Fulvestrant: Due to limited data in patients with prior fulvestrant use (n=39, study CBYL719X2101), efficacy is not considered established in this population (see Pharmacology: Pharmacodynamics under Actions).
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 Adverse Reactions). 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 Adverse Reactions).
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 4 (see Dosage & Administration).
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 7.
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). (See Table 7.)
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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 3 (see Dosage & Administration).
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 5 (see Dosage & Administration).
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'.
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 Adverse Reactions).