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 8) 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). (See Tables 8a and 8b.)
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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 Precautions.
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 8).
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 5). 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: The patient can report any suspected side effects associated with the use of health products to Novartis.
NOTE: Contact the health professional if information about how to manage side effects is needed.