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-based therapy.

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 based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available.

Posology

The recommended dose is 300 mg alpelisib (2x 150 mg film‑coated tablets) taken once daily on a continuous basis. The maximum recommended daily dose of Piqray is 300 mg.

If a dose is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day. On the next day, the dose should be taken at the usual time. If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Piqray should be co‑administered with fulvestrant. The recommended dose of fulvestrant is 500 mg administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose modifications may be necessary to improve tolerability.

Dose modifications

Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction, and/or discontinuation of Piqray. If dose reduction is required, the dose reduction guidelines for ADRs are listed in Table 1. A maximum of 2 dose reductions are recommended, after which the patient should be permanently discontinued from treatment with Piqray. Dose reduction should be based on the worst preceding toxicity.

Table 1 Recommended dose reduction guidelines for ADRs 1

Piqray dose level

Dose and schedule

Number and strength of tablets

Starting dose

300 mg/day continuously

2x 150 mg tablets

First dose reduction

250 mg/day continuously

1x 200 mg tablet and 1x 50 mg tablet

Second dose reduction

200 mg/day continuously

1x 200 mg tablet

1 Only one dose reduction is permitted for pancreatitis.

Tables 2‑5 summarise the recommendations for dose interruption, reduction or discontinuation of Piqray in the management of specific ADRs. The clinical judgement of the treating physician, including confirmation of laboratory values if deemed necessary, should guide the management plan of each patient based on the individual benefit/risk assessment.

Hyperglycaemia

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

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

Table 2 Dose modification and management for hyperglycaemia

Fasting glucose (FG) values1

Recommendation

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

>ULN‑160 mg/dl or >ULN‑8.9 mmol/l

No Piqray dose adjustment required.

Initiate or intensify oral antidiabetic treatment2.

>160‑250 mg/dl or >8.9‑13.9 mmol/l

No Piqray dose adjustment required.

Initiate or intensify oral antidiabetic treatment2.

If FG does not decrease to ≤160 mg/dl or 8.9 mmol/l within 21 days with appropriate oral antidiabetic treatment2,3, reduce Piqray dose by 1 dose level and follow FG‑value‑specific recommendations.

>250‑500 mg/dl or >13.9‑27.8 mmol/l

Interrupt Piqray.

Initiate or intensify oral antidiabetic treatment2 and consider additional antidiabetic medicinal products such as insulin3 for 1‑2 days until hyperglycaemia resolves, as clinically indicated.

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

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

If FG does not decrease to ≤160 mg/dl or 8.9 mmol/l within 3 to 5 days under appropriate antidiabetic treatment, consultation with a healthcare professional with expertise in the treatment of hyperglycaemia is recommended.

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

>500 mg/dl or >27.8 mmol/l

Interrupt Piqray.

Initiate or intensify appropriate antidiabetic treatment2,3 (administer intravenous hydration and consider appropriate treatment [e.g. intervention for electrolyte / ketoacidosis / hyperosmolar disturbances]), re‑check within 24 hours and as clinically indicated.

If FG decreases to ≤500 mg/dl or ≤27.8 mmol/l, then follow FG‑value‑specific recommendations for <500 mg/dl.

If FG is confirmed at >500 mg/dl or >27.8 mmol/l after 24 hours, permanently discontinue Piqray treatment.

1 Fasting glucose levels reflect hyperglycaemia grading according to CTCAE Version 4.03 CTCAE = Common Terminology Criteria for Adverse Events.

2 Applicable antidiabetic medicinal products, such as metformin, SGLT2 inhibitors or insulin sensitisers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), should be initiated and the respective prescribing information should be reviewed for dosing and dose titration recommendations, including local diabetic treatment guidelines. Metformin was recommended in the phase III clinical study with the following guidance: Metformin should be initiated at 500 mg once daily. Based on tolerability, the metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1000 mg with the evening meal, followed by further increase to 1000 mg twice daily if needed (see section 4.4).

3 As recommended in the phase III clinical study, insulin may be used for 1‑2 days until hyperglycaemia resolves. However, this may not be necessary in the majority of cases of alpelisib‑induced hyperglycaemia, given the short half‑life of alpelisib and the expectation that glucose levels will normalise following interruption of Piqray.

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

Rash

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

Topical corticosteroid treatment should be initiated at the first signs of rash and systemic corticosteroids should be considered for moderate to severe rashes. Based on the severity of rash, Piqray may require dose interruption, reduction or discontinuation as described in Table 3 (see section 4.8).

Table 3 Dose modification and management for rash

Grade1

Recommendation

All grades

Consultation with a dermatologist should always be considered.

Grade 1

(<10% body surface area [BSA] with active skin toxicity)

No Piqray dose adjustment required.

Initiate topical corticosteroid treatment.

Consider adding oral antihistamine treatment to manage symptoms.

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

Grade 2

(10‑30% BSA with active skin toxicity)

No Piqray dose adjustment required.

Initiate or intensify topical corticosteroid and oral antihistamine treatment.

Consider low‑dose systemic corticosteroid treatment.

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

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

(>30% BSA with active skin toxicity)

Interrupt Piqray until rash improves to grade ≤1.

Initiate or intensify topical/systemic corticosteroid and antihistamine treatment.

Once rash improves to grade ≤1, resume Piqray at next lower dose level.

Grade 4 (e.g. severe bullous, blistering or exfoliating skin conditions)

(any % BSA associated with extensive superinfection, with intravenous antibiotics indicated; life‑threatening consequences)

Permanently discontinue Piqray.

1 Grading according to CTCAE Version 5.0

Diarrhoea or colitis

Table 4 Dose modification and management for diarrhoea or colitis

Grade1

Recommendation

Grade 1

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

Grade 22

Interrupt Piqray dose.

Initiate or intensify appropriate medical therapy and monitor as clinically indicated.

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

For recurrent diarrhoea or colitis grade ≥2, interrupt Piqray dose until improvement to grade ≤1, then resume Piqray at the next lower dose level.

Grade 32,3

Interrupt Piqray dose.

Initiate or intensify appropriate medical therapy and monitor as clinically indicated.

If diarrhoea or colitis improves to grade ≤1, then resume Piqray at the next lower dose level.

Grade 42,3

Permanently discontinue Piqray.

1 Grading according to CTCAE Version 5.0.

2 For grade ≥2 consider additional treatment, such as steroids.

3 Patients should additionally be managed according to local standard of care, including electrolyte monitoring, administration of antiemetics and antidiarrhoeal medicinal products and/or fluid replacement and electrolyte supplements, as clinically indicated.

Other toxicities

Table 5 Dose modification and management for other toxicities (excluding hyperglycaemia, rash and diarrhoea or colitis)

Grade1

Recommendation

Grade 1 or 2

No Piqray dose adjustment required. Initiate appropriate medical therapy and monitor as clinically indicated2,3.

Grade 3

Interrupt Piqray dose until improvement to grade ≤1, then resume Piqray at the next lower dose level2.

Grade 4

Permanently discontinue Piqray3.

1 Grading according to CTCAE Version 5.0

2 For grade 2 and 3 pancreatitis, interrupt Piqray dose until improvement to grade ≤1 and resume at next lower dose level. Only one dose reduction is permitted. If toxicity recurs, permanently discontinue Piqray treatment.

3 For grade 2 total bilirubin elevation, interrupt Piqray dose until recovery to grade ≤1 and resume at the same dose if resolved in ≤14 days or resume at the next lower dose level if resolved in >14 days.

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

The safety and efficacy of Piqray in children aged 0‑18 years have not been established. No data are available.

Method of administration

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

The tablets should be taken immediately after food, at approximately the same time each day (see section 5.2).

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, anaphylactic shock and angioedema), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with Piqray (see section 4.8). Piqray should be permanently discontinued and should not be re‑introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated.

Severe cutaneous reactions

Severe cutaneous reactions have been reported with alpelisib. In the phase III clinical study, Stevens‑Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 1 (0.4%) and 3 (1.1%) patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post‑marketing setting (see section 4.8).

Treatment should not be initiated in patients with a history of severe cutaneous reactions.

Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu‑like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severe cutaneous reactions are present, Piqray should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended.

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

Hyperglycaemia

Severe hyperglycaemia, in some cases associated with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has been observed in patients treated with Piqray. Some cases of ketoacidosis with fatal outcome have been reported in the post-marketing setting.

In the phase III clinical study, hyperglycaemia occurred more frequently in patients who were diabetic (0 out of 12 patients [0%] with grade 1‑2, and 10 out of 12 patients [83.3%] with grade 3‑4), pre‑diabetic (43 out of 159 patients [27.0%] with grade 1‑2, and 77 out of 159 patients [48.4%] with grade 3‑4), had BMI ≥30 at screening (14 out of 74 patients [18.9%] with grade 1‑2, and 38 out of 74 patients [51.4%] with grade 3‑4) or ≥75 years of age (6 out of 34 patients [17.6%] with grade 1‑2, and 19 out of 34 patients [55.9%] with grade 3‑4).

As hyperglycaemia may occur with a rapid onset after starting treatment, it is recommended to self‑monitor frequently in the first 4 weeks and especially within the first 2 weeks of treatment, as clinically indicated. A specific schedule for fasting glucose monitoring is recommended in Table 6.

In the phase III clinical study, patients with a history of diabetes mellitus intensified use of antidiabetic medicinal products while on treatment with Piqray.

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

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 fasting glucose at weeks 1, 2, 4, 6 and 8 after treatment start and monthly thereafter.

Monitor/self‑monitor fasting glucose regularly, more frequently in the first 4 weeks and especially within the first 2 weeks of treatment, according to the instructions of a healthcare professional*.

Monitor/self‑monitor fasting glucose daily for the first 2 weeks of treatment. Then continue to monitor fasting glucose as frequently as needed to manage hyperglycaemia according to the instructions of a healthcare professional*.

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 191 patients with hyperglycaemia, 86.9% (166/191) were managed with antidiabetic medication, and 75.9% (145/191) reported use of metformin as single agent or in combination with other antidiabetic medication (e.g. insulin, dipeptidyl peptidase‑4 (DPP‑4) inhibitors, SGLT2 inhibitors and sulfonylureas).

Oral antidiabetic medication was used in 154 patients. Out of these 154 patients, 17 (11.0%) discontinued study treatment due to hyperglycaemia. Concomitant insulin medication was used in 56 patients; of these 13 (23.2%) discontinued study treatment due to hyperglycaemia.

Out of 164 patients with grade ≥2 hyperglycaemia, 157 had at least 1 grade improvement, median time to improvement from the first event was 8 days (95% CI: 8 to 10 days).

Of the patients with elevated FPG who continued fulvestrant treatment after discontinuing Piqray (n=61), 93.4% (n=57) had FPG levels that returned to baseline.

The safety of Piqray in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the phase III clinical study. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment and should be closely monitored.

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

Pneumonitis

Pneumonitis, including serious cases of pneumonitis/acute interstitial lung disease, have been reported in Piqray‑treated patients in clinical studies. Patients should be advised to report promptly any new or worsening respiratory symptoms. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, Piqray treatment should be interrupted immediately and the patient should be evaluated for pneumonitis. A diagnosis of non‑infectious pneumonitis should be considered in patients presenting with non‑specific respiratory signs and symptoms such as hypoxia, cough, dyspnoea, or interstitial infiltrates on radiological examination and in whom infectious, neoplastic and other causes have been excluded by means of appropriate investigations. Piqray should be permanently discontinued in all patients with confirmed pneumonitis.

Diarrhoea or colitis

Patients should be monitored for diarrhoea and other symptoms of colitis, such as abdominal pain and mucus or blood in stools.

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention. 59.9% of patients (n=170) experienced diarrhoea during treatment with Piqray. Grade 3 diarrhoea occurred in 7.4% (n=21) of patients with no reported cases of grade 4. Among patients with grade 2 or 3 diarrhoea (n=79), the median time to onset was 54 days (range: 1 to 1 731 days).

Dose reductions of Piqray were required in 6.3% of patients and 2.8% of patients discontinued Piqray due to diarrhoea. In the 170 patients who experienced diarrhoea, antidiarrhoeal medications (e.g. loperamide) were required to manage symptoms in 65.3% (111/170).

Based on the severity of the diarrhoea or colitis, Piqray may require dose interruption, reduction or discontinuation as described in Table 4 (see section 4.2).

Patients should be advised to start antidiarrhoeal treatment, increase oral fluids and notify their physician if diarrhoea or other symptoms of colitis occur while taking Piqray. In case of colitis, additional treatment, such as steroids, may be considered as clinically indicated.

Osteonecrosis of the jaw

Caution should be exercised when Piqray and bisphosphonates or RANK-ligand inhibitors (e.g. denosumab) are used either simultaneously or sequentially. Piqray treatment should not be initiated in patients with ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab. Patients should be advised to promptly report any new or worsening oral symptoms (such as dental mobility, pain or swelling, non‑healing of mouth sores, or discharge) during treatment with Piqray.

In patients who develop osteonecrosis of the jaw, standard medical management should be initiated.

Symptomatic visceral disease

The efficacy and safety of this medicinal product have not been studied in patients with symptomatic visceral disease.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film‑coated tablet, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

Medicinal products that may increase alpelisib plasma concentrations

Breast cancer resistance protein (BCRP) inhibitors

Alpelisib is a substrate for BCRP in vitro. BCRP is involved in the hepatobiliary export and intestinal secretion of alpelisib, therefore inhibition of BCRP in the liver and in the intestine during elimination may lead to an increase in systemic exposure of alpelisib. Therefore, caution and monitoring for toxicity are advised during concomitant treatment with inhibitors of BCRP (e.g. eltrombopag, lapatinib, pantoprazole).

Medicinal products that may decrease alpelisib plasma concentrations

Acid‑reducing agents

The co‑administration of the H2 receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure of alpelisib. In the presence of a low‑fat low‑calorie (LFLC) meal, AUCinf was decreased on average by 21% and Cmax by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUCinf and a 51% decrease in Cmax with ranitidine compared to the fasted state without co‑administration of ranitidine. Population pharmacokinetic analysis showed no significant effect of co‑administration of acid‑reducing agents, including proton pump inhibitors, H2 receptor antagonists and antacids, on the pharmacokinetics of alpelisib. Therefore, alpelisib can be co‑administered with acid‑reducing agents, provided alpelisib is taken immediately after food (see section 4.2).

CYP3A4 inducers

Once‑daily administration of 600 mg rifampin (a strong CYP3A4 inducer) for 7 days followed by co‑administration with a single 300 mg oral dose of alpelisib on day 8, decreased alpelisib Cmax by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampin 600 mg once daily for 15 days with alpelisib 300 mg once daily starting from day 8 to day 15 decreased the steady‑state alpelisib Cmax by 59% and AUC by 74%.

Co-administration with a strong CYP3A4 inducer decreases alpelisib AUC, which may reduce alpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g. apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered.

Medicinal products whose plasma concentrations may be altered by alpelisib

CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates

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

In a drug‑drug interaction study, co‑administration of alpelisib with everolimus, a sensitive CYP3A4 substrate, confirmed that there are no clinically significant pharmacokinetic interactions (decrease 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.

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 to administration 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 inhibit the activities of OAT3 drug transporters and intestinal BCRP and P‑gp. Alpelisib should be used with caution in combination with sensitive substrates of these transporters which exhibit a narrow therapeutic index because alpelisib 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) during therapy and for at least 1 week after stopping treatment with Piqray.

Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking Piqray and for at least 1 week after stopping treatment.

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

Pregnancy

Piqray is not indicated and is not to be used in women who are, or may be, pregnant (see section 4.1).

There are no data from the use of alpelisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Piqray is not recommended during pregnancy and in women of childbearing potential not using contraception.

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

Breast‑feeding

It is not known if alpelisib is excreted in human or animal milk.

Because of the potential for serious adverse reactions in the breast‑fed infant, it is recommended that women should not breast‑feed during treatment and for at least 1 week after the last dose of Piqray.

Fertility

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

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

Study CBYL719C2301 (SOLAR-1)

The safety profile is based on data from 284 patients in the Piqray plus fulvestrant arm of the double‑blind, placebo‑controlled phase III study.

The most common ADRs (reported at a frequency >20% in the combined mutant and non‑mutant study population) were plasma glucose increased (79.2%), creatinine increased (68.0%), diarrhoea (59.9%), lymphocyte count decreased (55.6%), gamma‑glutamyltransferase increased (54.2%), rash (52.1%), nausea (46.8%), anaemia (45.4%), alanine aminotransferase increased (45.1%), fatigue (44.0%), lipase increased (43.3%), decreased appetite (37.0%), stomatitis (30.6%), vomiting (29.6%), weight decreased (28.2%), hypocalcaemia (27.8%), plasma glucose decreased (27.5%), activated partial thromboplastin time (aPTT) prolonged (23.9%) and alopecia (20.4%).

The most common grade 3 or 4 ADRs (reported at a frequency ≥2%) were plasma glucose increased (39.4%), rash (19.4%), gamma‑glutamyltransferase increased (12.3%), lymphocyte count decreased (9.9%), diarrhoea (7.4%), lipase increased (7.0%), hypokalaemia (6.7%), weight decreased (6.0%), fatigue (5.6%), anaemia (5.3%), hypertension (5.3%), alanine aminotransferase increased (4.6%), creatinine increased (3.2%), nausea (2.8%), osteonecrosis of jaw (2.8%), stomatitis (2.5%), hypocalcaemia (2.1%), acute kidney injury (2.1%) and mucosal inflammation (2.1%).

The most common ADRs leading to treatment discontinuation were hyperglycaemia (6.3%), rash (4.2%), diarrhoea (2.8%) and fatigue (2.5%).

CBYL719X2402 (BYLieve)

Additional safety evaluations were performed in the Phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients (pre- and post-menopausal women, and men) with HR-positive, HER2-negative advanced breast cancer harbouring PIK3CA mutation(s) in the tumour, and whose disease has progressed on or after prior treatments.

In the cohort of patients who had progressed on or after a CDK4/6 inhibitor plus an aromatase inhibitor before treatment with alpelisib plus fulvestrant (Cohort A; n=127 patients), ADRs that were reported in ≥20% of patients were diarrhoea (59.8%), hyperglycaemia (58.3%), nausea (45.7%), rash (39.4%), fatigue (29.1%), decreased appetite (28.3%), stomatitis (26.8%) and vomiting (23.6%).

Grade 3 or grade 4 ADRs that were reported in ≥5% of patients were hyperglycaemia (28.3%), rash (18.9%), and diarrhoea (5.5%).

The most common serious adverse drug reactions (ADRs), reported in ≥2% of patients were hyperglycaemia (5.5%) and rash (3.1%). Serious adverse events reported in ≥2% of patients were dyspnoea (2.4%) and pleural effusion (2.4%). Serious adverse events related to the gastrointestinal tract included colitis and erosive oesophagitis (each 0.8%).

Tabulated list of adverse reactions

ADRs from the phase III clinical study and post‑marketing experience (Table 7) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 7 ADRs observed in phase III clinical study and during post‑marketing experience

Adverse drug reaction

Any grade (%)

Grade 3 or 4 (%)

Infections and infestations

Urinary tract infection1

Very common

29 (10.2)

2 (0.7)*

Blood and lymphatic system disorders

Anaemia

Very common

129 (45.4)

15 (5.3)*

Lymphocyte count decreased

Very common

158 (55.6)

28 (9.9)

Platelet count decreased

Very common

42 (14.8)

3 (1.1)

Immune system disorders

Hypersensitivity2

Common

12 (4.2)

2 (0.7)*

Metabolism and nutrition disorders

Glucose plasma increased

Very common

225 (79.2)

112 (39.4)

Glucose plasma decreased

Very common

78 (27.5)

1 (0.4)

Decreased appetite

Very common

105 (37.0)

3 (1.1)*

Hypokalaemia

Very common

43 (15.1)

19 (6.7)

Hypocalcaemia

Very common

79 (27.8)

6 (2.1)

Magnesium decreased

Very common

36 (12.7)

1 (0.4)*

Dehydration

Common

10 (3.5)

1 (0.4)*

Ketoacidosis3

Common

3 (1.1)

3 (1.1)

Hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) #

Not known

Not known

Not known

Psychiatric disorders

Insomnia

Common

22 (7.7)

Nervous system disorders

Headache

Very common

55 (19.4)

2 (0.7)*

Dysgeusia4

Very common

44 (15.5)

1 (0.4)*

Eye disorders

Vision blurred

Common

15 (5.3)

1 (0.4)*

Dry eye

Common

10 (3.5)

Uveitis

Not known

Not known

Not known

Vascular disorders

Hypertension

Very common

30 (10.6)

15 (5.3)

Lymphoedema

Common

17 (6.0)

Respiratory, thoracic and mediastinal disorders

Pneumonitis5

Common

5 (1.8)

1 (0.4)*

Gastrointestinal disorders

Diarrhoea

Very common

170 (59.9)

21 (7.4)*

Nausea

Very common

133 (46.8)

8 (2.8)*

Stomatitis6

Very common

87 (30.6)

7 (2.5)*

Vomiting

Very common

84 (29.6)

2 (0.7)*

Abdominal pain

Very common

53 (18.7)

4 (1.4)*

Dyspepsia

Very common

33 (11.6)

Toothache

Common

13 (4.6)

1 (0.4)*

Gingivitis

Common

11 (3.9)

1 (0.4)*

Gingival pain

Common

11 (3.9)

Cheilitis

Common

8 (2.8)

Pancreatitis

Uncommon

1 (0.4)

1 (0.4)

Colitis#

Not known

Not known

Not known

Skin and subcutaneous tissue disorders

Rash7

Very common

148 (52.1)

55 (19.4)*

Alopecia

Very common

58 (20.4)

Pruritus

Very common

54 (19.0)

2 (0.7)*

Dry skin8

Very common

53 (18.7)

1 (0.4)*

Erythema9

Common

19 (6.7)

2 (0.7)*

Dermatitis10

Common

10 (3.5)

2 (0.7)*

Palmar‑plantar erythrodysaesthesia syndrome

Common

5 (1.8)

Erythema multiforme

Common

3 (1.1)

2 (0.7)*

Stevens‑Johnson syndrome

Uncommon

1 (0.4)

1 (0.4)*

Drug reaction with eosinophilia and systemic symptoms (DRESS)#

Not known

Not known

Not known

Angioedema#

Not known

Not known

Not known

Musculoskeletal and connective tissue disorders

Muscle spasms

Common

23 (8.1)

Myalgia

Common

20 (7.0)

1 (0.4)*

Osteonecrosis of jaw

Common

16 (5.6)

8 (2.8)*

Renal and urinary disorders

Acute kidney injury

Common

17 (6.0)

6 (2.1)

General disorders and administration site conditions

Fatigue11

Very common

125 (44.0)

16 (5.6)*

Mucosal inflammation

Very common

56 (19.7)

6 (2.1)*

Oedema peripheral

Very common

48 (16.9)

Pyrexia

Very common

48 (16.9)

2 (0.7)

Mucosal dryness12

Very common

37 (13.0)

1 (0.4)

Oedema13

Common

20 (7.0)

Investigations

Weight decreased

Very common

80 (28.2)

17 (6.0)*

Blood creatinine increased

Very common

193 (68.0)

9 (3.2)

Gamma‑glutamyltransferase increased

Very common

154 (54.2)

35 (12.3)

Alanine aminotransferase increased

Very common

128 (45.1)

13 (4.6)

Lipase increased

Very common

123 (43.3)

20 (7.0)

Activated partial thromboplastin time (aPTT) prolonged

Very common

68 (23.9)

2 (0.7)*

Albumin decreased

Very common

44 (15.5)

1 (0.4)*

Glycosylated haemoglobin increased

Common

9 (3.2)

* No grade 4 ADRs were observed

# Adverse reactions reported during post‑marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.

1 Urinary tract infection: also includes a single case of urosepsis

2 Hypersensitivity: also includes allergic dermatitis

3 Ketoacidosis: also includes diabetic ketoacidosis (see section 4.4)

4 Dysgeusia: also includes ageusia, hypogeusia

5 Pneumonitis: also includes interstitial lung disease

6 Stomatitis: also includes aphthous ulcer and mouth ulceration

7 Rash: also includes rash maculopapular, rash macular, rash generalised, rash papular, rash pruritic

8 Dry skin: also includes skin fissures, xerosis, xeroderma

9 Erythema: also includes erythema generalised

10 Dermatitis: also includes dermatitis acneiform

11 Fatigue: also includes asthenia

12 Mucosal dryness: also includes dry mouth, vulvovaginal dryness

13 Oedema: also includes face swelling, face oedema, eyelid oedema

Description of selected ADRs

Hyperglycaemia

Hyperglycaemia was reported in 191 (67.3%) patients; grade 2 (FPG >160‑250 mg/dl), 3 (FPG >250‑500 mg/dl) and 4 (FPG >500 mg/dl) events were reported in 15.8%, 34.5% and 4.6% of patients, respectively.

Based on baseline FPG and HbA1c values, 56% of patients were considered pre‑diabetic (FPG >100‑125 mg/dl [5.6 to 6.9 mmol/l] and/or HbA1c 5.7‑6.4%) and 4.2% of patients were considered diabetic (FPG ≥126 mg/dl [≥7.0 mmol/l] and/or HbA1c ≥6.5%). 75.5% of patients who were pre‑diabetic at baseline experienced hyperglycaemia (any grade) when treated with alpelisib. Among all patients with hyperglycaemia of grade ≥2 (FPG >160 mg/dl), the median time to first occurrence was 15 days (range: 5 days to 1 458 days) (based on laboratory findings). The median duration of grade ≥2 hyperglycaemia was 10 days (95% CI: 8 to 13 days). In patients with grade ≥2 hyperglycaemia, median time to improvement (at least one grade from the first event) was 8 days (95% CI: 8 to 10 days). In 93.4% of patients who continued on fulvestrant after discontinuing Piqray, FPG levels returned to baseline (normal).

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

Rash

Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis and dermatitis acneiform) were reported in 154 (54.2%) patients. Rash was predominantly mild or moderate (grade 1 or 2) and responsive to therapy, and in some cases rash was accompanied by pruritus and dry skin. Grade 2 and 3 events were reported in 13.7% and 20.1% of patients, respectively, with a median time to first onset of 12 days (range: 2 days to 220 days).

Among patients who received prophylactic antirash treatment including antihistamines, rash was reported less frequently than in the overall population; 25.8% vs 54.2% for all grades, 11.2% vs 20.1% for grade 3, and 3.4% vs 4.2% for rash leading to the permanent discontinuation of Piqray. Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with Piqray.

Gastrointestinal toxicity (nausea, diarrhoea, vomiting)

Diarrhoea, nausea and vomiting were reported in 59.9%, 46.8% and 29.6% of the patients, respectively (see Table 7).

Grade 2 and 3 diarrhoea events were reported in 20.4% and 7.4% of patients, respectively, with a median time to onset of grade ≥2 diarrhoea of 54 days (range: 1 day to 1 731 days).

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with Piqray and resolved with appropriate intervention (see Table 4). Antiemetics (e.g. ondansetron) and antidiarrhoeal medicinal products (e.g. loperamide) were used in 29/153 (19.0%) and 111/170 (65.3%) patients, respectively, to manage symptoms.

Osteonecrosis of the jaw (ONJ)

ONJ was reported in 6.0% patients (17/284) in the Piqray plus fulvestrant arm. All patients experiencing ONJ were exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) or RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving Piqray and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded.

Special populations

Elderly

In patients ≥65 years of age treated with alpelisib plus fulvestrant, there was a higher incidence of grade 3‑4 hyperglycaemia (45.3%) compared to patients <65 years of age (34.7%), while in patients <75 years of age, grade 3‑4 hyperglycaemia was 36.8% compared to 55.9% in patients ≥75 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.