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Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur 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].
Angioedema has been reported in the postmarketing setting in patients treated with TREZILENT [see Postmarketing Experience under Adverse Reactions].
Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue TREZILENT in the event of severe hypersensitivity.
Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (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 TREZILENT.
In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively [see Clinical Trials Experience under Adverse Reactions]. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with TREZILENT in the postmarketing setting [see Postmarketing Experience under Adverse Reactions].
If signs or symptoms of SCARs occur, interrupt TREZILENT until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If a SCAR is confirmed, permanently discontinue TREZILENT. Do not reintroduce TREZILENT in patients who have experienced previous severe cutaneous adverse reactions during TREZILENT treatment.
If a SCAR is not confirmed, TREZILENT may require dose modifications, topical corticosteroids, or oral antihistamine treatment as described in Table 3 [see Dose Modifications for Adverse Reactions under Dosage & Administration].
Advise patients of the signs and symptoms of SCARs (e.g., 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 TREZILENT. Fatal cases of ketoacidosis have occurred in the postmarketing setting.
Hyperglycemia was reported in 65% of patients treated with TREZILENT. Grade 3 (FPG > 250 to 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 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 [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 fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with TREZILENT, 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 with TREZILENT 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 [see Use in the Elderly as follows].
If a patient experiences hyperglycemia after initiating treatment with TREZILENT, 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 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 controlled Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified hyperglycemic 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 4 [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, can occur 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 or Colitis: Severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, can occur 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).
In clinical trials, 63% of patients who experienced diarrhea required anti-diarrheal medications (e.g., loperamide) to manage symptoms. Dose reductions of TREZILENT were required in 6% of patients and 2.8% of patients permanently discontinued TREZILENT due to diarrhea.
Colitis has been reported in the postmarketing setting in patients treated with TREZILENT [see Postmarketing Experience under Adverse Reactions].
Monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Based on the severity of the diarrhea or colitis, 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 anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking TREZILENT.
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, 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. However, in the SOLAR-1 trial, an increase in the hyperglycemia adverse reactions (74% vs 66%) and Grade 3-4 (56% vs 36%) hyperglycemia were observed in patients ≥ 75 years of age compared to patients < 75 years of age, respectively [see Hyperglycemia as previously mentioned].
