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 endocrine-based therapy.

Treatment with Piqray should be initiated by a physician experienced in the use of anticancer therapies. 2 Patients with HR-positive, HER2-negative advanced breast cancer should be selected based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available. Posology The recommended dose is 300 mg alpelisib (2x 150 mg film-coated tablets) taken once daily on a continuous basis. The maximum recommended daily dose of Piqray is 300 mg. If a dose is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day. On the next day, the dose should be taken at the usual time. If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time. Piqray should be co-administered with fulvestrant. The recommended dose of fulvestrant is 500 mg administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose modifications may be necessary to improve tolerability. Dose modifications Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction, and/or discontinuation of Piqray. If dose reduction is required, the dose reduction guidelines for ADRs are listed in Table 1. A maximum of 2 dose reductions are recommended, after which the patient should be permanently discontinued from treatment with Piqray. Dose reduction should be based on the worst preceding toxicity. Table 1 Recommended dose reduction guidelines for ADRs 1 Piqray dose level Dose and schedule Number and strength of tablets Starting dose 300 mg/day continuously 2x 150 mg tablets First dose reduction 250 mg/day continuously 1x 200 mg tablet and 1x 50 mg tablet Second dose reduction 200 mg/day continuously 1x 200 mg tablet 1 Only one dose reduction is permitted for pancreatitis. Tables 2-5 summarise the recommendations for dose interruption, reduction or discontinuation of Piqray in the management of specific ADRs. The clinical judgement of the treating physician, including confirmation of laboratory values if deemed necessary, should guide the management plan of each patient based on the individual benefit/risk assessment. Hyperglycaemia Consultation with a healthcare professional experienced in the treatment of hyperglycaemia should always be considered and is recommended for patients who are pre-diabetic or those with fasting glucose (FG) >250 mg/dl or 13.9 mmol/l, body mass index (BMI) =30 or age =75 years. 3 Consultation with a diabetologist or a healthcare professional experienced in the treatment of hyperglycaemia should always take place for patients with diabetes. Table 2 Dose modification and management for hyperglycaemia Fasting glucose (FG) values1 Recommendation Dose modification and management should only be based on fasting glucose (plasma/blood) values. >ULN-160 mg/dl or >ULN-8.9 mmol/l No Piqray dose adjustment required. Initiate or intensify oral antidiabetic treatment2. >160-250 mg/dl or >8.9-13.9 mmol/l No Piqray dose adjustment required. Initiate or intensify oral antidiabetic treatment2. If FG does not decrease to =160 mg/dl or 8.9 mmol/l within 21 days with appropriate oral antidiabetic treatment2,3, reduce Piqray dose by 1 dose level and follow FG-value-specific recommendations. >250-500 mg/dl or >13.9-27.8 mmol/l Interrupt Piqray. Initiate or intensify oral antidiabetic treatment2 and consider additional antidiabetic medicinal products such as insulin3 for 1-2 days until hyperglycaemia resolves, as clinically indicated. Administer intravenous hydration and consider appropriate treatment (e.g. intervention for electrolyte / ketoacidosis / hyperosmolar disturbances). If FG decreases to =160 mg/dl or 8.9 mmol/l within 3 to 5 days under appropriate antidiabetic treatment, resume Piqray at next lower dose level. If FG does not decrease to =160 mg/dl or 8.9 mmol/l within 3 to 5 days under appropriate antidiabetic treatment, consultation with a healthcare professional with expertise in the treatment of hyperglycaemia is recommended. If FG does not decrease to =160 mg/dl or 8.9 mmol/l within 21 days following appropriate antidiabetic treatment2,3, permanently discontinue Piqray treatment. 4 >500 mg/dl or >27.8 mmol/l Interrupt Piqray. Initiate or intensify appropriate antidiabetic treatment2,3 (administer intravenous hydration and consider appropriate treatment [e.g. intervention for electrolyte / ketoacidosis / hyperosmolar disturbances]), re-check within 24 hours and as clinically indicated. If FG decreases to =500 mg/dl or =27.8 mmol/l, then follow FG-value-specific recommendations for <500 mg/dl. If FG is confirmed at >500 mg/dl or >27.8 mmol/l after 24 hours, permanently discontinue Piqray treatment. 1 Fasting glucose levels reflect hyperglycaemia grading according to CTCAE Version 4.03 CTCAE = Common Terminology Criteria for Adverse Events. 2 Applicable antidiabetic medicinal products, such as metformin, SGLT2 inhibitors or insulin sensitisers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), should be initiated and the respective prescribing information should be reviewed for dosing and dose titration recommendations, including local diabetic treatment guidelines. Metformin was recommended in the phase III clinical study with the following guidance: Metformin should be initiated at 500 mg once daily. Based on tolerability, the metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1000 mg with the evening meal, followed by further increase to 1000 mg twice daily if needed (see section 4.4). 3 As recommended in the phase III clinical study, insulin may be used for 1-2 days until hyperglycaemia resolves. However, this may not be necessary in the majority of cases of alpelisib-induced hyperglycaemia, given the short half-life of alpelisib and the expectation that glucose levels will normalise following interruption of Piqray. 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. These risk factors were present in 74.9% of patients with any grade of hyperglycaemia and in 84.7% of patients with grade 3 or 4 hyperglycaemia (see section 4.4). Rash Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with Piqray. Additionally, antihistamines are recommended to manage symptoms of rash. Topical corticosteroid treatment should be initiated at the first signs of rash and systemic corticosteroids should be considered for moderate to severe rashes. Based on the severity of rash, Piqray may require dose interruption, reduction or discontinuation as described in Table 3 (see section 4.8). 5 Table 3 Dose modification and management for rash Grade1 Recommendation All grades Consultation with a dermatologist should always be considered. Grade 1 (<10% body surface area [BSA] with active skin toxicity) No Piqray dose adjustment required. Initiate topical corticosteroid treatment. Consider adding oral antihistamine treatment to manage symptoms. If active rash is not improved within 28 days of appropriate treatment, add a low dose systemic corticosteroid. Grade 2 (10-30% BSA with active skin toxicity) No Piqray dose adjustment required. Initiate or intensify topical corticosteroid and oral antihistamine treatment. Consider low-dose systemic corticosteroid treatment. If rash improves to grade =1 within 10 days, systemic corticosteroid may be discontinued. Grade 3 (e.g. severe rash not responsive to medical management) (>30% BSA with active skin toxicity) Interrupt Piqray until rash improves to grade =1. Initiate or intensify topical/systemic corticosteroid and antihistamine treatment. Once rash improves to grade =1, resume Piqray at next lower dose level. Grade 4 (e.g. severe bullous, blistering or exfoliating skin conditions) (any % BSA associated with extensive superinfection, with intravenous antibiotics indicated; life-threatening consequences) Permanently discontinue Piqray. 1 Grading according to CTCAE Version 5.0 6 Diarrhoea or colitis Table 4 Dose modification and management for diarrhoea or colitis Grade1 Recommendation Grade 1 No Piqray dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Grade 22 Interrupt Piqray dose. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. If diarrhoea or colitis improves to grade =1, then resume Piqray at same dose level. For recurrent diarrhoea or colitis grade =2, interrupt Piqray dose until improvement to grade =1, then resume Piqray at the next lower dose level. Grade 32,3 Interrupt Piqray dose. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. If diarrhoea or colitis improves to grade =1, then resume Piqray at the next lower dose level. Grade 42,3 Permanently discontinue Piqray. 1 Grading according to CTCAE Version 5.0. 2 For grade =2 consider additional treatment, such as steroids. 3 Patients should additionally be managed according to local standard of care, including electrolyte monitoring, administration of antiemetics and antidiarrhoeal medicinal products and/or fluid replacement and electrolyte supplements, as clinically indicated. Other toxicities Table 5 Dose modification and management for other toxicities (excluding hyperglycaemia, rash and diarrhoea or colitis) Grade1 Recommendation Grade 1 or 2 No Piqray dose adjustment required. Initiate appropriate medical therapy and monitor as clinically indicated2,3. Grade 3 Interrupt Piqray dose until improvement to grade =1, then resume Piqray at the next lower dose level2. Grade 4 Permanently discontinue Piqray3. 1 Grading according to CTCAE Version 5.0 2 For grade 2 and 3 pancreatitis, interrupt Piqray dose until improvement to grade =1 and resume at next lower dose level. Only one dose reduction is permitted. If toxicity recurs, permanently discontinue Piqray treatment. 3 For grade 2 total bilirubin elevation, interrupt Piqray dose until recovery to grade =1 and resume at the same dose if resolved in =14 days or resume at the next lower dose level if resolved in >14 days. Special populations Elderly No dose regimen adjustment is required in patients aged 65 years or above (see section 5.2). There are limited data in patients aged =75 years, and especially for those =85 years. 7 Renal impairment Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2). Caution should be used in patients with severe renal impairment as there is no experience with Piqray in this population. Hepatic impairment Based on a hepatic impairment study in non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B or C, respectively) (see section 5.2). Paediatric population The safety and efficacy of Piqray in children aged 0-18 years have not been established. No data are available. Method of administration Piqray is for oral use. The tablets should be swallowed whole. They should not be chewed, crushed or split prior to swallowing. Tablets that are broken, cracked or otherwise not intact should not be ingested. The tablets should be taken immediately after food, at approximately the same time each day (see section 5.2).

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

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 phase III clinical study, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 1 (0.4%) 8 and 3 (1.1%) 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. In the phase III clinical study, hyperglycaemia occurred more frequently in patients who were diabetic (0 out of 12 patients [0%] with grade 1-2, and 10 out of 12 patients [83.3%] with grade 3-4), pre-diabetic (43 out of 159 patients [27.0%] with grade 1-2, and 77 out of 159 patients [48.4%] with grade 3-4), had BMI =30 at screening (14 out of 74 patients [18.9%] with grade 1-2, and 38 out of 74 patients [51.4%] with grade 3-4) or =75 years of age (6 out of 34 patients [17.6%] with grade 1-2, and 19 out of 34 patients [55.9%] with grade 3-4). 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 fasting glucose monitoring is recommended in Table 6. In the phase III clinical study, patients with a history of diabetes mellitus intensified use of antidiabetic medicinal products while on treatment with Piqray. All patients should be instructed on lifestyle changes that may reduce hyperglycaemia (e.g. dietary restrictions and physical activity). 9 Table 6 Schedule of fasting glucose monitoring Recommended schedule for the monitoring of fasting glucose and HbA1c levels in all patients treated with Piqray Recommended schedule of monitoring of fasting glucose and HbA1c levels in patients with diabetes, pre-diabetes, BMI =30 or age =75 years treated with Piqray At screening, before initiating treatment with Piqray Test for fasting plasma glucose (FPG), HbA1c, and optimise the patient’s level of blood glucose (see Table 2). Monitor fasting glucose at weeks 1, 2, 4, 6 and 8 after treatment start and monthly thereafter. Monitor/self-monitor fasting glucose regularly, more frequently in the first 4 weeks and especially within the first 2 weeks of treatment, according to the instructions of a healthcare professional*. Monitor/self-monitor fasting glucose daily for the first 2 weeks of treatment. Then continue to monitor fasting glucose as frequently as needed to manage hyperglycaemia according to the instructions of a healthcare professional*. After initiating treatment with Piqray HbA1c should be monitored after 4 weeks of treatment and every 3 months thereafter. Monitor fasting glucose regularly, as per local standard of care and at least until fasting glucose decreases to normal levels. If hyperglycaemia develops after initiating treatment with Piqray During treatment with antidiabetic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks, and monitor fasting glucose according to the instructions of a healthcare professional with expertise in the treatment of hyperglycaemia. * All glucose monitoring should be performed at the physician’s discretion as clinically indicated. Patients should be advised of the signs and symptoms of hyperglycaemia (e.g. excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss). In the 191 patients with hyperglycaemia, 86.9% (166/191) were managed with antidiabetic medication, and 75.9% (145/191) reported use of metformin as single agent or in combination with other antidiabetic medication (e.g. insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors and sulfonylureas). Oral antidiabetic medication was used in 154 patients. Out of these 154 patients, 17 (11.0%) discontinued study treatment due to hyperglycaemia. Concomitant insulin medication was used in 56 patients; of these 13 (23.2%) discontinued study treatment due to hyperglycaemia. Out of 164 patients with grade =2 hyperglycaemia, 157 had at least 1 grade improvement, median time to improvement from the first event was 8 days (95% CI: 8 to 10 days). 10 Of the patients with elevated FPG who continued fulvestrant treatment after discontinuing Piqray (n=61), 93.4% (n=57) had FPG levels that returned to baseline. The safety of Piqray in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the phase III clinical study. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment and should be closely monitored. Based on the severity of the hyperglycaemia, Piqray may require dose interruption, reduction or discontinuation as described in Table 2 (see section 4.2). Pneumonitis Pneumonitis, including serious cases of pneumonitis/acute interstitial lung disease, have been reported in Piqray-treated patients in clinical studies. Patients should be advised to report promptly any new or worsening respiratory symptoms. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, Piqray treatment should be interrupted immediately and the patient should be evaluated for pneumonitis. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnoea, or interstitial infiltrates on radiological examination and in whom infectious, neoplastic and other causes have been excluded by means of appropriate investigations. Piqray should be permanently discontinued in all patients with confirmed pneumonitis. Diarrhoea or colitis Patients should be monitored for diarrhoea and other symptoms of colitis, such as abdominal pain and mucus or blood in stools. Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention. 59.9% of patients (n=170) experienced diarrhoea during treatment with Piqray. Grade 3 diarrhoea occurred in 7.4% (n=21) of patients with no reported cases of grade 4. Among patients with grade 2 or 3 diarrhoea (n=79), the median time to onset was 54 days (range: 1 to 1 731 days). Dose reductions of Piqray were required in 6.3% of patients and 2.8% of patients discontinued Piqray due to diarrhoea. In the 170 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 65.3% (111/170). Based on the severity of the diarrhoea or colitis, Piqray may require dose interruption, reduction or discontinuation as described in Table 4 (see section 4.2). Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify their physician if diarrhoea or other symptoms of colitis occur while taking Piqray. In case of colitis, additional treatment, such as steroids, may be considered as clinically indicated. 11 Osteonecrosis of the jaw Caution should be exercised when Piqray and bisphosphonates or RANK-ligand inhibitors (e.g. denosumab) are used either simultaneously or sequentially. Piqray treatment should not be initiated in patients with ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab. Patients should be advised to promptly report any new or worsening oral symptoms (such as dental mobility, pain or swelling, non-healing of mouth sores, or discharge) during treatment with Piqray. In patients who develop osteonecrosis of the jaw, standard medical management should be initiated. Symptomatic visceral disease The efficacy and safety of this medicinal product have not been studied in patients with symptomatic visceral disease. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

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%. 12 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 concentrations may be altered by alpelisib CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates No dose adjustment is required when co-administering alpelisib with CYP3A4 substrates (e.g. everolimus, midazolam), CYP2C8 substrates (e.g. repaglinide), CYP2C9 substrates (e.g. warfarin), CYP2C19 substrates (e.g. omeprazole). For CYP2B6 substrate, no relevant changes in the exposure were observed when co-administered with alpelisib however the results should be considered with caution due to limited data (see section 5.2). In a drug-drug

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). 13 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. 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).

Piqray has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or blurred vision during treatment (see section 4.8). 14

Summary of the safety profile Study CBYL719C2301 (SOLAR-1) The safety profile is based on data from 284 patients in the Piqray plus fulvestrant arm of the double-blind, placebo-controlled phase III study. The most common ADRs (reported at a frequency >20% in the combined mutant and non-mutant study population) were plasma glucose increased (79.2%), creatinine increased (68.0%), diarrhoea (59.9%), lymphocyte count decreased (55.6%), gamma-glutamyltransferase increased (54.2%), rash (52.1%), nausea (46.8%), anaemia (45.4%), alanine aminotransferase increased (45.1%), fatigue (44.0%), lipase increased (43.3%), decreased appetite (37.0%), stomatitis (30.6%), vomiting (29.6%), weight decreased (28.2%), hypocalcaemia (27.8%), plasma glucose decreased (27.5%), activated partial thromboplastin time (aPTT) prolonged (23.9%) and alopecia (20.4%). The most common grade 3 or 4 ADRs (reported at a frequency =2%) were plasma glucose increased (39.4%), rash (19.4%), gamma-glutamyltransferase increased (12.3%), lymphocyte count decreased (9.9%), diarrhoea (7.4%), lipase increased (7.0%), hypokalaemia (6.7%), weight decreased (6.0%), fatigue (5.6%), anaemia (5.3%), hypertension (5.3%), alanine aminotransferase increased (4.6%), creatinine increased (3.2%), nausea (2.8%), osteonecrosis of jaw (2.8%), stomatitis (2.5%), hypocalcaemia (2.1%), acute kidney injury (2.1%) and mucosal inflammation (2.1%). The most common ADRs leading to treatment discontinuation were hyperglycaemia (6.3%), rash (4.2%), diarrhoea (2.8%) and fatigue (2.5%). CBYL719X2402 (BYLieve) Additional safety evaluations were performed in the Phase II, multicenter, open-label, three- cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients (pre- and post-menopausal women, and men) with HR-positive, HER2- negative advanced breast cancer harbouring PIK3CA mutation(s) in the tumour, and whose disease has progressed on or after prior treatments. In the cohort of patients who had progressed on or after a CDK4/6 inhibitor plus an aromatase inhibitor before treatment with alpelisib plus fulvestrant (Cohort A; n=127 patients), ADRs that were reported in =20% of patients were diarrhoea (59.8%), hyperglycaemia (58.3%), nausea (45.7%), rash (39.4%), fatigue (29.1%), decreased appetite (28.3%), stomatitis (26.8%) and vomiting (23.6%). Grade 3 or grade 4 ADRs that were reported in =5% of patients were hyperglycaemia (28.3%), rash (18.9%), and diarrhoea (5.5%). The most common serious adverse drug reactions (ADRs), reported in =2% of patients were hyperglycaemia (5.5%) and rash (3.1%). Serious adverse events reported in =2% of patients were dyspnoea (2.4%) and pleural effusion (2.4%). Serious adverse events related to the gastrointestinal tract included colitis and erosive oesophagitis (each 0.8%). 15 Tabulated list of adverse reactions ADRs from the phase III clinical study 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 study and during post-marketing experience Adverse drug reaction Any grade (%) Grade 3 or 4 (%) Infections and infestations Urinary tract infection1 Very common 29 (10.2) 2 (0.7)* Blood and lymphatic system disorders Anaemia Very common 129 (45.4) 15 (5.3)* Lymphocyte count decreased Very common 158 (55.6) 28 (9.9) Platelet count decreased Very common 42 (14.8) 3 (1.1) Immune system disorders Hypersensitivity2 Common 12 (4.2) 2 (0.7)* Metabolism and nutrition disorders Glucose plasma increased Very common 225 (79.2) 112 (39.4) Glucose plasma decreased Very common 78 (27.5) 1 (0.4) Decreased appetite Very common 105 (37.0) 3 (1.1)* Hypokalaemia Very common 43 (15.1) 19 (6.7) Hypocalcaemia Very common 79 (27.8) 6 (2.1) Magnesium decreased Very common 36 (12.7) 1 (0.4)* Dehydration Common 10 (3.5) 1 (0.4)* Ketoacidosis3 Common 3 (1.1) 3 (1.1) Hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) # Not known Not known Not known Psychiatric disorders Insomnia Common 22 (7.7) Nervous system disorders Headache Very common 55 (19.4) 2 (0.7)* Dysgeusia4 Very common 44 (15.5) 1 (0.4)* Eye disorders Vision blurred Common 15 (5.3) 1 (0.4)* Dry eye Common 10 (3.5) Uveitis Not known Not known Not known Vascular disorders Hypertension Very common 30 (10.6) 15 (5.3) Lymphoedema Common 17 (6.0) Respiratory, thoracic and mediastinal disorders Pneumonitis5 Common 5 (1.8) 1 (0.4)* 16 Gastrointestinal disorders Diarrhoea Very common 170 (59.9) 21 (7.4)* Nausea Very common 133 (46.8) 8 (2.8)* Stomatitis6 Very common 87 (30.6) 7 (2.5)* Vomiting Very common 84 (29.6) 2 (0.7)* Abdominal pain Very common 53 (18.7) 4 (1.4)* Dyspepsia Very common 33 (11.6) Toothache Common 13 (4.6) 1 (0.4)* Gingivitis Common 11 (3.9) 1 (0.4)* Gingival pain Common 11 (3.9) Cheilitis Common 8 (2.8) Pancreatitis Uncommon 1 (0.4) 1 (0.4) Colitis# Not known Not known Not known Skin and subcutaneous tissue disorders Rash7 Very common 148 (52.1) 55 (19.4)* Alopecia Very common 58 (20.4) Pruritus Very common 54 (19.0) 2 (0.7)* Dry skin8 Very common 53 (18.7) 1 (0.4)* Erythema9 Common 19 (6.7) 2 (0.7)* Dermatitis10 Common 10 (3.5) 2 (0.7)* Palmar-plantar erythrodysaesthesia syndrome Common 5 (1.8) Erythema multiforme Common 3 (1.1) 2 (0.7)* Stevens-Johnson syndrome Uncommon 1 (0.4) 1 (0.4)* Drug reaction with eosinophilia and systemic symptoms (DRESS)# Not known Not known Not known Angioedema# Not known Not known Not known Musculoskeletal and connective tissue disorders Muscle spasms Common 23 (8.1) Myalgia Common 20 (7.0) 1 (0.4)* Osteonecrosis of jaw Common 16 (5.6) 8 (2.8)* Renal and urinary disorders Acute kidney injury Common 17 (6.0) 6 (2.1) General disorders and administration site conditions Fatigue11 Very common 125 (44.0) 16 (5.6)* Mucosal inflammation Very common 56 (19.7) 6 (2.1)* Oedema peripheral Very common 48 (16.9) Pyrexia Very common 48 (16.9) 2 (0.7) Mucosal dryness12 Very common 37 (13.0) 1 (0.4) Oedema13 Common 20 (7.0) 17 Investigations Weight decreased Very common 80 (28.2) 17 (6.0)* Blood creatinine increased Very common 193 (68.0) 9 (3.2) Gamma-glutamyltransferase increased Very common 154 (54.2) 35 (12.3) Alanine aminotransferase increased Very common 128 (45.1) 13 (4.6) Lipase increased Very common 123 (43.3) 20 (7.0) Activated partial thromboplastin time (aPTT) prolonged Very common 68 (23.9) 2 (0.7)* Albumin decreased Very common 44 (15.5) 1 (0.4)* Glycosylated haemoglobin increased Common 9 (3.2) * No grade 4 ADRs were observed # Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product. 1 Urinary tract infection: also includes a single case of urosepsis 2 Hypersensitivity: also includes allergic dermatitis 3 Ketoacidosis: also includes diabetic ketoacidosis (see section 4.4) 4 Dysgeusia: also includes ageusia, hypogeusia 5 Pneumonitis: also includes interstitial lung disease 6 Stomatitis: also includes aphthous ulcer and mouth ulceration 7 Rash: also includes rash maculopapular, rash macular, rash generalised, rash papular, rash pruritic 8 Dry skin: also includes skin fissures, xerosis, xeroderma 9 Erythema: also includes erythema generalised 10 Dermatitis: also includes dermatitis acneiform 11 Fatigue: also includes asthenia 12 Mucosal dryness: also includes dry mouth, vulvovaginal dryness 13 Oedema: also includes face swelling, face oedema, eyelid oedema Description of selected ADRs Hyperglycaemia Hyperglycaemia was reported in 191 (67.3%) patients; grade 2 (FPG >160-250 mg/dl), 3 (FPG >250-500 mg/dl) and 4 (FPG >500 mg/dl) events were reported in 15.8%, 34.5% and 4.6% of patients, respectively. Based on baseline FPG and HbA1c values, 56% of patients were considered pre-diabetic (FPG >100-125 mg/dl [5.6 to 6.9 mmol/l] and/or HbA1c 5.7-6.4%) and 4.2% of patients were considered diabetic (FPG =126 mg/dl [=7.0 mmol/l] and/or HbA1c =6.5%). 75.5% of patients who were pre-diabetic at baseline experienced hyperglycaemia (any grade) when treated with alpelisib. Among all patients with hyperglycaemia of grade =2 (FPG >160 mg/dl), the median time to first occurrence was 15 days (range: 5 days to 1 458 days) (based on laboratory findings). The median duration of grade =2 hyperglycaemia was 10 days (95% CI: 8 to 13 days). In patients with grade =2 hyperglycaemia, median time to improvement (at least one grade from the first event) was 8 days (95% CI: 8 to 10 days). In 93.4% of patients who continued on fulvestrant after discontinuing Piqray, FPG levels returned to baseline (normal). Hyperglycaemia was managed with antidiabetic medicinal products, see section 4.4. 18 Rash Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis and dermatitis acneiform) were reported in 154 (54.2%) patients. Rash was predominantly mild or moderate (grade 1 or 2) and responsive to therapy, and in some cases rash was accompanied by pruritus and dry skin. Grade 2 and 3 events were reported in 13.7% and 20.1% of patients, respectively, with a median time to first onset of 12 days (range: 2 days to 220 days). Among patients who received prophylactic antirash treatment including antihistamines, rash was reported less frequently than in the overall population; 25.8% vs 54.2% for all grades, 11.2% vs 20.1% for grade 3, and 3.4% vs 4.2% for rash leading to the permanent discontinuation of Piqray. Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with Piqray. Gastrointestinal toxicity (nausea, diarrhoea, vomiting) Diarrhoea, nausea and vomiting were reported in 59.9%, 46.8% and 29.6% of the patients, respectively (see Table 7). Grade 2 and 3 diarrhoea events were reported in 20.4% and 7.4% of patients, respectively, with a median time to onset of grade =2 diarrhoea of 54 days (range: 1 day to 1 731 days). Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention (see Table 4). Antiemetics (e.g. ondansetron) and antidiarrhoeal medicinal products (e.g. loperamide) were used in 29/153 (19.0%) and 111/170 (65.3%) patients, respectively, to manage symptoms. Osteonecrosis of the jaw (ONJ) ONJ was reported in 6.0% patients (17/284) in the Piqray plus fulvestrant arm. All patients experiencing ONJ were exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) or RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving Piqray and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded. Special populations Elderly In patients =65 years of age treated with alpelisib plus fulvestrant, there was a higher incidence of grade 3-4 hyperglycaemia (45.3%) compared to patients <65 years of age (34.7%), while in patients <75 years of age, grade 3-4 hyperglycaemia was 36.8% compared to 55.9% in patients =75 years of age. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. 19

Symptoms The adverse reactions associated with have been consistent with the safety profile of Piqray and included hyperglycaemia, nausea, asthenia and rash. Management General symptomatic and supportive measures should be initiated in all cases of where necessary. There is no known antidote for Piqray.

Pharmacotherapeutic group: Antineoplastic agents, Protein kinase inhibitors, Phosphatidylinositol-3-kinase (PI3K) inhibitors, ATC code: L01EM03 Mechanism of action Alpelisib is an a-specific class I phosphatidylinositol3kinase (PI3Ka) inhibitor. Gain-of-function mutations in the gene encoding the catalytic a-subunit of PI3K (PIK3CA) lead to activation of PI3Ka and AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo models. In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets including AKT, and showed activity in cell lines harbouring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/AKT signalling pathway and reduced tumour growth in xenograft models, including models of breast cancer. PI3K inhibition by alpelisib treatment has been shown to induce an increase in oestrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines. The PI3K/AKT signalling pathway is responsible for glucose homeostasis, and hyperglycaemia is an expected on-target adverse reaction of PI3K inhibition. Clinical efficacy and safety Study CBYL719C2301 (SOLAR-1) Piqray was evaluated in a pivotal phase III, randomised, double-blind, placebo-controlled study of alpelisib in combination with fulvestrant in postmenopausal women, and men, with HR+, HER2- advanced (locoregionally recurrent or metastatic) breast cancer whose disease 20 had progressed or recurred on or after an aromatase-inhibitor-based treatment (with or without CDK4/6 inhibitor combination). A total of 572 patients were enrolled into two cohorts, one cohort with PIK3CA mutation and one cohort without PIK3CA mutation breast cancer. Patients were randomised to receive either alpelisib 300 mg plus fulvestrant or placebo plus fulvestrant in a 1:1 ratio. Randomisation was stratified by presence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s). In the cohort with PIK3CA mutation, 169 patients with one or more PIK3CA mutations (C420R, E542K, E545A, E545D [1635G>T only], E545G, E545K, Q546E, Q546R, H1047L, H1047R or H1047Y) were randomised to receive alpelisib in combination with fulvestrant and 172 patients were randomised to receive placebo in combination with fulvestrant. In this cohort 170 (49.9%) patients had liver/lung metastases and 20 (5.9%) patients had received prior CDK4/6 inhibitor treatment. Patients had a median age of 63 years (range: 25 to 92 years). 44.9% patients were 65 years of age or older and =85 years. The patients included were White (66.3%), Asian (21.7%) and Black or African American (1.2%). The study population included one male subject enrolled in the PIK3CA mutant cohort and treated with alpelisib and fulvestrant. 66.0% and 33.4% of subjects had an ECOG performance status of 0 and 1, respectively. 97.7% of patients had received prior endocrine therapy. In 67.7% of subjects, the last therapy prior to study enrollment was endocrine therapy. Letrozole and anastrozole were the most commonly used endocrine therapies. The setting of last endocrine therapy prior to study enrollment was therapeutic in 47.8% of subjects and adjuvant therapy in 51.9% of subjects. Overall, 85.6% of the patients were considered to have endocrine-resistant disease; primary endocrine resistance (de novo resistance) was observed in 13.2% and secondary endocrine resistance (relapse/progression following an initial response) in 72.4% of patients. In both cohorts (with or without PIK3CA mutation), demographics and baseline disease characteristics, ECOG performance status, tumour burden and prior antineoplastic therapy were well balanced between the study arms. During the randomised treatment phase, alpelisib 300 mg or placebo was administered orally once daily on a continuous basis. Fulvestrant 500 mg was administered intramuscularly on cycle 1 days 1 and 15 and then at day 1 of a 28-day cycle during treatment phase (administration ±3 days). Patients were not allowed to cross over from placebo to alpelisib during the study or after disease progression. The primary endpoint for the study was progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in patients harbouring a PIK3CA mutation. The key secondary endpoint was overall survival (OS) for patients with a PIK3CA mutation status. Other secondary endpoints included PFS for patients without PIK3CA mutation, OS for patients without PIK3CA mutation. 21 Primary efficacy analysis At the final PFS analysis, the median duration of follow-up (between randomisation and data cut-off date of 12-June 2018) was 20 months. The results demonstrated a statistically significant improvement in PFS by investigator assessment in the PIK3CA mutant cohort for patients receiving alpelisib plus fulvestrant, compared to patients receiving placebo plus fulvestrant with an estimated 35% risk reduction of disease progression or death in favour of treatment with alpelisib plus fulvestrant. Primary PFS results were supported by consistent results from a blinded independent review committee (BIRC) assessment in this cohort, from a randomly selected subset of 50% of randomised patients. Table 8 Study C2301 - Summary of efficacy results (cohort with PIK3CA mutation) Piqray + fulvestrant (n=169) Placebo + fulvestrant (n=172) Data using primary analysis data cut-off date of 12 June 2018 Median progression free survival (PFS) (months, 95% CI) Investigator radiological assessment# PIK3CA mutant cohort (N=341) 11.0 (7.5 to 14.5) 5.7 (3.7 to7.4) Hazard ratio (95% CI) 0.65 (0.50 to 0.85) p-valuea 0.00065 Blinded independent review committee assessment*# PIK3CA mutant cohort (N=173) 11.1 (7.3 to16.8) 3.7 (2.1 to5.6) Hazard ratio (95% CI) 0.48 (0.32 to 0.71) p-value N/A CI = confidence interval; N = number of patients; N/A = is not applicable a p-value is obtained from the one-sided stratified log-rank test. # Per RECIST 1.1 * Based on 50% sample-based audit approach In the cohort with PIK3CA mutation, PFS subgroup analyses per investigator assessment by randomisation stratification factors showed a generally consistent treatment effect in favour of the alpelisib arm, irrespective of presence or absence of lung/liver metastases. In the subgroup of 170 patients with presence of lung/liver metastases, the PFS HR (95% CI) was 0.56 (0.40, 0.79); median PFS was 3.7 months (95% CI: 2.9, 6.1) in the placebo plus fulvestrant arm and 9.0 months (95% CI: 5.6, 14.5) in the alpelisib plus fulvestrant arm. Among 20 patients with prior CDK4/6 inhibitor use the hazard ratio (HR) for PFS was 0.48 (95% CI: 0.17, 1.36); median PFS was 1.8 months (95% CI: 1.7, 3.6) in the placebo plus fulvestrant arm and 5.5 months (95% CI: 1.6, 16.8) in the alpelisib plus fulvestrant arm. Overall response rates are summarized in Table 9. 22 Table 9 Overall response rate and clinical benefit rate in the PIK3CA mutant cohort per investigator assessment (Data cut-off date: 18-Jun-2018) Analysis Piqray plus fulvestrant (%, 95% CI) Placebo plus fulvestrant (%, 95% CI) p-valuec Full analysis set N=169 N=172 Objective Response Ratea 26.6 (20.1 to 34.0) 12.8 (8.2 to 18.7) 0.0006 Clinical Benefit Rateb 61.5 (53.8to 68.9) 45.3 (37.8 to 53.1) 0.002 Patients with measurable diseased N=126 N=136 Objective Response Ratea 35.7 (27.4 to 44.7) 16.2 (10.4 to 23.5) 0.0002 Clinical Benefit Rateb 57.1 (48.0 to 65.9) 44.1 (35.6 to 52.9) 0.02 a ORR= proportion of patients with confirmed Complete Response or Partial Response b CBR: proportion of patients with confirmed Complete Response or Partial Response, or (Stable Disease or Non-Complete Response/Non-Progression Disease >=24 weeks) c p-values are nominal and are obtained from the Cochran-Mantel Haenszel test. d measurable disease: the presence of at least one measurable nodal or non-nodal lesion at Baseline. 23 Figure 1 Kaplan-Meier plot of progression free survival in the PIK3CA mutant cohort per investigator assessment (Data cut-off date: 18-Jun-2018) Event-free probability (% ) 24 Final overall survival analysis The final OS analysis was conducted using a data cut-off date of 23-Apr-2020. With a median duration from randomisation to data cut-off of approximately 42 months, a total of 87 (51.5%) deaths were reported in the alpelisib plus fulvestrant arm and 94 (54.7%) in the placebo plus fulvestrant arm, the HR was 0.86 (95% CI: 0.64, 1.15; p = 0.15, one-sided) and the pre-specified O’Brien-Fleming efficacy boundary of p = 0.0161 was not crossed. Median OS was 31.4 months (95% CI: 26.8, 41.3) in the placebo plus fulvestrant arm and 39.3 months (95% CI: 34.1, 44.9) in the alpelisib plus fulvestrant arm. Figure 2 Kaplan-Meier plot of overall survival in cohort with PIK3CA mutation (cut- off date of 23-Apr-2020) OS subgroup analyses by randomisation stratification factors demonstrated a generally consistent treatment effect. Cohort without PIK3CA mutation No PFS benefit was observed in patients whose tumours did not have a PIK3CA tissue mutation. CBYL719X2402 (BYLieve) Alpelisib was evaluated in a Phase II, multicenter, open-label, three-cohort, non-comparative study in combination with endocrine therapy (either fulvestrant or letrozole) in adult patients (pre- and post-menopausal women and men), 18 years or older, with HR-positive, HER2- negative locally advanced or metastatic breast cancer harbouring PIK3CA mutation(s), and whose disease has progressed on or after prior treatments. Table 10 CBYL719X2402 Patients assignment based on most recent prior therapy and treatment regimen Cohort A Cohort B Cohort C 25 Patient inclusion, based on their most recent prior therapy CDK4/6i plus any AI CDK4/6i plus fulvestrant Patients who failed prior AI based therapy and received systemic chemotherapy or endocrine therapy Treatment received in Study X2402 Alpelisib 300 mg plus fulvestrant (500 mg) Alpelisib 300 mg plus letrozole (2.5 mg) Alpelisib 300 mg plus fulvestrant (500 mg) Patients were treated until disease progression, intolerable toxicity, or until 18 months after last subject first treatment. Treatment crossover between cohorts was not permitted in this study The primary objective of the study was to assess the proportion of patients who were alive without disease progression at 6 months based on local Investigator assessment per RECIST 1.1. Analysis of the primary endpoint was to be performed separately for each cohort. Using a data cut-off date of 17 December 2019, data for Cohort A only are available. The primary analysis was performed for the modified Full analysis set (mFAS), defined as all subjects in Cohort A with a PIK3CA mutation confirmed by a Novartis-designated laboratory who received at least one dose of study treatment (n=121). With a median duration of follow- up of 11.7 months (calculated from the start of treatment to the date of data cut-off), 61/121 patients (50.4%, 95% CI: 41.2, 59.6) were alive without disease progression at 6 months. Median progression-free survival (PFS), one of the secondary endpoints was 7.3 months (95% CI: 5.6, 8.3) in Cohort A, based on investigator assessment. Figure 3 Kaplan-Meier plot of time of PFS per local Investigator assessment (Cohort A) – mFAS (cut-off date of 17-Dec-2019) Prior use of fulvestrant in study CBYL719X2102 Patients with prior fulvestrant use were not included in the pivotal study. In the phase I study CBYL719X2101, 39 subjects reported prior fulvestrant use. The best overall responses to treatment with alpelisib plus fulvestrant for the 21 subjects with PIK3CA mutations and 26 measurable disease at baseline were partial response in 7 subjects, stable disease in 11 subjects, and progressive disease in 2 subjects. Hence, the evidence of efficacy of this treatment in patients previously treated with fulvestrant is not established due to the limited data at this time (see section 4.4). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Piqray in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

The pharmacokinetics of alpelisib were investigated in patients under an oral dosing regimen ranging from 30 to 450 mg daily. Healthy subjects received single oral doses ranging from 300 to 400 mg. The pharmcokinetics were comparable in both oncology patients and healthy subjects. Absorption Following oral administration of alpelisib, median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours, independent of dose, time or regimen. Based on absorption modelling bioavailability was estimated to be very high (>99%) under fed conditions but lower under fasted conditions (~68.7% at a 300 mg dose). Steady-state plasma levels of alpelisib after daily dosing can be expected to be reached on day 3 following onset of therapy in most patients. Food effect Alpelisib absorption is affected by food. In healthy volunteers after a single 300 mg oral dose of alpelisib, compared to the fasted state, a high-fat high-calorie (HFHC) meal (985 calories with 58.1 g of fat) increased AUCinf by 73% and Cmax by 84%, and a LFLC meal (334 calories with 8.7 g of fat) increased AUCinf by 77% and Cmax by 145%. No significant difference was found for AUCinf between LFLC and HFHC with a geometric mean ratio of 0.978 (CI: 0.876, 1.09), showing that neither fat content nor overall calorific intake has a considerable impact on absorption. The increase in gastrointestinal solubility by bile, secreted in response to food intake, is the potential cause of the food effect. Hence, Piqray should be taken immediately after food at approximately the same time each day. Distribution Alpelisib moderately binds to protein with a free fraction of 10.8% regardless of concentration. Alpelisib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.03. As alpelisib is a substrate of human efflux transporters, penetration of the blood-brain barrier is not expected to occur in humans. The volume of distribution of alpelisib at steady state (Vss/F) is estimated at 114 litres (intersubject CV% 49%). 27 Biotransformation In vitro studies demonstrated that formation of the hydrolysis metabolite BZG791 by chemical and enzymatic amide hydrolysis was a major metabolic pathway, followed by CYP3A4-mediated hydroxylation. Alpelisib hydrolysis occurs systemically by both chemical decomposition and enzymatic hydrolysis via ubiquitously expressed, high-capacity enzymes (esterases, amidases, choline esterase) not limited to the liver. CYP3A4-mediated metabolites and glucuronides amounted to ~15% of the dose; BZG791 accounted for ~40-45% of the dose. The rest of the dose, which was found as unchanged alpelisib in urine and faeces, was either excreted as alpelisib or not absorbed. Elimination Alpelisib exhibits low clearance with 9.2 l/h (CV% 21%) based on population pharmacokinetic analysis under fed conditions. The population-derived half-life, independent of dose and time, was 8 to 9 hours at steady state with 300 mg once daily. In a human mass-balance study, after oral administration, alpelisib and its metabolites were primarily found in the faeces (81.0%) as alpelisib, or metabolised as BZG791. Excretion in the urine is minor (13.5%), with unchanged alpelisib (2%). Following a single oral dose of [14C]-alpelisib, 94.5% of the total administered radioactive dose was recovered within 8 days. Linearity/non-linearity The pharmacokinetics were found to be linear with respect to dose and time under fed conditions between 30 and 450 mg. After multiple doses, alpelisib exposure (AUC) at steady state is only slightly higher than that of a single dose, with an average accumulation of 1.3 to 1.5 with a daily dosing regimen. Metabolic

Safety pharmacology and repeated dose toxicity The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisib as a p110a-specific inhibitor of the PI3K pathway, such as the influence on the glucose homeostasis resulting in hyperglycaemia and the risk of increased blood pressure. The bone marrow and lymphoid tissue, pancreas and some reproductive organs of both genders were the main target organs for adverse events. Effects on bone marrow and lymphoid tissue were generally reversible on cessation of treatment. Effects on the pancreas and reproductive organs did not fully reverse but showed a tendency towards reversion. In exploratory rat studies evidence of inflammatory changes of the skin was found. Cardiovascular safety pharmacology In vitro inhibition of hERG channels (IC50 of 9.4 µM) was shown at concentrations ~13-fold higher than the exposure in humans, at the recommended dose of 300 mg/day. No relevant electrophysiological effect was seen in dogs. Genotoxicity / Carcinogenicity Results of standard genotoxicity in vitro studies with alpelisib were negative. Alpelisib was not genotoxic in a repeated-dose rat toxicity study where micronucleus analysis was integrated, up to exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg. Alpelisib was not carcinogenic in a 2-year carcinogenicity study conducted in rats when administered by daily oral gavage at doses up to 4 mg/kg (approximately 0.2 times the clinical exposure in patients at the highest recommended dose of 300 mg/day based on AUC). Reproductive toxicity Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity. In rats and rabbits, following prenatal exposure to alpelisib, increased incidences of pre- and post-implantation losses, reduced foetal weights and increased incidences of foetal abnormalities (enlarged brain ventricle, decreased bone ossification and skeletal malformations) were observed starting at exposures below those in humans at the highest recommended dose of 300 mg, indicating potential clinical relevance. In repeated dose toxicity studies, adverse events were observed in reproductive organs, such as vaginal or uterine atrophy and oestrus cycle variations in rats, decreases in prostate and testes weight in rats and dogs and prostate atrophy in dogs at clinically relevant doses based on AUC. In fertility studies conducted in male and female rats, similar effects on fertility were observed. In females, increased pre- and post-implantation losses, which led to reduced 30 numbers of implantation sites and live embryos, were observed at exposure levels (AUC) approximately twice the recommended human dose of 300 mg. In males, fertility and reproductive performance, including sperm count and motility parameters, were unaffected at exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg. However, at exposure levels (AUC) at or below the recommended human dose of 300 mg, accessory gland weights (seminal vesicles, prostate) were reduced and correlated microscopically with atrophy and/or reduced secretion in prostate and seminal vesicles, respectively. Phototoxicity An in vitro phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.

Tablet core Cellulose microcrystalline Mannitol Sodium starch glycolate Hypromellose Magnesium stearate Film coating Hypromellose Iron oxide, black (E172) Iron oxide, red (E172) Titanium dioxide (E171) Macrogol Talc

Not applicable. 31

4 years.

This medical product does not require any special storage conditions.

PVC/PCTFE/alu (polyvinylchloride/polychlorotrifluoroethylene/aluminium) blister sealed into a blister card containing 14 film-coated tablets. Packs containing 28 film-coated tablets (14 of 50 mg and 14 of 200 mg) or 56 film-coated tablets (28 of 50 mg and 28 of 200 mg). Multipacks containing 168 film-coated tablets (3x 56, each comprising 28 tablets of 50 mg and 28 tablets of 200 mg).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

spc-doc_PLGB 00101-1181.pdf

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