Trezilent

Alpelisib.

TREZILENT film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 150 mg and 200 mg of alpelisib.
TREZILENT (alpelisib) is a kinase inhibitor. The chemical name of alpelisib is (2S)-N¹-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide. Alpelisib is a white to almost white powder. The molecular formula for alpelisib is C₁₉H₂₂F₃N₅O₂S and the relative molecular mass is 441.47 g/mol.
The tablets also contain hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains hypromellose, iron oxide black, iron oxide red, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.

Pharmacology: Mechanism of Action: Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.
In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
Pharmacodynamics: Cardiac Electrophysiology: Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of alpelisib on the QTcF interval in patients with advanced cancer. An analysis of clinical ECG data demonstrates the absence of a large effect (i.e., > 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant.
Clinical Studies: SOLAR-1 (NCT02437318) was a randomized, double-blind, placebo-controlled trial of TREZILENT plus fulvestrant versus placebo plus fulvestrant in 572 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment (with or without CDK4/6 combination). Patients were excluded if they had inflammatory breast cancer, diabetes mellitus Type 1 or uncontrolled Type 2, or pneumonitis. Randomization was stratified by presence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s). Overall, 60% of enrolled patients had tumors with one or more PIK3CA mutations in tissue, 50% had liver/lung metastases, and 6% had previously been treated with a CDK4/6 inhibitor.
There were 341 patients enrolled by tumor tissue in the cohort with a PIK3CA mutation and 231 enrolled in the cohort without a PIK3CA mutation. Of the 341 patients in the cohort with a PIK3CA mutation, 336 (99%) patients had one or more PIK3CA mutations confirmed in tumor tissue using the FDA-approved therascreen PIK3CA RGQ PCR Kit. Out of the 336 patients with PIK3CA mutations confirmed in tumor tissue, 19 patients had no plasma specimen available for testing with the FDA-approved therascreen PIK3CA RGQ PCR Kit. Of the remaining 317 patients with PIK3CA mutations confirmed in tumor tissue, 177 patients (56%) had PIK3CA mutations identified in plasma specimen, and 140 patients (44%) did not have PIK3CA mutations identified in plasma specimen.
Patients received either TREZILENT (300 mg) or placebo orally once daily on a continuous basis, plus fulvestrant (500 mg) administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle. Patients received treatment until radiographic disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks for the first 18 months and every 12 weeks thereafter.
The median age of patients was 63 years (range, 25 to 92). Most patients were women (99.8%) and most patients were white (66%), followed by Asian (22%), Other/Unknown (10%), Black or African American (1.4%), and American Indian or Alaskan Native (0.9%). Baseline ECOG performance status was 0 (68%) or 1 (32%).
Patient demographics for those with PIK3CA-mutated tumors were generally representative of the broader study population. The median duration of exposure to TREZILENT plus fulvestrant was 8.2 months with 59% of patients exposed for > 6 months.
The majority of patients (98%) received prior hormonal therapy as the last treatment (48% metastatic setting, 52% adjuvant setting). Primary endocrine resistance, defined as relapsed within 24 months on adjuvant endocrine therapy or progression within 6 months on endocrine therapy for advanced disease, was observed in 13% of patients and secondary endocrine resistance, defined as relapsed after 24 months on adjuvant endocrine therapy, relapsed within 12 months of the end of adjuvant endocrine therapy, or progression after 6 months on endocrine therapy for advanced disease, was observed in 72% of patients.
The major efficacy outcome was investigator-assessed progression-free survival (PFS) in the cohort with a PIK3CA mutation per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were overall response rate (ORR) and overall survival (OS) in the cohort with a PIK3CA mutation.
Efficacy results for the cohort with a PIK3CA mutation in tumor tissue are presented in Table 1 and figure. PFS results for the cohort with a PIK3CA mutation by investigator assessment were supported by consistent results from a blinded independent review committee (BIRC) assessment. Consistent results were seen in patients with tissue or plasma PIK3CA mutations. At the time of final PFS analysis, 27% (92/341) of patients had died, and overall survival follow-up was immature.
No PFS benefit was observed in patients whose tumors did not have a PIK3CA tissue mutation (HR = 0.85; 95% CI: 0.58, 1.25). (See Table 1 and figure.)

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Pharmacokinetics: The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors. Steady-state alpelisib maximum plasma concentration (C_max) and AUC increased proportionally over the dose range of 30 mg to 450 mg (0.1 to 1.5 times the approved recommended dosage) under fed conditions. The mean accumulation of alpelisib is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 days following daily dosage. In adult patients who received TREZILENT 300 mg once daily in the SOLAR-1 trial, population approach derived mean steady-state alpelisib [coefficient of variation (CV%)] for C_max was 2480 (23%) ng/mL and AUC_0-24hr was 33224 (21%) ng*h/mL.
Absorption: The median time to reach peak plasma concentration (T_max) ranged between 2.0 to 4.0 hours.
Effect of food: A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and C_max by 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and C_max by 145% following a single dose of TREZILENT. No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.
Distribution: The mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 L (46%). Protein binding of alpelisib is 89% and is independent of concentration.
Elimination: The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (% CV) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.
Metabolism: Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to a lesser extent by CYP3A4, in vitro.
Excretion: Following a single oral dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.
Specific Populations: No clinically significant differences in the pharmacokinetics of alpelisib were predicted based on age (21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min based on the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of alpelisib is unknown.
Drug Interaction Studies: Clinical Studies: Acid Reducing Agents: TREZILENT can be coadministered with acid reducing agents, since TREZILENT should be taken with food. Food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH value.
Coadministration of the H₂ receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib decreased the absorption and overall exposure of alpelisib. In the presence of a low-fat low-calorie meal, AUC was decreased on average by 21% and C_max by 36% with ranitidine. Under the fasted state, AUC was decreased on average by 30% and C_max by 51% with ranitidine.
CYP3A4 Substrates: No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when coadministered with alpelisib.
In Vitro Studies: Effect of Alpelisib on CYP Enzymes: Alpelisib inhibits CYP3A4 in a time-dependent manner and induces CYP2B6, CYP2C9 and CYP3A4.
Effect of Transporter on Alpelisib: Alpelisib is a substrate of BCRP.
Effect of Alpelisib on Transporters: Alpelisib is an inhibitor of P-gp. Alpelisib has a low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with alpelisib.
Alpelisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, or aneugenic or clastogenic in human cell micronucleus and chromosome aberration tests in vitro. Alpelisib was not genotoxic in an in vivo rat micronucleus test.
Fertility studies in animals have not been conducted. In repeated-dose toxicity studies up to 13 weeks duration, adverse effects were observed in reproductive organs, including vaginal atrophy and estrous cycle variations in rats at doses ≥ 6 mg/kg/day (approximately 0.6 times the exposure in humans at the recommended dose of 300 mg/day based on AUC), and prostate atrophy in dogs at doses ≥ 15 mg/kg/day (approximately 2.6 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).

TREZILENT is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

Patient Selection: Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with TREZILENT, based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. If no mutation is detected in a plasma specimen, test tumor tissue.
Dosage and Administration: The recommended dose of TREZILENT is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food [see Pharmacology: Pharmacokinetics under Actions].
Continue treatment until disease progression or unacceptable toxicity occurs [see Dose Modifications for Adverse Reactions as follows].
Patients should take their dose of TREZILENT at approximately the same time each day.
Swallow TREZILENT tablets whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
If a dose of TREZILENT is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take TREZILENT at the usual time.
If the patient vomits after taking the dose, advise the patient not to take an additional dose on that day, and to resume the dosing schedule the next day at the usual time.
When given with TREZILENT, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant.
Dose Modifications for Adverse Reactions: The recommended dose modifications for adverse reactions (ARs) are listed in Table 2. (See Table 2.)

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Tables 3, 4, 5, and 6 summarize recommendations for dose interruption, reduction, or discontinuation of TREZILENT in the management of specific ARs.
Cutaneous Adverse Reactions: If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue TREZILENT. Do not reintroduce TREZILENT in patients who have experienced previous SCAR during TREZILENT treatment [see Severe Cutaneous Adverse Reactions under Precautions]. (See Table 3.)

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Hyperglycemia: 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. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Hyperglycemia under Precautions]. (See Table 4.)

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Diarrhea or Colitis: (See Table 5.)

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Other Toxicities: (See Table 6.)

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Refer to the Full Prescribing Information of fulvestrant for dose modification guidelines in the event of toxicity and for other relevant safety information.
Special populations: Renal impairment: Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild or moderate renal impairment. Caution should be used in patients with severe renal impairment as there is no experience with TREZILENT in this population.
Hepatic impairment: Based on a hepatic impairment study in non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild, moderate and severe hepatic impairment (Child-Pugh class A, B or C, respectively).
Refer to the product information of fulvestrant for dose modifications related to hepatic impairment.
Paediatric use: The safety and efficacy of TREZILENT in paediatric patients have not been established.
Use in the elderly: No dosage regimen adjustment is required in patients 65 years or above.

There is limited experience of overdose with TREZILENT in clinical trials. In the clinical studies, TREZILENT was administered at doses up to 450 mg once daily.
In cases where accidental overdosage of TREZILENT was reported in the clinical studies, the adverse reactions associated with the overdose were consistent with the known safety profile of TREZILENT and included hyperglycemia, nausea, asthenia, and rash.
Initiate general symptomatic and supportive measures in all cases of overdosage where necessary. There is no known antidote for TREZILENT.

TREZILENT is contraindicated in patients with severe hypersensitivity to it or any of its components [see Severe Hypersensitivity under Precautions].

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].

Pregnancy: Risk Summary: TREZILENT is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.
Based on animal data and mechanism of action, TREZILENT can cause fetal harm when administered to a pregnant woman [see Pharmacology: Mechanism of Action under Actions]. There are no available data in pregnant women to inform the drug-associated risk. 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 ≥ 0.8 times the exposure in humans based on AUC at the recommended dose of 300 mg/day (see Data as follows). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.
Data: Animal Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib up to 30 mg/kg/day during the period of organogenesis.
In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At a dose of 10 mg/kg/day (approximately 0.8 times the exposure in humans at the recommended dose of 300 mg/day based on AUC), toxicities included reduced fetal weight and increased incidences of skeletal malformations (bent scapula and thickened or bent long bones) and fetal variations (enlarged brain ventricle, decreased bone ossification).
In a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (post-implantation loss). Doses ≥ 15 mg/kg/day resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head. At 15 mg/kg/day in rabbits, the maternal exposure was approximately 5 times the exposure achieved at the recommended human dose of 300 mg/day based on AUC.
Lactation: TREZILENT is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.
There is no data on the presence of alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with TREZILENT and for 1 week after the last dose.
Females and Males of Reproductive Potential: TREZILENT is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.
Pregnancy Testing: Verify the pregnancy status in females of reproductive potential prior to initiating TREZILENT.
Contraception: Females: TREZILENT can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned]. Advise females of reproductive potential to use effective contraception during treatment with TREZILENT and for 1 week after the last dose.
Males: 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.
Infertility: Based on findings from animal studies, TREZILENT may impair fertility in males and females of reproductive potential [see Pharmacology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].

The following adverse reactions are discussed in greater detail in other sections of the labeling: Severe Hypersensitivity [see Severe Hypersensitivity under Precautions]; Severe Cutaneous Adverse Reactions [see Severe Cutaneous Adverse Reactions under Precautions]; Hyperglycemia [see Hyperglycemia under Precautions]; Pneumonitis [see Pneumonitis under Precautions]; Diarrhea or Colitis [see Diarrhea or Colitis under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TREZILENT was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Patients received either TREZILENT 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15 and then at Day 1 of each 28-day cycle during treatment phase.
Two patients (0.7%) died while on treatment with TREZILENT plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment.
Serious adverse reactions occurred in 35% of patients receiving TREZILENT plus fulvestrant. Serious adverse reactions in > 2% of patients receiving TREZILENT plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the TREZILENT plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK-ligand inhibitor administration.
Among patients receiving TREZILENT plus fulvestrant, 4.6% permanently discontinued both TREZILENT and fulvestrant and 21% permanently discontinued TREZILENT alone, due to ARs. The most frequent ARs leading to treatment discontinuation of TREZILENT in > 2% patients receiving TREZILENT plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
Dose reductions due to ARs occurred in 55% of patients receiving TREZILENT plus fulvestrant. The most frequent ARs leading to dose reduction in > 2% patients receiving TREZILENT plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%).
The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia.
Adverse reactions and laboratory abnormalities are listed in Table 7 and Table 8, respectively. (See Table 7.)

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Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days. A subgroup of 86 patients received prophylaxis, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of TREZILENT (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash. (See Table 8.)

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Postmarketing Experience: The following adverse reactions have been identified during post-approval use of TREZILENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: Colitis.
Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).
Skin and subcutaneous tissue disorders: Angioedema, Drug reaction with eosinophilia and systemic symptoms (DRESS).

Effect of Other Drugs on TREZILENT: CYP3A4 Inducer: Coadministration of TREZILENT with a strong CYP3A4 inducer may decrease alpelisib concentration [see Pharmacology: Pharmacokinetics under Actions], which may decrease alpelisib activity. Avoid coadministration of TREZILENT with strong CYP3A4 inducers.
Breast Cancer Resistance Protein Inhibitors: Coadministration of TREZILENT with a breast cancer resistance protein (BCRP) inhibitor may increase alpelisib concentration [see Pharmacology: Pharmacokinetics under Actions], which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with TREZILENT. If unable to use alternative drugs, when TREZILENT is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.
Effect of TREZILENT on Other Drugs: CYP2C9 Substrates: Coadministration of TREZILENT with CYP2C9 substrates (e.g., warfarin) may reduce plasma concentration of these drugs [see Pharmacology: Pharmacokinetics under Actions]. Closely monitor when TREZILENT is used in combination with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.

Targeted Cancer Therapy

L01EM03 - alpelisib ; Belongs to the class of phosphatidylinositol-3-kinase (Pi3K) inhibitors. Used in the treatment of cancer.

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