Piqray Special Precautions

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 PIQRAY. 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 etiology 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 5 (see Dosage & Administration).
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.
Hyperglycaemia was reported in 64.8% of patients treated with PIQRAY in the phase III clinical study. Grade 2 (FPG 160 - 250 mg/dL), 3 (FPG >250 - 500 mg/dL) or 4 (FPG >500 mg/dL) hyperglycaemia were reported in 15.8%, 33.1% and 3.9% of patients, respectively, in phase III clinical study. Patients should be advised of the signs and symptoms of hyperglycaemia (e.g. excessive thirst, urinating more often than usual or higher amount of urine than usual, and increased appetite with weight loss).
In the phase III clinical study, 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%). There were no patients with type 1 diabetes mellitus based on reported medical history in the phase III clinical study. Among those pre-diabetic patients at baseline, 74.2% experienced hyperglycaemia (any Grade) when treated with PIQRAY. Among the patients who had Grade ≥2 (FPG 160 - 250 mg/dL) hyperglycaemia , the median time to first occurrence of Grade ≥2 (FPG >160 - 250 mg/dL) hyperglycaemia was 15 days (range: 5 days to 517 days) (based on laboratory findings). The median duration of Grade 2 (FPG >160 - 250 mg/dL) or higher hyperglycaemia (based on laboratory findings) was 10 days (95% CI: 8 to 13 days).
In the phase III clinical study, in patients with hyperglycaemia, 163/187 (87.2%) were managed with anti-diabetic medication and 142/187 (75.9%) reported use of metformin as single agent or in combination with other anti-diabetic medication. The maximum dose of metformin recommended in phase III clinical study was 2000 mg per day.
In patients with hyperglycaemia of at least Grade 2 (FPG 160 - 250 mg/dL), median time to improvement by at least 1 Grade of the first event was 8 days (95% CI of 8 to 10 days). In all patients with elevated FPG, who continued fulvestrant treatment after discontinuing PIQRAY, all FPG levels returned to baseline (normal).
In the phase III clinical study, patients with a history of diabetes mellitus intensified anti-diabetic medication(s) while on treatment with PIQRAY; therefore these patients require monitoring and possibly intensified anti-diabetic treatment. Patients with poor glycaemic control may be at a higher risk of developing severe hyperglycaemia and associated complications.
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. Based on the severity of the hyperglycaemia, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 4 (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 promptly report 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 radiologic exams 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, including dehydration and acute kidney injury, occurred in patients treated with PIQRAY. Most patients (58%) experienced diarrhoea during treatment with PIQRAY. Grade 3 diarrhoea occurred in 7% (n = 19) of patients. Among patients with Grade 2 or 3 diarrhoea (n = 71), the median time to onset was 46 days (range: 1 to 442 days).
Dose reductions of PIQRAY were required in 6% of patients and 2.8% of patients permanently discontinued PIQRAY due to diarrhoea. In the 164 patients that experienced diarrhoea, anti-diarrhoeal medications (e.g., loperamide) were required to manage symptoms in 63% (104/164) of these patients.
Based on the severity of the diarrhoea, PIQRAY may require dose interruption, reduction or discontinuation as described in Table 6 (see Dosage & Administration).
Advise patients to start antidiarrhoeal treatment, increase oral fluids and notify their healthcare provider if diarrhoea occurs while taking PIQRAY.
Use in hepatic impairment: See Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics under Action.
Use in renal impairment: See Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics under Action.
Effects on laboratory tests: Refer to Table 9.
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 during treatment with PIQRAY (see Adverse Reactions).
Use in Children: See Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics under Action.
Use in the Elderly: See Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics under Action.