Vijoice · 4.1 Therapeutic indications · 2

HOS-100985 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile In adult patients enrolled in the retrospective chart review studies, the most common ADRs (all grades) were hyperglycaemia (27.8%), diarrhoea (27.8%), headache (22.2%), stomatitis (16.7%), alopecia (16.7%), dermatitis (16.7%), dry skin (16.7%) and nausea (11.1%). Grade 3-4 ADRs were decreased blood phosphate (11.1%), dehydration (5.6%), increased blood creatinine (5.6%) and increased glucose (5.6%). Serious ADRs (all grades) were dehydration (5.6%) and hyperglycaemia (5.6%). The ADR alopecia (all grades) led to dose reduction (5.6%). ADRs leading to dose interruptions (all grades) were vomiting (5.6%), nausea (5.6%), mucosal dryness (5.6%) and headache (5.6%). In paediatric patients enrolled in the retrospective chart review studies, the most common ADRs (all grades) were stomatitis (23.1%) and diarrhoea (12.8%). No grade 3-4 ADRs were reported. Serious ADRs (all grades) were vomiting (2.6%) and dehydration (2.6%). ADRs leading to dose interruptions (all grades) were vomiting (2.6%) and dehydration (2.6%). The most common ADRs in paediatric patients enrolled in the phase II interventional clinical study (all grades) were abdominal pain (33.7%), headache (30.3%), diarrhoea (28.1%) and vomiting (24.7%). Grade 3-4 ADRs were increased lipase (3.4%), decreased appetite (1.1%) and diarrhoea (1.1%). Serious ADRs (all grades) were diarrhoea (1.1%), headache (1.1%) and rash (1.1%). Dose interruptions due to an ADR occurred in 9.0% of patients; the most common ADRs which required dose interruption were vomiting (2.2%), rash (2.2%) and diarrhoea (2.2%). ADRs leading to permanent discontinuation (all grades) were alopecia (2.2%) and decreased appetite (1.1%). Tabulated list of adverse reactions The list of adverse reactions is based on data from retrospective chart review studies in 18 adult and 39 paediatric patients, who were treated with alpelisib in a compassionate use programme with an initial starting dose of 250 mg in adult patients and 50 mg in paediatric patients. The median duration of exposure was 42 months (range: 3.4 to 74.8 months). The list of adverse reactions is also based on data from a phase II interventional clinical study in 89 paediatric patients (including 82 patients 6 to < 18 years of age and 7 patients 2 to < 6 years of age), who were treated with alpelisib with an initial starting dose of 50 mg, for a median duration of exposure of approximately 30 months. Within each system organ class, the ADRs are ranke

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HOS-100991 · has-adverse-reaction-information · PDF-Seite 38

Summary of the safety profile In adult patients enrolled in the retrospective chart review studies, the most common ADRs (all grades) were hyperglycaemia (27.8%), diarrhoea (27.8%), headache (22.2%), stomatitis (16.7%), alopecia (16.7%), dermatitis (16.7%), dry skin (16.7%) and nausea (11.1%). Grade 3-4 ADRs were decreased blood phosphate (11.1%), dehydration (5.6%), increased blood creatinine (5.6%) and increased glucose (5.6%). Serious ADRs (all grades) were dehydration (5.6%) and hyperglycaemia (5.6%). The ADR alopecia (all grades) led to dose reduction (5.6%). ADRs leading to dose interruptions (all grades) were vomiting (5.6%), nausea (5.6%), mucosal dryness (5.6%) and headache (5.6%). In paediatric patients enrolled in the retrospective chart review studies, the most common ADRs (all grades) were stomatitis (23.1%) and diarrhoea (12.8%). No grade 3-4 ADRs were reported. Serious ADRs (all grades) were vomiting (2.6%) and dehydration (2.6%). ADRs leading to dose interruptions (all grades) were vomiting (2.6%) and dehydration (2.6%). The most common ADRs in paediatric patients enrolled in the phase II interventional clinical study (all grades) were abdominal pain (33.7%), headache (30.3%), diarrhoea (28.1%) and vomiting (24.7%). Grade 3-4 ADRs were increased lipase (3.4%), decreased appetite (1.1%) and diarrhoea (1.1%). Serious ADRs (all grades) were diarrhoea (1.1%), headache (1.1%) and rash (1.1%). Dose interruptions due to an ADR occurred in 9.0% of patients; the most common ADRs which required dose interruption were vomiting (2.2%), rash (2.2%) and diarrhoea (2.2%). ADRs leading to permanent discontinuation (all grades) were alopecia (2.2%) and decreased appetite (1.1%). Tabulated list of adverse reactions The list of adverse reactions is based on data from retrospective chart review studies in 18 adult and 39 paediatric patients, who were treated with alpelisib in a compassionate use programme with an initial starting dose of 250 mg in adult patients and 50 mg in paediatric patients. The median duration of exposure was 42 months (range: 3.4 to 74.8 months). The list of adverse reactions is also based on data from a phase II interventional clinical study in 89 paediatric patients (including 82 patients 6 to < 18 years of age and 7 patients 2 to < 6 years of age), who were treated with alpelisib with an initial starting dose of 50 mg, for a median duration of exposure of approximately 30 months. Within each system organ class, the ADRs are ranke

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HOS-100981 · has-contraindication-information · PDF-Seite 9

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

HOS-100987 · has-contraindication-information · PDF-Seite 33

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

HOS-100980 · has-indication-information · PDF-Seite 2

Vijoice is indicated for the treatment of adult and paediatric patients aged 2 years and older with severe or life-threatening manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. 2

HOS-100986 · has-indication-information · PDF-Seite 26

Vijoice is indicated for the treatment of adult and paediatric patients aged 2 years and older with severe or life-threatening manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.

HOS-100983 · has-interaction-information · PDF-Seite 11

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. ciclosporin). 11 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 recommended in the oncology setting 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 PK 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 rifampicin (a strong CYP3A4 inducer) for 7 days followed by co-administration with a single oral dose of alpelisib 300 mg on day 8, decreased alpelisib Cmax by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampicin 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%. 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, rifampicin, St. John’s wort [Hypericum perforatum]) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered. Medicinal produc

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HOS-100989 · has-interaction-information · PDF-Seite 35

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. ciclosporin). 35 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 recommended in the oncology setting 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 PK 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 rifampicin (a strong CYP3A4 inducer) for 7 days followed by co-administration with a single oral dose of alpelisib 300 mg on day 8, decreased alpelisib Cmax by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampicin 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%. 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, rifampicin, St. John’s wort [Hypericum perforatum]) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered. Medicinal produc

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HOS-100984 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential/Contraception in males and females Women of childbearing potential should use effective contraception during treatment and for at least 1 week after stopping treatment. As it is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives, women using hormonal contraceptives should also use a barrier method. Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking Vijoice and for at least 1 week after stopping treatment. Pregnancy There are no data from the use of alpelisib in pregnant women. However, the mechanism of action of alpelisib suggests a risk of congenital malformation. Studies in animals have shown reproductive toxicity (see section 5.3). Vijoice should not be used during pregnancy unless the clinical condition of the woman requires treatment with alpelisib. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Vijoice. Breast-feeding It is not known if alpelisib is excreted in human 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 Vijoice. Fertility There are no clinical data 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-100990 · has-pregnancy-information · PDF-Seite 37

Women of childbearing potential/Contraception in males and females Women of childbearing potential should use effective contraception during treatment and for at least 1 week after stopping treatment. As it is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives, women using hormonal contraceptives should also use a barrier method. Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking Vijoice and for at least 1 week after stopping treatment. Pregnancy There are no data from the use of alpelisib in pregnant women. However, the mechanism of action of alpelisib suggests a risk of congenital malformation. Studies in animals have shown reproductive toxicity (see section 5.3). Vijoice should not be used during pregnancy unless the clinical condition of the woman requires treatment with alpelisib. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Vijoice. Breast-feeding It is not known if alpelisib is excreted in human 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 Vijoice. Fertility There are no clinical data 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-100988 · has-warning-information · PDF-Seite 33

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, have occurred in patients treated with Vijoice (see section 4.8). Vijoice should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated. Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with Vijoice. Treatment should not be initiated in patients with a history of SCARs. Patients should be advised of the signs and symptoms of SCARs (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of SCARs occur, Vijoice should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended. If a SCAR is confirmed, Vijoice should be permanently discontinued. Vijoice should not be re- introduced in patients who have experienced previous SCARs. If a SCAR is not confirmed, Vijoice may require dose modifications, topical or systemic corticosteroids, or oral antihistamine treatment as described in Table 4 (see section 4.2). Hyperglycaemia Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS), has occurred in patients treated with Vijoice (see section 4.8). Fatal cases of ketoacidosis have occurred in patients treated with alpelisib in the oncology setting. 33 Baseline diabetic and pre-diabetic status, baseline BMI ≥ 30 and baseline age ≥ 75 years have been found to be risk factors for hyperglycaemia in patients treated with alpelisib in the oncology setting. As hyperglycaemia may occur with a rapid onset after starting treatment, it is recommended to self- monitor frequently in the first 4 weeks and especially within the first 2 weeks of treatment, as clinically indicated. A specific schedule for FG monitoring is recommended in Table 7. All patients should be instructed

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HOS-100982 · has-warning-information · PDF-Seite 9

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, have occurred in patients treated with Vijoice (see section 4.8). Vijoice should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated. Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with Vijoice. Treatment should not be initiated in patients with a history of SCARs. Patients should be advised of the signs and symptoms of SCARs (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of SCARs occur, Vijoice should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended. If a SCAR is confirmed, Vijoice should be permanently discontinued. Vijoice should not be re-introduced in patients who have experienced previous SCARs. If a SCAR is not confirmed, Vijoice may require dose modifications, topical or systemic corticosteroids, or oral antihistamine treatment as described in Table 4 (see section 4.2). Hyperglycaemia Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS), has occurred in patients treated with Vijoice (see section 4.8). Fatal cases of ketoacidosis have occurred in patients treated with alpelisib in the oncology setting. Baseline diabetic and pre-diabetic status, baseline BMI ≥ 30 and baseline age ≥ 75 years have been found to be risk factors for hyperglycaemia in patients treated with alpelisib in the oncology setting. 9 As hyperglycaemia may occur with a rapid onset after starting treatment, it is recommended to self- monitor frequently in the first 4 weeks and especially within the first 2 weeks of treatment, as clinically indicated. A specific schedule for FG monitoring is recommended in Table 7. All patients should be instructed o

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