PIQRAY Film-coated tablet Ref.[108865] Active ingredients: Alpelisib

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).

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 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 (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 and physical activity).

Table 6. Schedule of fasting glucose monitoring:

^* 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, has 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. 59.5% 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 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’.

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, AUC_inf was decreased on average by 21% and C_max by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUC_inf and a 51% decrease in C_max 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 C_max 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 C_max 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 Piqray 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 Piqray however the results should be considered with caution due to limited data (see section 5.2).

In a drug-drug interaction study, coadministration 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.

In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin) with alpelisib increased S-warfarin exposure on average by 34% and 19% for AUC_inf and C_max respectively, compared to administration with S-warfarin alone, which indicates that alpesilib 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. 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.

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

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

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:

^* 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 (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) or RANKligand 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.

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 national reporting system listed in Appendix V.

Not applicable.