PIQRAY 200mg tablets medication leaflet

Piqray 50 mg film-coated tablets

Piqray 150 mg film-coated tablets

Piqray 200 mg film-coated tablets

Piqray 50 mg film-coated tablets

Each film-coated tablet contains 50 mg alpelisib.

Piqray 150 mg film-coated tablets

Each film-coated tablet contains 150 mg alpelisib.

Piqray 200 mg film-coated tablets

Each film-coated tablet contains 200 mg alpelisib.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Piqray 50 mg film-coated tablets

Light pink, round, curved film-coated tablet with bevelled edges, imprinted with “L7” on one side and“NVR” on the other side. Approximate diameter: 7.2 mm.

Piqray 150 mg film-coated tablets

Pale red, ovaloid, curved film-coated tablet with bevelled edges, imprinted with “UL7” on one sideand “NVR” on the other side. Approximate size: 14.2 mm (length); 5.7 mm (width).

Piqray 200 mg film-coated tablets

Light red, ovaloid, curved film-coated tablet with bevelled edges, imprinted with “YL7” on one sideand “NVR” on the other side. Approximate size: 16.2 mm (length); 6.5 mm (width).

Piqray is indicated in combination with fulvestrant for the treatment of postmenopausal women, andmen, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after diseaseprogression following endocrine therapy as monotherapy (see section 5.1).

Treatment with Piqray should be initiated by a physician experienced in the use of anticancertherapies.

Patients with HR-positive, HER2-negative advanced breast cancer should be selected based on thepresence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation isnot detected in a plasma specimen, tumour tissue should be tested if available.

The recommended dose is 300 mg alpelisib (2x 150 mg film-coated tablets) taken once daily on acontinuous 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 isusually administered. After more than 9 hours, the dose should be skipped for that day. On the nextday, the dose should be taken at the usual time. If the patient vomits after taking the dose, the patientshould not take an additional dose on that day and should resume the usual dosing schedule the nextday at the usual time.

Piqray should be co-administered with fulvestrant. The recommended dose of fulvestrant is 500 mgadministered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to thefull 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.

Management of severe or intolerable adverse drug reactions (ADRs) may require temporary doseinterruption, reduction, and/or discontinuation of Piqray. If dose reduction is required, the dosereduction guidelines for ADRs are listed in Table 1. A maximum of 2 dose reductions arerecommended, 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 ADRs1

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 tablet1 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 planof each patient based on the individual benefit/risk assessment.

Consultation with a healthcare professional experienced in the treatment of hyperglycaemia shouldalways be considered and is recommended for patients who are pre-diabetic or those with fastingglucose (FG) >250 mg/dl or 13.9 mmol/l, body mass index (BMI) ≥30 or age ≥75 years.

Consultation with a diabetologist or a healthcare professional experienced in the treatment ofhyperglycaemia should always take place for patients with diabetes.

Table 2 Dose modification and management for hyperglycaemia

Fasting glucose (FG) Recommendationvalues1

Dose modification and management should only be based on fasting glucose (plasma/blood)values.

>ULN-160 mg/dl or No Piqray dose adjustment required.

>ULN-8.9 mmol/l Initiate or intensify oral antidiabetic treatment2.

>160-250 mg/dl or >8.9- No Piqray dose adjustment required.

13.9 mmol/l Initiate or intensify oral antidiabetic treatment2.

If FG does not decrease to ≤160 mg/dl or 8.9 mmol/l within 21 dayswith appropriate oral antidiabetic treatment2,3, reduce Piqray dose by1 dose level and follow FG-value-specific recommendations.

>250-500 mg/dl or Interrupt Piqray.

>13.9-27.8 mmol/l Initiate or intensify oral antidiabetic treatment2 and consider additionalantidiabetic medicinal products such as insulin3 for 1-2 days untilhyperglycaemia resolves, as clinically indicated.

Administer intravenous hydration and consider appropriate treatment(e.g. intervention for electrolyte/ketoacidosis/hyperosmolardisturbances).

If FG decreases to ≤160 mg/dl or 8.9 mmol/l within 3 to 5 days underappropriate antidiabetic treatment, resume Piqray at next lower doselevel.

If FG does not decrease to ≤160 mg/dl or 8.9 mmol/l within 3 to 5 daysunder appropriate antidiabetic treatment, consultation with a healthcareprofessional with expertise in the treatment of hyperglycaemia isrecommended.

If FG does not decrease to ≤160 mg/dl or 8.9 mmol/l within 21 daysfollowing appropriate antidiabetic treatment2,3, permanently discontinue

Piqray treatment.

>500 mg/dl or Interrupt Piqray.

>27.8 mmol/l Initiate or intensify appropriate antidiabetic treatment2,3 (administerintravenous 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 respectiveprescribing information should be reviewed for dosing and dose titration recommendations, includinglocal diabetic treatment guidelines. Metformin was recommended in the phase III clinical study withthe following guidance: Metformin should be initiated at 500 mg once daily. Based on tolerability, themetformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and1 000 mg with the evening meal, followed by further increase to 1 000 mg twice daily if needed (seesection 4.4).3 As recommended in the phase III clinical study, insulin may be used for 1-2 days until hyperglycaemiaresolves. However, this may not be necessary in the majority of cases of alpelisib-inducedhyperglycaemia, given the short half-life of alpelisib and the expectation that glucose levels willnormalise following interruption of Piqray.

Baseline diabetic and pre-diabetic status, baseline BMI ≥30 and baseline age ≥75 years have beenfound to be risk factors for hyperglycaemia in patients treated with alpelisib. These risk factors werepresent in 74.9% of patients with any grade of hyperglycaemia and in 84.7% of patients with grade 3or 4 hyperglycaemia (see section 4.4).

Oral antihistamine administration may be considered prophylactically, at the time of initiation oftreatment with Piqray. Additionally, antihistamines are recommended to manage symptoms of rash.

Topical corticosteroid treatment should be initiated at the first signs of rash and systemiccorticosteroids 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 (seesection 4.8).

Table 3 Dose modification and management for rash

Grade1 Recommendation

All grades Consultation with a dermatologist should always beconsidered.

Grade 1 No Piqray dose adjustment required.

(<10% body surface area [BSA] with Initiate topical corticosteroid treatment.

active skin toxicity) Consider adding oral antihistamine treatment to managesymptoms.

If active rash is not improved within 28 days of appropriatetreatment, add a low dose systemic corticosteroid.

Grade 2 No Piqray dose adjustment required.

(10-30% BSA with active skin Initiate or intensify topical corticosteroid and oraltoxicity) antihistamine treatment.

Consider low-dose systemic corticosteroid treatment.

If rash improves to grade ≤1 within 10 days, systemiccorticosteroid may be discontinued.

Grade 3 (e.g. severe rash not Interrupt Piqray until rash improves to grade ≤1.

responsive to medical management) Initiate or intensify topical/systemic corticosteroid and(>30% BSA with active skin antihistamine treatment.

toxicity) Once rash improves to grade ≤1, resume Piqray at nextlower dose level.

Grade 4 (e.g. severe bullous, Permanently discontinue Piqray.

blistering or exfoliating skinconditions)(any % BSA associated withextensive superinfection, withintravenous antibiotics indicated;life-threatening consequences)1 Grading according to CTCAE Version 5.0

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 andmonitor as clinically indicated.

Grade 22 Interrupt Piqray dose.

Initiate or intensify appropriate medical therapy and monitor as clinicallyindicated.

If diarrhoea or colitis improves to grade ≤1, then resume Piqray at same doselevel.

For recurrent diarrhoea or colitis grade ≥2, interrupt Piqray dose untilimprovement 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 clinicallyindicated.

If diarrhoea or colitis improves to grade ≤1, then resume Piqray at the nextlower 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 electrolytemonitoring, administration of antiemetics and antidiarrhoeal medicinal products and/or fluidreplacement 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 andmonitor as clinically indicated2,3.

Grade 3 Interrupt Piqray dose until improvement to grade ≤1, then resume Piqray at thenext lower dose level2.

Grade 4 Permanently discontinue Piqray3.1 Grading according to CTCAE Version 5.02 For grade 2 and 3 pancreatitis, interrupt Piqray dose until improvement to grade ≤1 and resume at nextlower 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 thesame dose if resolved in ≤14 days or resume at the next lower dose level if resolved in >14 days.

No dose regimen adjustment is required in patients aged 65 years or above (see section 5.2). There arelimited data in patients aged ≥75 years, and especially for those ≥85 years.

Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mildor moderate renal impairment (see section 5.2). Caution should be used in patients with severe renalimpairment as there is no experience with Piqray in this population.

Based on a hepatic impairment study in non-cancer subjects with impaired hepatic function, no doseadjustment is necessary in patients with mild, moderate or severe hepatic impairment (Child-Pughclass A, B or C, respectively) (see section 5.2).

The safety and efficacy of Piqray in children aged 0-18 years have not been established. No data areavailable.

Piqray is for oral use. The tablets should be swallowed whole. They should not be chewed, crushed orsplit prior to swallowing. Tablets that are broken, cracked or otherwise not intact should not beingested.

The tablets should be taken immediately after food, at approximately the same time each day (seesection 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 isnot considered established in this population (see section 5.1).

Hypersensitivity (including anaphylactic reaction)

Serious hypersensitivity reactions (including anaphylactic reaction, anaphylactic shock andangioedema), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever ortachycardia, were reported in patients treated with Piqray (see section 4.8). Piqray should bepermanently discontinued and should not be re-introduced in patients with serious hypersensitivityreactions. 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%) and 3 (1.1%)patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has beenreported 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 prodromeof fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severecutaneous reactions are present, Piqray should be interrupted until the aetiology of the reaction hasbeen determined. A consultation with a dermatologist is recommended.

If a severe cutaneous reaction is confirmed, Piqray should be permanently discontinued. It should notbe re-introduced in patients who have experienced previous severe cutaneous reactions. If a severecutaneous reaction is not confirmed, Piqray may require treatment interruption, dose reduction ortreatment discontinuation as described in Table 3 (see section 4.2).

Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketoticsyndrome (HHNKS) or ketoacidosis, has been observed in patients treated with Piqray. Some cases ofketoacidosis 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%] withgrade 3-4), had BMI ≥30 at screening (14 out of 74 patients [18.9%] with grade 1-2, and 38 out of74 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, asclinically 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 antidiabeticmedicinal products while on treatment with Piqray.

All patients should be instructed on lifestyle changes that may reduce hyperglycaemia (e.g. dietaryrestrictions and physical activity).

Table 6 Schedule of fasting glucose monitoring

Recommended schedule for the Recommended schedule ofmonitoring of fasting glucose and monitoring of fasting glucose and

HbA1c levels in all patients treated HbA1c levels in patients withwith Piqray diabetes, pre-diabetes, BMI ≥30 orage ≥75 years treated with Piqray

At screening, before Test for fasting plasma glucose (FPG), HbA1c, and optimise the patient’sinitiating treatment level of blood glucose (see Table 2).

with Piqray

After initiating Monitor fasting glucose at weeks 1, 2, 4, 6 and 8 after treatment start andtreatment with Piqray m onthly thereafter.

Monitor/self-monitor fasting glucose Monitor/self-monitor fasting glucoseregularly, more frequently in the first daily for the first 2 weeks of treatment.

4 weeks and especially within the first Then continue to monitor fasting2 weeks of treatment, according to the glucose as frequently as needed toinstructions of a healthcare manage hyperglycaemia according toprofessional*. the instructions of a healthcareprofessional*.

HbA1c should be monitored after 4 weeks of treatment and every 3 monthsthereafter.

If hyperglycaemia Monitor fasting glucose regularly, as per local standard of care and at leastdevelops after until fasting glucose decreases to normal levels.

initiating treatmentwith Piqray During treatment with antidiabetic medication, continue monitoring fastingglucose at least once a week for 8 weeks, followed by once every 2 weeks,and monitor fasting glucose according to the instructions of a healthcareprofessional 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 weightloss).

In the 191 patients with hyperglycaemia, 86.9% (166/191) were managed with antidiabeticmedication, and 75.9% (145/191) reported use of metformin as single agent or in combination withother antidiabetic medication (e.g. insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2inhibitors 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 in56 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 timeto improvement from the first event was 8 days (95% CI: 8 to 10 days).

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 establishedas 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 intensifieddiabetic treatment and should be closely monitored.

Based on the severity of the hyperglycaemia, Piqray may require dose interruption, reduction ordiscontinuation as described in Table 2 (see section 4.2).

Pneumonitis

Pneumonitis, including serious cases of pneumonitis/acute interstitial lung disease, has been reportedin Piqray-treated patients in clinical studies. Patients should be advised to report promptly any new orworsening respiratory symptoms. In patients who have new or worsening respiratory symptoms or aresuspected to have developed pneumonitis, Piqray treatment should be interrupted immediately and thepatient should be evaluated for pneumonitis. A diagnosis of non-infectious pneumonitis should beconsidered 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 shouldbe 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 andmucus or blood in stools.

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have beenreported 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 Piqraydue 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 ordiscontinuation as described in Table 4 (see section 4.2).

Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify theirphysician 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.

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 inpatients with ongoing osteonecrosis of the jaw from previous or concurrent treatment withbisphosphonates/denosumab. Patients should be advised to promptly report any new or worsening oralsymptoms (such as dental mobility, pain or swelling, non-healing of mouth sores, or discharge) duringtreatment 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 symptomaticvisceral disease.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially '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 intestinalsecretion of alpelisib, therefore inhibition of BCRP in the liver and in the intestine during eliminationmay lead to an increase in systemic exposure of alpelisib. Therefore, caution and monitoring fortoxicity are advised during concomitant treatment with inhibitors of BCRP (e.g. eltrombopag,lapatinib, pantoprazole).

Medicinal products that may decrease alpelisib plasma concentrations

The co-administration of the H2-receptor antagonist ranitidine in combination with a single 300 mgoral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure ofalpelisib. In the presence of a low-fat low-calorie (LFLC) meal, AUCinf was decreased on average by21% and Cmax by 36% with ranitidine. In the absence of food, the effect was more pronounced with a30% decrease in AUCinf and a 51% decrease in Cmax with ranitidine compared to the fasted statewithout co-administration of ranitidine. Population pharmacokinetic analysis showed no significanteffect of co-administration of acid-reducing agents, including proton pump inhibitors, H2 receptorantagonists and antacids, on the pharmacokinetics of alpelisib. Therefore, alpelisib can be co-administered with acid-reducing agents, provided alpelisib is taken immediately after food (seesection 4.2).

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 for15 days with alpelisib 300 mg once daily starting from day 8 to day 15 decreased the steady-statealpelisib Cmax by 59% and AUC by 74%.

Co-administration with a strong CYP3A4 inducer decreases alpelisib AUC, which may reducealpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g. apalutamide,carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) should be avoided andselection 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 exposurewere observed when co-administered with alpelisib however the results should be considered withcaution due to limited data (see section 5.2).

In a drug-drug interaction study, co-administration of alpelisib with everolimus, a sensitive CYP3A4substrate, confirmed that there are no clinically significant pharmacokinetic interactions (increase in

AUC by 11.2%) between alpelisib and CYP3A4 substrates. No change in everolimus exposure wasobserved at alpelisib doses ranging from 250 to 300 mg.

In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin) with alpelisib increased S-warfarin exposure on average by 34% and 19% for AUCinf and Cmax respectively, compared toadministration with S-warfarin alone, which indicates that alpelisib is a mild inhibitor of CYP2C9.

Substances that are substrates of transporters

In vitro evaluations indicated that alpelisib (and/or its metabolite BZG791) has a potential to inhibitthe activities of OAT3 drug transporters and intestinal BCRP and P-gp. Alpelisib should be used withcaution in combination with sensitive substrates of these transporters which exhibit a narrowtherapeutic index because alpelisib may increase the systemic exposure of these substrates.

No clinical studies were conducted assessing the drug-drug interaction potential between alpelisib andhormonal contraceptives.

Piqray is indicated in men and postmenopausal women. It is not to be used in women who are, or maybe, pregnant or breast-feeding (see section 4.1).

Females of reproductive potential should be advised that animal studies and the mechanism of actionhave shown that alpelisib can be harmful to the developing foetus. Embryo-foetal development studiesin rats and rabbits have demonstrated that oral administration of alpelisib during organogenesisinduced 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 pregnantshould use condoms during sexual intercourse while taking Piqray and for at least 1 week afterstopping treatment.

Please refer to section 4.6 of the prescribing information for fulvestrant.

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 shownreproductive toxicity (see section 5.3). Piqray is not recommended during pregnancy and in women ofchildbearing potential not using contraception.

The pregnancy status of females of reproductive potential should be verified prior to starting treatmentwith Piqray.

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 thatwomen should not breast-feed during treatment and for at least 1 week after the last dose of Piqray.

There are no clinical data available on the effects of alpelisib on fertility. Based on repeated dosetoxicity and fertility studies in animals, alpelisib may impair fertility in males and females ofreproductive potential (see section 5.3).

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

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-mutantstudy 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%), activatedpartial 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%).

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 orderof decreasing seriousness. In addition, the corresponding frequency category for each adverse drugreaction 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 (%)

Urinary tract infection1 Very common 29 (10.2) 2 (0.7)*

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)

Hypersensitivity2 Common 12 (4.2) 2 (0.7)*

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 Not known Not known Not knownhyperosmolar nonketotic syndrome(HHNKS) #

Insomnia Common 22 (7.7)

Headache Very common 55 (19.4) 2 (0.7)*

Dysgeusia4 Very common 44 (15.5) 1 (0.4)*

Vision blurred Common 15 (5.3) 1 (0.4)*

Dry eye Common 10 (3.5)

Uveitis Not known Not known Not known

Hypertension Very common 30 (10.6) 15 (5.3)

Lymphoedema Common 17 (6.0)

Adverse drug reaction Any grade (%) Grade 3 or 4 (%)

Pneumonitis5 Common 5 (1.8) 1 (0.4)*

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

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 Common 5 (1.8)syndrome

Erythema multiforme Common 3 (1.1) 2 (0.7)*

Stevens-Johnson syndrome Uncommon 1 (0.4) 1 (0.4)*

Drug reaction with eosinophilia and Not known Not known Not knownsystemic symptoms (DRESS)#

Angioedema# Not known Not known Not known

Muscle spasms Common 23 (8.1)

Myalgia Common 20 (7.0) 1 (0.4)*

Osteonecrosis of jaw Common 16 (5.6) 8 (2.8)*

Acute kidney injury Common 17 (6.0) 6 (2.1)

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)

Adverse drug reaction Any grade (%) Grade 3 or 4 (%)

Weight decreased Very common 80 (28.2) 17 (6.0)*

Blood creatinine increased Very common 193 (68.0) 9 (3.2)

Gamma-glutamyltransferase Very common 154 (54.2) 35 (12.3)increased

Alanine aminotransferase increased Very common 128 (45.1) 13 (4.6)

Lipase increased Very common 123 (43.3) 20 (7.0)

Activated partial thromboplastin Very common68 (23.9) 2 (0.7)*time (aPTT) prolonged

Albumin decreased Very common 44 (15.5) 1 (0.4)*

Glycosylated haemoglobin Common9 (3.2)increased

* No grade 4 ADRs were observed# Adverse reactions reported during post-marketing experience. These are derived from spontaneousreports for which it is not always possible to reliably establish frequency or a causal relationship toexposure to the medicinal product.1 Urinary tract infection: also includes a single case of urosepsis2 Hypersensitivity: also includes allergic dermatitis3 Ketoacidosis: also includes diabetic ketoacidosis (see section 4.4)4 Dysgeusia: also includes ageusia, hypogeusia5 Pneumonitis: also includes interstitial lung disease6 Stomatitis: also includes aphthous ulcer and mouth ulceration7 Rash: also includes rash maculopapular, rash macular, rash generalised, rash papular, rash pruritic8 Dry skin: also includes skin fissures, xerosis, xeroderma9 Erythema: also includes erythema generalised10 Dermatitis: also includes dermatitis acneiform11 Fatigue: also includes asthenia12 Mucosal dryness: also includes dry mouth, vulvovaginal dryness13 Oedema: also includes face swelling, face oedema, eyelid oedema

Description of selected ADRs

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 atbaseline experienced hyperglycaemia (any grade) when treated with alpelisib. Among all patients withhyperglycaemia 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 ≥2hyperglycaemia 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 to10 days). In 93.4% of patients who continued on fulvestrant after discontinuing Piqray, FPG levelsreturned to baseline (normal).

Hyperglycaemia was managed with antidiabetic medicinal products, see section 4.4.

Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis anddermatitis acneiform) were reported in 154 (54.2%) patients. Rash was predominantly mild ormoderate (grade 1 or 2) and responsive to therapy, and in some cases rash was accompanied bypruritus 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 wasreported 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 treatmentwith 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 amedian 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 beenreported 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 in29/153 (19.0%) and 111/170 (65.3%) patients, respectively, to manage symptoms.

ONJ was reported in 6.0% patients (17/284) in the Piqray plus fulvestrant arm. All patientsexperiencing ONJ were exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) or

RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving Piqray andbisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot beexcluded.

In patients ≥65 years of age treated with alpelisib plus fulvestrant, there was a higher incidence ofgrade 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 ofage.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The adverse reactions associated with overdose have been consistent with the safety profile of Piqrayand included hyperglycaemia, nausea, asthenia and rash.

General symptomatic and supportive measures should be initiated in all cases of overdose wherenecessary. There is no known antidote for Piqray.

Pharmacotherapeutic group: Antineoplastic agents, Protein kinase inhibitors, Phosphatidylinositol-3-kinase (PI3K) inhibitors, ATC code: L01EM03

Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-functionmutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kαand AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivomodels.

In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targetsincluding 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 xenograftmodels, 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 demonstratedincreased 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 anexpected on-target adverse reaction of PI3K inhibition.

Piqray was evaluated in a pivotal phase III, randomised, double-blind, placebo-controlled study ofalpelisib in combination with fulvestrant in postmenopausal women, and men, with HR+, HER2-advanced (locoregionally recurrent or metastatic) breast cancer whose disease had progressed orrecurred on or after an aromatase-inhibitor-based treatment (with or without CDK4/6 combination).

A total of 572 patients were enrolled into two cohorts, one cohort with PIK3CA mutation and onecohort without PIK3CA mutation breast cancer. Patients were randomised to receive either alpelisib300 mg plus fulvestrant or placebo plus fulvestrant in a 1:1 ratio. Randomisation was stratified bypresence 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 wererandomised to receive placebo in combination with fulvestrant. In this cohort 170 (49.9%) patients hadliver/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 orolder 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 mutantcohort and treated with alpelisib and fulvestrant. 66.0% and 33.4% of subjects had an ECOGperformance status of 0 and 1, respectively.

97.7% of patients had received prior endocrine therapy. In 67.7% of subjects, the last therapy prior tostudy enrollment was endocrine therapy. Letrozole and anastrozole were the most commonly usedendocrine therapies. The setting of last endocrine therapy prior to study enrollment was therapeutic in47.8% of subjects and adjuvant therapy in 51.9% of subjects. Overall, 85.6% of the patients wereconsidered to have endocrine-resistant disease; primary endocrine resistance (de novo resistance) wasobserved in 13.2% and secondary endocrine resistance (relapse/progression following an initialresponse) in 72.4% of patients.

Demographics and baseline disease characteristics, ECOG performance status, tumour burden andprior antineoplastic therapy were well balanced between the study arms.

During the randomised treatment phase, alpelisib 300 mg or placebo was administered orally oncedaily on a continuous basis. Fulvestrant 500 mg was administered intramuscularly on cycle 1 days 1and 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 diseaseprogression.

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 with a

PIK3CA mutation. The key secondary endpoint was overall survival (OS) for patients with a PIK3CAmutation.

Other secondary endpoints included PFS for patients without a PIK3CA mutation, OS for patientswithout a PIK3CA mutation.

Primary efficacy analysis

The study met its primary objective at the final PFS analysis (cut-off date 12-Jun-2018),demonstrating a statistically significant improvement in PFS per investigator assessment in the

PIK3CA mutant cohort for patients receiving alpelisib plus fulvestrant, compared to patients receivingplacebo plus fulvestrant with an estimated 35% risk reduction of disease progression or death infavour of treatment with alpelisib plus fulvestrant (see Table 8).

Table 8 Study C2301 primary efficacy analysis - Summary of efficacy results based on

RECIST (FAS, cohort with PIK3CA mutation). Data cut-off date: 12-Jun-2018

Piqray + fulvestrant Placebo + fulvestrant(n=169) (n=172)

Median progression free survival (PFS) (months, 95% CI)

Investigator radiological assessment#

PIK3CA mutant cohort 11.0 5.7(N=341) (7.5 to 14.5) (3.7 to 7.4)

Hazard ratio (95% CI) 0.65 (0.50 to 0.85)p-valuea 0.00065

Blinded independent review committee assessment*#

PIK3CA mutant cohort 11.1 3.7(N=173) (7.3 to 16.8) (2.1 to 5.6)

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 applicablea 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 byrandomisation stratification factors showed a generally consistent treatment effect in favour of thealpelisib arm, irrespective of presence or absence of lung/liver metastases.

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 and5.5 months (95% CI: 1.6, 16.8) in the alpelisib plus fulvestrant arm.

Using a data cut-off date of 12-Jun-2018, PFS results for the subgroup of endocrine resistant patients(HR=0.64; 95% CI: 0.49, 0.85, n=292) and endocrine sensitive patients (HR=0.87; 95% CI: 0.35,2.17, n=39) were in favour of the alpelisib plus fulvestrant arm. The number of endocrine sensitivepatients with a PIK3CA mutation was limited (n=39) and the results should be interpreted withcaution.

Using a data cut-off date of 12-Jun-2018, the overall response rate in patients with measurable diseaseat baseline was 35.7% (95% CI: 27.4, 44.7) in the alpelisib plus fulvestrant arm and 16.2% (95% CI:

10.4, 23.5) in the placebo plus fulvestrant arm.

At the time when the final OS analysis was conducted (data cut-off date of 23-Apr-2020) a descriptivefollow-up efficacy analysis for PFS data was performed. With a median duration from randomisationto data cut-off of approximately 42 months, the reported PFS results were consistent with those fromthe primary PFS analysis. There was an estimated 36% risk reduction of progression or death in favourof treatment with alpelisib plus fulvestrant (HR=0.64; 95% CI: 0.50, 0.81) (Figure 1).

Figure 1 Study C2301 - Kaplan-Meier plot of PFS per investigator assessment (FAS,

PIK3CA mutant cohort): descriptive update with data cut-off date of 23-Apr-2020

CCeennssoorirning gti mTiemse s

Allppeelliissiibb ++ fFuluvlv. ( n(n/N/N = = 1 1242/41/6196)9 )

Placeebboo + + f uFlvu.l v(n (/nN/ N= =14 194/197/12)7 2)

Haazzaarrdd r aRtiaot i=o 0=. 604. 6495% % C CI I[ 0[0.5.05;0 0;0.8.18]1 ]

Kaplan-Meier medians (months)

AKalppellaisni-bM +e fieulrv m.: e1d1.ia0 ns (Months)

PAllapceelbisoi b+ +fu Flvu.l:v 5 .:7 1 1.0

Placebo + Fulv : 5.70 4 8 12 16 20 24 28 32 36 40 44 48 52 56

TTimimee ( m(Monotnhtsh) s)

NuNmumbbeerr ooff s suubjbecjetsc ststi lsl atitl rli sakt risk

TimTiem e(m (Moonntthhss)) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

AlpAellpiesliibsi b+ + f Fuulvlv. 169 123 85 66 54 44 37 29 24 18 12 6 1 0 0

PlaPcleacbeob o+ + f Fuulvlv. 172 89 67 51 40 33 22 13 10 7 4 1 1 1 0

Final overall survival analysis

At the final OS analysis, the study did not meet its key secondary objective. As of the data cut-off dateof 23-Apr-2020, 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 OSwas 39.3 months (95% CI: 34.1, 44.9) in the alpelisib plus fulvestrant arm and 31.4 months (95% CI:

26.8, 41.3) in the placebo plus fulvestrant arm (Figure 2).

EveEnvte-nfrt-efere pe rporbobaabbiliiltiyty ( %(%))

Figure 2 Study C2301 key secondary analysis - Kaplan-Meier plot of OS (FAS, PIK3CAmutant cohort) with cut-off date of 23-Apr-2020

Censoring times

Censoring Times

Alpelisib + fulv. (n/N = 87/169)

Alpelisib + Fulv (n/N = 87/169)

PPlalaccebeob o+ +fu Flvu. lv(n /(Nn/ N= 9=4 9/147/21)7 2)

Hazaardrd r aRtiaot i=o 0=. 806. 8695 % CI [0.64;1.15]95% CI [0.64; 1.15]

Kapllann--MMeeieierr m meeddiainasn s(m (oMnothnst)h s)

Alpelisib + Fulv : 39.3

Alpelisib + fulv.: 39.3

Placebo + Fulv : 31.4

Placebo + fulv.: 31.4

Logrank0 Log rank pp--vvaaluluee 1 -1s-isdeidde =d 0=. 105. 150 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Number of subjects still at risk Time (Months)

Number of subjects still at risk Time (months)

TimTime e( m(Moont hss)) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

AlpAellpieslisbib + + fFuullv. 169 162 159 156 145 141 138 133 126 122 112 111 108 103 102 94 91 85 68 56 47 35 26 19 9 4 1 0

PlaPclaecbeob o + + fFuullv. 172 164 155 150 149 143 133 126 119 115 111 104 98 92 86 80 74 73 60 49 42 29 20 13 7 6 3 0

In patients with prior CDK4/6i treatment (n=20), the median OS in the alpelisib plus fulvestrant armwas 29.8 months (95% CI: 6.7, 38.2) compared to 12.9 months (95% CI: 2.5, 34.6) in the placebo plusfulvestrant arm (HR=0.67; 95% CI: 0.21, 2.18).

Cohort without PIK3CA mutation

No PFS benefit was observed in patients whose tumours did not have a PIK3CA tissue mutation.

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 treatmentwith alpelisib plus fulvestrant for the 21 subjects with PIK3CA mutations and measurable disease atbaseline were partial response in 7 subjects, stable disease in 11 subjects, and progressive disease in2 subjects. Hence, the evidence of efficacy of this treatment in patients previously treated withfulvestrant is not established due to the limited data at this time (see section 4.4).

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 onpaediatric use).

EveEnvte-nftr-efree ep rporbobaabbiilliittyy ( %(%) )

The pharmacokinetics of alpelisib were investigated in patients under an oral dosing regimen rangingfrom 30 to 450 mg daily. Healthy subjects received single oral doses ranging from 300 to 400 mg. Thepharmcokinetics were comparable in both oncology patients and healthy subjects.

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 modellingbioavailability was estimated to be very high (>99%) under fed conditions but lower under fastedconditions (~68.7% at a 300 mg dose). Steady-state plasma levels of alpelisib after daily dosing can beexpected to be reached on day 3 following onset of therapy in most patients.

Alpelisib absorption is affected by food. In healthy volunteers after a single 300 mg oral dose ofalpelisib, compared to the fasted state, a high-fat high-calorie (HFHC) meal (985 calories with 58.1 gof 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 fatcontent nor overall calorific intake has a considerable impact on absorption. The increase ingastrointestinal solubility by bile, secreted in response to food intake, is the potential cause of the foodeffect. Hence, Piqray should be taken immediately after food at approximately the same time each day.

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%).

In vitro studies demonstrated that formation of the hydrolysis metabolite BZG791 by chemical andenzymatic amide hydrolysis was a major metabolic pathway, followed by CYP3A4-mediatedhydroxylation. Alpelisib hydrolysis occurs systemically by both chemical decomposition andenzymatic hydrolysis via ubiquitously expressed, high-capacity enzymes (esterases, amidases, cholineesterase) 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 asunchanged alpelisib in urine and faeces, was either excreted as alpelisib or not absorbed.

Alpelisib exhibits low clearance with 9.2 l/h (CV% 21%) based on population pharmacokineticanalysis under fed conditions. The population-derived half-life, independent of dose and time, was 8 to9 hours at steady state with 300 mg once daily.

In a human mass-balance study, after oral administration, alpelisib and its metabolites were primarilyfound 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 thetotal administered radioactive dose was recovered within 8 days.

The pharmacokinetics were found to be linear with respect to dose and time under fed conditionsbetween 30 and 450 mg. After multiple doses, alpelisib exposure (AUC) at steady state is only slightlyhigher than that of a single dose, with an average accumulation of 1.3 to 1.5 with a daily dosingregimen.

Metabolic interaction

CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates

In a drug-drug interaction study, co-administration of repeated doses of alpelisib 300 mg with a singledose of sensitive substrates of CYP3A4 (midazolam), CYP2C8 (repaglinide), CYP2C9 (warfarin),

CYP2C19 (omeprazole) and CYP2B6 (bupropion), administered as a cocktail, showed that there is noclinically signficant pharmacokinetic interaction. The data from CYP2B6 substrate (bupropion) shouldbe interpreted with caution due to the small sample size.

In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin) - with repeated doses of300 mg alpelisib at steady state, increased S-warfarin exposure on average by 34% and 19% for

AUCinf and Cmax respectively, compared to administration of S-warfarin alone. This indicates thatalpelisib is a mild inhibitor of CYP2C9.

In a drug-drug interaction study with the sensitive CYP3A4 and P-gp substrate everolimus, in patientswith advanced solid tumours, AUC increased by 11.2%. No clinically meaningful change is expectedas a result of drug interaction with CYP3A4 substrates.

In a drug-drug interaction study co-administration of alpelisib and rifampin, a strong CYP3A4inducer, confirmed that there is a clinically significant pharmacokinetic interaction between alpelisiband strong CYP3A4 inducers (see section 4.5).

Transporter-based interaction

Based on in vitro data, inhibition of the renal organic anion transporter OAT3 by alpelisib (and/or itsmetabolite BZG791) cannot be discarded in patients at the therapeutic dose.

Alpelisib showed only weak in vitro inhibition towards the ubiquitously expressed efflux transporters(P-gp, BCRP, MRP2, BSEP), solute carrier transporters at the liver inlet (OATP1B1, OATP1B3,

OCT1) and solute carrier transporters in the kidney (OAT1, OCT2, MATE1, MATE2K). As unboundsystemic steady-state concentrations (or concentrations at the liver inlet) at both the therapeutic doseand maximum tolerated dose are significantly lower than the experimentally determined unboundinhibition constants or IC50, the inhibition will not translate into clinical significance. Due to highalpelisib concentrations in the intestinal lumen, an effect on intestinal P-gp and BCRP cannot be fullyexcluded.

Effect of age, weight and gender

The population pharmacokinetic analysis showed that there are no clinically relevant effects of age,body weight, or gender on the systemic exposure of alpelisib that would require Piqray doseadjustment.

Paediatric patients (below 18 years)

The pharmacokinetics of Piqray in children aged 0-18 years have not been established. No data areavailable.

Elderly (age 65 years or above)

Of 284 patients who received Piqray in the phase III study (in the alpelisib plus fulvestrant arm),117 patients were ≥65 years of age and 34 patients were between 75 and 87 years of age. No overalldifferences in exposure of Piqray were observed between these patients and younger patients (seesection 4.2).

Population pharmacokinetic analyses and pharmacokinetic analyses from a phase I study in Japanesecancer patients showed that there are no clinically relevant effects of ethnicity on the systemicexposure of Piqray.

Non-compartmental pharmacokinetic parameters after single and multiple daily doses of Piqray for

Japanese patients were very similar to those reported in the Caucasian population.

Based on a population pharmacokinetic analysis that included 117 patients with normal renal function(eGFR ≥90 ml/min/1.73 m2)/(CLcr ≥90 ml/min), 108 patients with mild renal impairment (eGFR 60to <90 ml/min/1.73 m2)/ (CLcr 60 to <90 ml/min), and 45 patients with moderate renal impairment(eGFR 30 to <60 ml/min/1.73 m2), mild and moderate renal impairment had no effect on the exposureof alpelisib (see section 4.2).

Based on a pharmacokinetic study in patients with hepatic impairment, moderate and severe hepaticimpairment had negligible effect on the exposure of alpelisib (see section 4.2). The mean exposure foralpelisib was increased 1.26-fold in patients with severe (GMR: 1.00 for Cmax; 1.26 for

AUClast/AUCinf) hepatic impairment.

Based on a population pharmacokinetic analysis that included 230 patients with normal hepaticfunction, 41 patients with mild hepatic impairment and no patients with moderate hepatic impairment,further supporting the findings from the dedicated hepatic impairment study, mild and moderatehepatic impairment had no effect on the exposure of alpelisib (see section 4.2).

Safety pharmacology and repeated dose toxicity

The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisibas a p110α-specific inhibitor of the PI3K pathway, such as the influence on the glucose homeostasisresulting in hyperglycaemia and the risk of increased blood pressure. The bone marrow and lymphoidtissue, pancreas and some reproductive organs of both genders were the main target organs for adverseevents. Effects on bone marrow and lymphoid tissue were generally reversible on cessation oftreatment. Effects on the pancreas and reproductive organs did not fully reverse but showed a tendencytowards 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 higherthan the exposure in humans, at the recommended dose of 300 mg/day. No relevantelectrophysiological effect was seen in dogs.

No carcinogenicity studies have been conducted.

Results of standard genotoxicity in vitro studies with alpelisib were negative. Alpelisib was notgenotoxic in a repeated-dose rat toxicity study where micronucleus analysis was integrated, up toexposure levels approximately twice the estimated exposure (AUC) in humans at the recommendeddose of 300 mg.

Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration ofalpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity. In rats andrabbits, following prenatal exposure to alpelisib, increased incidences of pre- and post-implantationlosses, reduced foetal weights and increased incidences of foetal abnormalities (enlarged brainventricle, decreased bone ossification and skeletal malformations) were observed starting at exposuresbelow those in humans at the highest recommended dose of 300 mg, indicating potential clinicalrelevance.

In repeated dose toxicity studies, adverse events were observed in reproductive organs, such as vaginalor uterine atrophy and oestrus cycle variations in rats, decreases in prostate and testes weight in ratsand 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. Infemales, increased pre- and post-implantation losses, which led to reduced numbers of implantationsites and live embryos, were observed at exposure levels (AUC) approximately twice therecommended human dose of 300 mg. In males, fertility and reproductive performance, includingsperm count and motility parameters, were unaffected at exposure levels approximately twice theestimated exposure (AUC) in humans at the recommended dose of 300 mg. However, at exposurelevels (AUC) at or below the recommended human dose of 300 mg, accessory gland weights (seminalvesicles, prostate) were reduced and correlated microscopically with atrophy and/or reduced secretionin prostate and seminal vesicles, respectively.

An in vitro phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevantphototoxicity potential for alpelisib.

Cellulose microcrystalline

Mannitol

Sodium starch glycolate

Hypromellose

Magnesium stearate

Hypromellose

Iron oxide, black (E172)

Iron oxide, red (E172)

Titanium dioxide (E171)

Macrogol

Talc

Not applicable.

4 years.

This medical product does not require any special storage conditions.

PVC/PCTFE/alu (polyvinylchloride/polychlorotrifluoroethylene/aluminium) blister sealed into ablister card containing 14 film-coated tablets.

Piqray 50 mg and 200 mg film-coated tablets

Packs containing 28 film-coated tablets (14 of 50 mg and 14 of 200 mg) or 56 film-coated tablets (28of 50 mg and 28 of 200 mg).

Multipacks containing 168 film-coated tablets (3x 56, each comprising 28 tablets of 50 mg and28 tablets of 200 mg).

Piqray 150 mg film-coated tablets

Packs containing 28 or 56 film-coated tablets.

Multipacks containing 168 (3x 56) film-coated tablets.

Piqray 200 mg film-coated tablets

Packs containing 14 or 28 film-coated tablets.

Multipacks containing 84 (3x 28) film-coated tablets.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/20/1455/001-009

Date of first authorisation: 27 July 2020

Date of latest renewal: 07 February 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu