Piqray

HOS-287407 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The safety profile is based on pooled safety data from 376 patients in the Piqray plus fulvestrant arm of the double-blind, placebo-controlled phase III studies CBYL719C2301 (N=284) and CBYL719C2303 (N=92). The most common ADRs (reported at a frequency >20% in the combined mutant and non-mutant study population) were plasma glucose increased (77.4%), creatinine increased (68.9%), diarrhoea (57.7%), lymphocyte count decreased (56.4%), gamma-glutamyltransferase increased (54.5%), rash (50.0%), alanine aminotransferase increased (47.6%), nausea (46.3%), anaemia (45.7%), fatigue (43.4%), lipase increased (40.2%), decreased appetite (35.4%), stomatitis (27.1%), plasma glucose decreased (26.9%), vomiting (26.9%), weight decreased (25.0%), activated partial thromboplastin time (aPTT) prolonged (24.5%), hypocalcaemia (23.7%) and mucosal inflammation (20.5%). The most common grade 3 or 4 ADRs (reported at a frequency ≥2%) were plasma glucose increased (35.6%), rash (20.2%), gamma-glutamyltransferase increased (13.3%), lymphocyte count decreased (8.8%), lipase increased (6.6%), diarrhoea (6.1%), weight decreased (5.9%), fatigue (5.3%), hypokalaemia (5.1%), alanine aminotransferase increased (4.5%), anaemia (4.0%), hypertension (4.0%), creatinine increased (2.9%), stomatitis (2.9%), nausea (2.4%), osteonecrosis of jaw (2.4%), mucosal inflammation (2.4%) and acute kidney injury (2.1%). The most common ADRs leading to treatment discontinuation were hyperglycaemia (5.6%), rash (5.1%), diarrhoea (2.7%) and fatigue (1.9%). 12 Tabulated list of adverse reactions ADRs from the phase III clinical studies and post-marketing experience (Table 7) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on 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); not known (cannot be estimated from the available data). Table 7 ADRs observed in phase III clinical studies and during post-marketing experience Adverse drug reaction Any grade (%) Grade 3 or 4 (%) Infections and infe

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HOS-287403 · has-contraindication-information · PDF-Seite 7

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

HOS-287402 · has-indication-information · PDF-Seite 2

Piqray is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following an endocrine-based regimen (see section 5.1 and for biomarker-based patient selection see section 4.2). 2

HOS-287405 · has-interaction-information · PDF-Seite 10

Medicinal products that may increase alpelisib plasma concentrations Breast cancer resistance protein (BCRP) inhibitors Alpelisib is a substrate for BCRP in vitro. BCRP is involved in the hepatobiliary export and intestinal secretion of alpelisib, therefore inhibition of BCRP in the liver and in the intestine during elimination may lead to an increase in systemic exposure of alpelisib. Therefore, caution and monitoring for toxicity are advised during concomitant treatment with inhibitors of BCRP (e.g. eltrombopag, lapatinib, pantoprazole). Medicinal products that may decrease alpelisib plasma concentrations Acid-reducing agents The co-administration of the H2-receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure of alpelisib. In the presence of a low-fat low-calorie (LFLC) meal, AUCinf was decreased on average by 21% and Cmax by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUCinf and a 51% decrease in Cmax with ranitidine compared to the fasted state without co-administration of ranitidine. Population pharmacokinetic analysis showed no significant effect of co-administration of acid-reducing agents, including proton pump inhibitors, H2 receptor antagonists and antacids, on the pharmacokinetics of alpelisib. Therefore, alpelisib can be co- administered with acid-reducing agents, provided alpelisib is taken immediately after food (see section 4.2). CYP3A4 inducers Once-daily administration of 600 mg rifampin (a strong CYP3A4 inducer) for 7 days followed by co- administration with a single 300 mg oral dose of alpelisib on day 8, decreased alpelisib Cmax by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampin 600 mg once daily for 15 days with alpelisib 300 mg once daily starting from day 8 to day 15 decreased the steady-state alpelisib Cmax by 59% and AUC by 74%. 10 Co-administration with a strong CYP3A4 inducer decreases alpelisib AUC, which may reduce alpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g. apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered. Medicinal products whose plasma concen

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HOS-287406 · has-pregnancy-information · PDF-Seite 11

Piqray is indicated in men and postmenopausal women. It is not to be used in women who are, or may be, pregnant or breast-feeding (see section 4.1). Women of childbearing potential/Contraception in males and females Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus. Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity (see section 5.3). In case females of reproductive potential take Piqray, they should use effective contraception (e.g. double-barrier method) during therapy and for at least 1 week after stopping treatment with Piqray. Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking Piqray and for at least 1 week after stopping treatment. Please refer to section 4.6 of the prescribing information for fulvestrant. 11 Pregnancy Piqray is not indicated and is not to be used in women who are, or may be, pregnant (see section 4.1). There are no data from the use of alpelisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Piqray is not recommended during pregnancy and in women of childbearing potential not using contraception. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Piqray. Breast-feeding It is not known if alpelisib is excreted in human or animal milk. Because of the potential for serious adverse reactions in the breast-fed infant, it is recommended that women should not breast-feed during treatment and for at least 1 week after the last dose of Piqray. Fertility There are no clinical data available on the effects of alpelisib on fertility. Based on repeated dose toxicity and fertility studies in animals, alpelisib may impair fertility in males and females of reproductive potential (see section 5.3).

HOS-287404 · has-warning-information · PDF-Seite 7

Fulvestrant Due to limited data in patients with prior fulvestrant use (n=39, study CBYL719X2101), efficacy is not considered established in this population (see section 5.1). Hypersensitivity (including anaphylactic reaction) Serious hypersensitivity reactions (including anaphylactic reaction, anaphylactic shock and angioedema), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with Piqray (see section 4.8). Piqray should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated. Severe cutaneous reactions Severe cutaneous reactions have been reported with alpelisib. In the pooled safety dataset from phase III clinical studies, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 2 (0.5%) and 3 (0.8%) patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post-marketing setting (see section 4.8). Treatment should not be initiated in patients with a history of severe cutaneous reactions. Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severe cutaneous reactions are present, Piqray should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended. If a severe cutaneous reaction is confirmed, Piqray should be permanently discontinued. It should not be re-introduced in patients who have experienced previous severe cutaneous reactions. If a severe cutaneous reaction is not confirmed, Piqray may require treatment interruption, dose reduction or treatment discontinuation as described in Table 3 (see section 4.2). Hyperglycaemia Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has been observed in patients treated with Piqray. Some cases of ketoacidosis with fatal outcome have been reported in the post-marketing setting. 7 In the pooled safety dataset from phase III clinical studies, hyperglycaemia occurred more frequently in patients who were diabetic (1 out of 18 patients [5.6%] with grade 1-2, and 15 out of 18 patients [83.3%] with grade 3-4), pr

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