Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, were reported in patients treated with TREZILENT. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia.
The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7% [see Adverse Reactions].
Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue TREZILENT in the event of severe hypersensitivity.
Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson Syndrome (SJS) and Erythema Multiforme (EM) were reported in patients treated with TREZILENT [see Adverse Reactions].
SJS and EM were reported in 0.4% and 1.1% of patients, respectively. Do not initiate TREZILENT treatment in patients with a history of SJS, EM, or Toxic Epidermal Necrolysis (TEN).
If signs or symptoms of severe cutaneous reactions occur, interrupt TREZILENT until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If SJS, TEN, or EM is confirmed, permanently discontinue TREZILENT. Do not reintroduce TREZILENT in patients who have experienced previous severe cutaneous reactions during TREZILENT treatment.
If SJS, TEN, or EM is not confirmed, TREZILENT may require dose modifications, topical corticosteroids, or oral antihistamine treatment as described in Table 4 [see Dose Modifications for Adverse Reactions under Dosage & Administration].
Advise patients of the signs and symptoms of severe cutaneous reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash).
Hyperglycemia: Severe hyperglycemia, including ketoacidosis, has been reported in patients treated with TREZILENT. Hyperglycemia was reported in 65% of patients treated with TREZILENT. 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 TREZILENT.
Among the patients who experienced Grade ≥ 2 (FPG 160-250 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-diabetic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-diabetic medication [i.e., 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 TREZILENT (n = 54), 96% (n = 52) of patients had FPG levels that returned to baseline.
Before initiating treatment with TREZILENT, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with TREZILENT, monitor blood glucose and/or FPG 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.
If a patient experiences hyperglycemia after initiating treatment with TREZILENT, monitor blood glucose and/or FPG as clinically indicated, and at least twice weekly until blood glucose or FPG decreases to normal levels. During treatment with anti-diabetic medication, continue monitoring blood glucose or FPG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
The safety of TREZILENT 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 Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.
Based on the severity of the hyperglycemia, TREZILENT may require dose interruption, reduction, or discontinuation as described in Table 3 [see Dose Modifications for Adverse Reactions under Dosage & Administration].
Advise patients of the signs and symptoms of hyperglycemia (e.g., 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, has been reported in patients treated with TREZILENT.
Pneumonitis was reported in 1.8% of patients treated with TREZILENT.
In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt TREZILENT immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific 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 TREZILENT in all patients with confirmed pneumonitis.
Advise patients to immediately report new or worsening respiratory symptoms.
Diarrhea: Severe diarrhea, including dehydration and acute kidney injury, occurred in patients treated with TREZILENT. Most patients (58%) experienced diarrhea during treatment with TREZILENT. 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).
Dose reductions of TREZILENT were required in 6% of patients and 2.8% of patients permanently discontinued TREZILENT due to diarrhea. In the 164 patients that experienced diarrhea, anti-diarrheal medications (e.g., loperamide) were required to manage symptoms in 63% (104/164) of these patients.
Based on the severity of the diarrhea, TREZILENT may require dose interruption, reduction, or discontinuation as described in Table 5 [see Dose Modifications for Adverse Reactions under Dosage & Administration].
Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking TREZILENT.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, TREZILENT can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures based on area under the curve (AUC) that were ≥ 0.8 times the exposure in humans at the recommended dose of 300 mg/day. 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 TREZILENT 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 TREZILENT and for 1 week after the last dose [see Pregnancy, Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
Renal Impairment: The effect of severe renal impairment (CLcr < 30 mL/min) on alpelisib pharmacokinetics is unknown [see Pharmacology: Pharmacokinetics under Actions].
No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min).
Use in children: The safety and efficacy of TREZILENT in pediatric patients have not been established.
Use in the elderly: Of 284 patients who received TREZILENT in the SOLAR-1 trial, 117 patients were ≥ 65 years of age and 34 patients were ≥ 75 years of age. In patients treated with TREZILENT plus fulvestrant, there was a higher incidence of Grade 3-4 hyperglycemia in patients ≥ 65 years of age (44%) compared to patients < 65 years of age (32%). No overall differences in effectiveness of TREZILENT were observed between patients ≥ 65 years of age compared to younger patients. There are an insufficient number of patients ≥ 75 years of age to assess whether there are differences in safety or effectiveness.