP3A4 inhibitors should be avoided (see section 4.5). If use of strong CYP3A4 inhibitors is required, it is recommended that Joenja be discontinued 2 days before administration of CYP3A4 inhibitor. Joenja may be restarted 7 days after CYP3A4 inhibitor discontinuation. Combination with CYP3A4 inducers Concomitant use may result in reduced leniolisib exposure and thus reduced leniolisib efficacy. Therefore, concomitant use of leniolisib with strong and moderate CYP3A4 inducers should be avoided (see section 4.5). 3 Combination with BCRP inhibitors Concomitant use may result in increased leniolisib exposure, which could lead to an increased risk of adverse reactions. Therefore, concomitant use of leniolisib with strong breast cancer resistance protein (BCRP) transporter inhibitors should be avoided (see section 4.5). Combination with organic anion transporter (OAT)P1B1, OATP1B3, and breast cancer resistance protein (BCRP) substrates When co-administered, leniolisib increased rosuvastatin systemic exposure 2-fold. Concomitant use of leniolisib with medicinal products that are substrates of these transporters should be avoided (see section 4.5). Combination with OAT3 substrates For OAT3 substrates with a narrow therapeutic index (e.g., methotrexate), monitor patients for adverse events and consider dose adjustments if co-administration cannot be avoided (See section 4.5). UDP-glucuronosyltransferase (UGT) 1A1 substrates In vitro, leniolisib is an inhibitor of UGT1A1, and although a relevant clinical interaction is not expected, concomitant administration of leniolisib with a UGT1A1 substrate should be avoided (see section 4.5). Gastric acid reducing agents For patients using antacids chronically, the antacid

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