This information is intended for use by health professionals

  This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Piqray®50 mg film-coated tablets

Piqray®150 mg film-coated tablets

Piqray®200 mg film-coated tablets

2. Qualitative and quantitative composition

Piqray 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of alpelisib.

Piqray 150 mg film-coated tablets

Each film-coated tablet contains 150 mg of alpelisib.

Piqray 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of alpelisib.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

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 side and “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 side and “NVR” on the other side. Approximate size: 16.2 mm (length); 6.5 mm (width).

4. Clinical particulars
4.1 Therapeutic indications

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 therapy as monotherapy (see section 5.1).

4.2 Posology and method of administration

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

Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with Piqray 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. Piqray should be taken immediately after food, at approximately the same time each day (see section 5.2). The maximum recommended daily dose of Piqray is 300 mg.

If a dose of Piqray 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, Piqray should be taken at the usual time. If the patient vomits after taking the Piqray 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 for Piqray1

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 for treatment with Piqray.

Hyperglycaemia

Table 2 Dose modification and management for hyperglycaemia1

Fasting glucose values1

Recommendation

Dose reductions should only be based on fasting glucose (plasma/blood) values.

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.

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

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

>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 further 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.

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.

>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 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 74.7% of patients with any grade of hyperglycaemia and in 86.2% 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 oral 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).

Table 3 Dose modification and management for rash1

Grade

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.

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 oral corticosteroid treatment.

Grade 3 (e.g. severe rash not responsive to medical management)

(>30% BSA with active skin toxicity)

Interrupt Piqray until rash is grade ≤1.

Initiate or intensify topical/oral corticosteroid and antihistamine treatment.

Once improved to grade ≤1, then resume Piqray at the same dose level for first occurrence of rash and at next lower dose level, in case of second occurrence.

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

Diarrhoea

Table 4 Dose modification and management for diarrhoea

Grade1

Recommendation

Grade 1

No Piqray dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.

Grade 2

Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt Piqray dose until recovery to grade ≤1, then resume Piqray at same dose level.

Grade 3 or 42

Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt Piqray dose until recovery to grade ≤1, then resume Piqray at the next lower dose level.

1 Grading according to CTCAE Version 5.0.

2 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)1

Grade

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 recovery 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.

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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 and anaphylactic shock), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with Piqray in clinical studies (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%) 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).

Piqray 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. Piqray 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 hyperglycemia, including ketoacidosis, has been reported in patients treated with Piqray.

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 (42 out of 159 patients [26.4%] with grade 1-2, and 77 out of 159 patients [48.4%] with grade 3-4), had BMI ≥30 at screening (13 out of 74 patients [17.6%] 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).

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).

After initiating treatment with Piqray

Monitor FPG 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*.

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

If hyperglycaemia develops after initiating treatment with Piqray

Monitor fasting glucose regularly, as per local standard of care and at least until fasting glucose decreases to normal levels.

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 190 patients with hyperglycaemia, 87.4% (166/190) were managed with antidiabetic medication, and 75.8% (144/190) 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 54 patients; of these 13 (24.1%) discontinued study treatment due to hyperglycaemia.

Out of 162 patients with grade ≥2 hyperglycaemia, 155 had at least 1 grade improvement, median time to 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=58), 98.3% (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

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention. 59.5% of patients (n=169) experienced diarrhoea during treatment with Piqray. Grade 3 diarrhoea occurred in 7% (n=20) of patients with no reported cases of grade 4. Among patients with grade 2 or 3 diarrhoea (n=76), the median time to onset was 50 days (range: 1 to 954 days).

Dose reductions of Piqray were required in 5.6% of patients and 2.8% of patients discontinued Piqray due to diarrhoea. In the 169 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 64.5% (109/169).

Based on the severity of the diarrhoea, 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 occurs while taking Piqray.

Osteonecrosis of the jaw

Caution should be exercised when Piqray and bisphosphonates or 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'.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that may increase alpelisib plasma concentrations

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 inhibibitors 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).

Medicinal products whose plasma concentrations may be altered by alpelisib

Based on the results of metabolic in vitro induction and inhibition studies, alpelisib may induce the metabolic clearance of co-administered medicinal products metabolised by CYP2B6, CYP2C9 and CYP3A and may inhibit the metabolic clearance of co-administered medicinal products metabolised by CYP2C8, CYP2C9, CYP2C19 and CYP3A4 (time-dependent inhibition) if sufficiently high concentrations are achieved in vivo.

CYP3A4 substrates

No dose adjustment is required when co-administering Piqray with CYP3A4 substrates (e.g. everolimus, midazolam).

In a drug-drug interaction study, co-administration of alpelisib with everolimus, a sensitive CYP3A4 substrate, 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 was observed at alpelisib doses ranging from 250 to 300 mg.

Caution is recommended when Piqray is used in combination with CYP3A4 substrates that also possess an additional time-dependent inhibition and induction potential on CYP3A4 that affects their own metabolism (e.g. rifampicin, ribociclib, encorafenib).

CYP2C9 substrates with narrow therapeutic index

In the absence of clinical data on CYP2C9, caution is recommended. In vitro evaluations indicated that the pharmacological activity of CYP2C9 substrates with a narrow therapeutic index such as warfarin may be reduced by the CYP2C9 induction effects of alpelisib.

CYP2B6 sensitive substrates with narrow therapeutic index

Sensitive CYP2B6 substrates (e.g. bupropion) or CYP2B6 substrates with a narrow therapeutic window should be used with caution in combination with Piqray, as alpelisib may reduce the clinical activity of such medicinal products.

Substances that are substrates of transporters

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

Hormonal contraceptives

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

4.6 Fertility, pregnancy and lactation

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

Women of childbearing potential/Contraception in males and females

Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus. Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).

In case females of reproductive potential take Piqray, they should use effective contraception (e.g. double-barrier method) when taking Piqray 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 with Piqray.

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 data on the effects of alpelisib on fertility. Based on repeated dose toxicity studies in animals, alpelisib may impair fertility in males and females of reproductive potential (see section 5.3).

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

Summary of the safety profile

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 (67.6%), diarrhoea (59.5%), gamma-glutamyltransferase increased (53.2%), rash (51.8%), lymphocyte count decreased (55.3%), nausea (46.8%), alanine aminotransferase increased (44.0%), anaemia (44.0%), fatigue (43.3%), lipase increased (42.6%), decreased appetite (35.9%), stomatitis (30.3%), vomiting (28.5%), weight decreased (27.8%), hypocalcaemia (27.8%), plasma glucose decreased (26.8%), activated partial thromboplastin time (aPTT) prolonged (22.2%) and alopecia (20.4%).

The most common grade 3 or 4 ADRs (reported at a frequency ≥2%) were plasma glucose increased (39.1%), rash (19.4%), gamma-glutamyltransferase increased (12.0%), lymphocyte count decreased (9.2%), diarrhoea (7.0%), lipase increased (7.0%), hypokalaemia (6.3%), fatigue (5.6%), weight decreased (5.3%), anaemia (4.9%), hypertension (4.6%), alanine aminotransferase increased (4.2%), nausea (2.8%), creatinine increased (2.8%), stomatitis (2.5%), hypocalcaemia (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%).

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

125 (44.0)

14 (4.9)*

Lymphocyte count decreased

Very common

157 (55.3)

26 (9.2)

Platelet count decreased

Very common

43 (15.1)

4 (1.4)*

Immune system disorders

Hypersensitivity2

Common

11 (3.9)

2 (0.7)*

Metabolism and nutrition disorders

Glucose plasma increased

Very common

225 (79.2)

111 (39.1)

Glucose plasma decreased

Very common

76 (26.8)

1 (0.4)

Decreased appetite

Very common

102 (35.9)

2 (0.7)*

Hypokalaemia

Very common

42 (14.8)

18 (6.3)

Hypocalcaemia

Very common

79 (27.8)

6 (2.1)

Magnesium decreased

Very common

34 (12.0)

1 (0.4)

Dehydration

Common

10 (3.5)

1 (0.4)*

Ketoacidosis3

Uncommon

2 (0.7)

2 (0.7)

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)

Vascular disorders

Hypertension

Common

27 (9.5)

13 (4.6)

Lymphoedema

Common

16 (5.6)

Respiratory, thoracic and mediastinal disorders

Pneumonitis5

Common

5 (1.8)

1 (0.4)*

Gastrointestinal disorders

Diarrhoea

Very common

169 (59.5)

20 (7.0)*

Nausea

Very common

133 (46.8)

8 (2.8)*

Stomatitis6

Very common

86 (30.3)

7 (2.5)*

Vomiting

Very common

81 (28.5)

2 (0.7)*

Abdominal pain

Very common

50 (17.6)

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

9 (3.2)

Cheilitis

Common

8 (2.8)

Pancreatitis

Uncommon

1 (0.4)

1 (0.4)

Skin and subcutaneous tissue disorders

Rash7

Very common

147 (51.8)

55 (19.4)*

Alopecia

Very common

58 (20.4)

Pruritus

Very common

53 (18.7)

2 (0.7)*

Dry skin8

Very common

53 (18.7)

1 (0.4)*

Erythema9

Common

18 (6.3)

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

Musculoskeletal and connective tissue disorders

Muscle spasms

Common

22 (7.7)

Myalgia

Common

19 (6.7)

1 (0.4)*

Osteonecrosis of jaw

Common

16 (5.6)

5 (1.8)*

Renal and urinary disorders

Acute kidney injury

Common

16 (5.6)

5 (1.8)

General disorders and administration site conditions

Fatigue11

Very common

123 (43.3)

16 (5.6)*

Mucosal inflammation

Very common

56 (19.7)

6 (2.1)*

Oedema peripheral

Very common

47 (16.5)

Pyrexia

Very common

45 (15.8)

2 (0.7)

Mucosal dryness12

Very common

36 (12.7)

1 (0.4)

Oedema13

Common

18 (6.3)

Investigations

Weight decreased

Very common

79 (27.8)

15 (5.3)*

Blood creatinine increased

Very common

192 (67.6)

8 (2.8)*

Gamma-glutamyltransferase increased

Very common

151 (53.2)

34 (12.0)

Alanine aminotransferase increased

Very common

125 (44.0)

12 (4.2)*

Lipase increased

Very common

121 (42.6)

20 (7.0)

Activated partial thromboplastin time (aPTT) prolonged

Very common

63 (22.2)

2 (0.7)

Albumin decreased

Very common

41 (14.4)

1 (0.4)

Glycosylated haemoglobin increased

Common

8 (2.8)

0

* 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

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 (FPG >160 mg/dl) was reported in 190 (66.9%) patients; grade 2 (FPG 160-250 mg/dl), 3 (FPG >250-500 mg/dl) and 4 (FPG >500 mg/dl) events were reported in 16.2%, 33.8% and 4.6% of patients, respectively.

Based on baseline FPG and HbA1c values, 56% of patients were considered pre-diabetic (FPG >100-126 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%). 74.8% 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 900 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 all 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.

Rash

Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis and dermatitis acneiform) were reported in 153 (53.9%) 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; 26.1% vs 53.9% for all grades, 11.4% 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 59.5%, 46.8% and 28.5% of the patients, respectively (see Table 7).

Grade 2 and 3 diarrhoea events were reported in 19.7% and 7.0% of patients, respectively, with a median time to onset of grade ≥2 diarrhoea of 50 days (range: 1 day to 954 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 28/153 (17.6%) and 109/169 (64.5%) patients, respectively, to manage symptoms.

Osteonecrosis of the jaw (ONJ)

ONJ was reported in 5.6% patients (16/284) in the Piqray plus fulvestrant arm. Fifteen patients experiencing ONJ were exposed to concomitant bisphosphonates (e.g. zoledronic acid). Therefore, in patients receiving Piqray and bisphosphonates, an increased risk of development of ONJ cannot be excluded.

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 (33.5%), while in patients <75 years of age, grade 3-4 hyperglycaemia was 36% 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.

4.9 Overdose

Symptoms

The adverse reactions associated with overdose 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 overdose where necessary. There is no known antidote for Piqray.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX65

Mechanism of action

Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα 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

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 had progressed or recurred 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 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.

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 with PIK3CA mutation advanced breast cancer. The key secondary endpoint was overall survival (OS) for patients with PIK3CA mutation status.

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

The median duration of follow-up (between randomisation and data cut-off date of 12-June-2018) in the cohort with PIK3CA mutation was 20 months.

The efficacy results in the cohort with PIK3CA mutation demonstrated a statistically significant improvement in PFS in patients receiving alpelisib plus fulvestrant, compared to patients receiving placebo plus fulvestrant with an estimated 35% risk reduction of disease progression or death.

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

(7.5-14.5)

5.7

(3.7-7.4)

Hazard ratio (95% CI)

0.65 (0.50-0.85)

p-valuea

0.00065

Blinded independent review committee assessment*#

PIK3CA mutant cohort

(N=173)

11.1

(7.3-16.8)

3.7

(2.1-5.6)

Hazard ratio (95% CI)

0.48 (0.32-0.71)

p-value

N/A

Data using 2nd interim OS data cut-off date of 30 September 2019

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

Investigator radiological assessment#

PIK3CA mutant cohort

(N=341)

11.0

(7.5-14.5)

5.7

(3.7-7.4)

Hazard ratio (95% CI)

0.64 (0.50-0.81)

p-value

N/A

Overall survival (OS) (months, 95% CI)

PIK3CA mutant cohort

(N=341)

40.6

(32.2-NE)

31.2

(26.8-NE)

Hazard ratio (95% CI)

0.77 (0.56-1.06)

p-valuea

0.06

CI = confidence interval; N = number of patients; N/A = is not applicable; NE = not evaluable

a p-value is obtained from the one-sided stratified log-rank test.

# Per RECIST 1.1

* Based on 50% audit-based 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.

Among 20 patients with prior CDK4/6 inhibitor use the hazard ratio (HR) 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.

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 sensitive patients with a PIK3CA mutation was limited (n=39) and the results should be interpreted with caution.

Using a data cut-off date of 12-Jun-2018, the overall response rate in patients with measurable disease at 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.

Figure 1 Kaplan-Meier plot of progression free survival in cohort with PIK3CA mutation per local investigator assessment

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 treatment with alpelisib plus fulvestrant for the 21 subjects with PIK3CA mutations and 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).

5.2 Pharmacokinetic properties

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 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% 46%).

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 minor contribution of CYP3A4. 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 absorbed fraction of the dose was excreted as alpelisib.

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 excreted in the faeces (81.0%), mainly through hepatobiliary export and/or intestinal secretion of alpelisib, or metabolised to 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 interaction

CYP3A4 substrates

In a drug-drug interaction study with the sensitive CYP3A4 substrate everolimus, AUC increased by 11.2%. No clinically meaningful change is expected as a result of drug interaction with CYP3A4 substrates.

CYP3A4 inducers and inhibitors

The effects of CPY3A4 inducers or inhibitors have not been evaluated in clinical studies. No clinically meaningful changes in overall exposure are expected as a result of the low fraction (<15%) metabolised by CYP3A4.

Transporter-based interaction

Based on in vitro data, inhibition of the renal organic anion transporter OAT3 by alpelisib (and/or its metabolite 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 unbound systemic steady-state concentrations (or concentrations at the liver inlet) at both the therapeutic dose and maximum tolerated dose are significantly lower than the experimentally determined unbound inhibition constants or IC50, the inhibition will not translate into clinical significance. Due to high alpelisib concentrations in the intestinal lumen, an effect on intestinal P-gp and BCRP cannot be fully excluded.

Special populations

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 dose adjustment.

Paediatric patients (below 18 years)

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

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 overall differences in exposure of Piqray were observed between these patients and younger patients (see section 4.2).

Race/Ethnicity

Population pharmacokinetic analyses and pharmacokinetic analyses from a phase I study in Japanese cancer patients showed that there are no clinically relevant effects of ethnicity on the systemic exposure 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.

Renal impairment

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 60 to <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 exposure of alpelisib (see section 4.2).

Hepatic impairment

Based on a pharmacokinetic study in patients with hepatic impairment, moderate and severe hepatic impairment had negligible effect on the exposure of alpelisib (see section 4.2). The mean exposure for alpelisib 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 hepatic function, 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 moderate hepatic impairment had no effect on the exposure of alpelisib (see section 4.2).

5.3 Preclinical safety data

Safety pharmacology and repeated dose toxicity

The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisib as a p110α-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 effects. 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.

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.

Carcinogenicity and mutagenicity

No carcinogenicity studies have been conducted.

Results of standard genotoxicity studies with alpelisib were negative. In a repeated-dose rat toxicity study, where micronucleus analysis was integrated, exposure levels of alpelisib were 1.4-fold higher in males and 2-fold higher in females than therapeutic exposure in adult humans treated with the recommended dose. Therefore, the genotoxicity potential of alpelisib in humans cannot be ruled out.

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.

A fertility study in rats has not been performed. However, in repeated dose toxicity studies, adverse effects 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.

Phototoxicity

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

6. Pharmaceutical particulars
6.1 List of excipients

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medical product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PCTFE/alu (polyvinylchloride/polychlorotrifluoroethylene/aluminium) blister sealed into a blister 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 (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).

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.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

8. Marketing authorisation number(s)

EU/1/20/1455/001-009

9. Date of first authorisation/renewal of the authorisation

27 July 2020

10. Date of revision of the text

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

LEGAL CATEGORY

POM