Severe Cutaneous Adverse Reactions (SCARs): SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with PIQRAY. In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of patients, respectively. DRESS was reported in patients in the postmarketing setting. If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If a SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous SCARs during PIQRAY treatment. If a SCAR is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment.
Advise patients of the signs and symptoms of SCARs (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).
Hyperglycemia: Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Fatal cases of ketoacidosis have occurred in the postmarketing setting.
Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG >250-500 mg/dL) and grade 4 (FPG >500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n=2) treated with PIQRAY.
Among the patients who experienced Grade ≥2 (FPG 160 to 250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range, 5 to 517 days).
In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-hyperglycemic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-hyperglycemic medication [ie, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas]. In patients with Grade ≥2 hyperglycemia with at least 1 grade improvement (n=153), median time to improvement from the first event was 8 days (range, 2 to 65 days).
In all patients with elevated FPG who continued fulvestrant treatment after discontinuing PIQRAY (n=54), 96% (n=52) of patients had FPG levels that returned to baseline.
Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. Monitor fasting glucose more frequently for the first few weeks during treatment in patients with risk factors for hyperglycemia such as obesity (BMI ≥30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥75.
If a patient experiences hyperglycemia after initiating treatment, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a health care practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
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 SOLAR-1 trial. Patients with a medical history of controlled type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes.
Consider premedication with metformin prior to the initiation of PIQRAY in combination with fulvestrant based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation. In the METALLICA study, use of metformin starting 7 days prior to the initiation of PIQRAY appeared to decrease the incidence and severity of hyperglycemia events, but increased the incidence and severity of nausea, vomiting, and diarrhea adverse reactions.
Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients of the signs and symptoms of hyperglycemia (eg, excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).
Pneumonitis: Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, can occur in patients treated with PIQRAY. Pneumonitis was reported in 1.8% of patients treated with PIQRAY.
In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.
Permanently discontinue PIQRAY in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.
Diarrhea or Colitis: Severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, can occur in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7% (n=19) of patients. Among patients with Grade 2 or 3 diarrhea (n=71), the median time to onset was 46 days (range, 1 to 442 days). In clinical trials, 63% of patients who experienced diarrhea required antidiarrheal medications (eg, loperamide) to manage symptoms. Dose reductions of PIQRAY were required in 6% of patients, and 2.8% of patients permanently discontinued PIQRAY due to diarrhea. Colitis has been reported in the postmarketing setting in patients treated with PIQRAY. Monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus, or blood in the stool. Based on the severity of the diarrhea or colitis, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their health care provider if diarrhea occurs while taking PIQRAY. For patients with colitis, additional treatment, such as enteric-acting and/or systemic steroids, may be required.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose. Refer to the full Prescribing Information of fulvestrant for pregnancy and contraception information.
The most common adverse reactions (all grades, incidence ≥20%) were diarrhea (58%), rash (52%), nausea (45%), fatigue (42%), decreased appetite (36%), stomatitis (30%), vomiting (27%), weight decreased (27%), and alopecia (20%). The most common grade 3/4 adverse reactions (incidence ≥2%) were rash (20%), diarrhea (7%), fatigue (5%), weight decreased (3.9%), nausea (2.5%), stomatitis (2.5%), and mucosal inflammation (2.1%).
The most common laboratory abnormalities (all grades, incidence ≥20%) were glucose increased (79%), creatinine increased (67%), lymphocyte count decreased (52%), gamma-glutamyl transferase (GGT) increased (52%), alanine aminotransferase (ALT) increased (44%), hemoglobin decreased (42%), lipase increased (42%), calcium decreased (27%), glucose decreased (26%), and activated partial thromboplastin time (aPTT) prolonged (21%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were glucose increased (39%), GGT increased (11%), lymphocyte count decreased (8%), lipase increased (7%), and potassium decreased (6%).
Please see full Prescribing Information.