PIQRAY

Indications and Usage ( 1 ) 1/2024 Dosage and Administration, Dose Modifications for Adverse Reactions ( 2.3 ) 1/2024 Warnings and Precautions, Hyperglycemia ( 5.3 ) 1/2024

1 INDICATIONS AND USAGE PIQRAY is indicated in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. PIQRAY is a kinase inhibitor indicated in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

2 DOSAGE AND ADMINISTRATION Recommended Dose: 300 mg (two 150 mg tablets) taken orally once daily with food. ( 2.2 ) For adverse reactions, consider dose interruption, dose reduction, or discontinuation. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with PIQRAY, based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens [see Clinical Studies (14)] . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Dosage and Administration The recommended dose of PIQRAY is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food [see Clinical Pharmacology (12.3)] . Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)] . Patients should take their dose of PIQRAY at approximately the same time each day. Swallow PIQRAY 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 PIQRAY 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 PIQRAY 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 PIQRAY, 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. 2.3 Dose Modifications for Adverse Reactions The recommended dose modifications for adverse reactions are listed in Table 1. Table 1: PIQRAY Dose Reduction Guidelines for Adverse Reactions 1 1 Only one dose reduction is permitted for pancreatitis. 2 If further dose reduction below 200 mg once daily is required, discontinue PIQRAY. PIQRAY dose level Dose and schedule Number and strength of tablets Starting dose 300 mg once daily Two 150 mg tablets First-dose reduction 250 mg once daily One 200 mg tablet and one 50 mg tablet Second-dose reduction 200 mg once daily 2 One 200 mg tablet Tables 2, 3, 4, and 5 summarize recommendations for dose interruption, reduction, or discontinuation of PIQRAY in the management of specific adverse reactions. Cutaneous Adverse Reactions If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous SCAR during PIQRAY treatment [see Warnings and Precautions (5.2)] . Table 2: Dose Modification and Management for Rash and Severe Cutaneous Adverse Reactions (SCARs) 1 Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2 For all grades of rash, consider consultation with a dermatologist. 3 Antihistamines administered prior to rash onset may decrease incidence and severity of rash based on the SOLAR-1 trial. [see Warnings and Precautions (5.1, 5.2)] Grade 1,2 Recommendation 3 Grade 1 ( 30% BSA with active skin toxicity) Interrupt PIQRAY. Initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment. If the etiology is SCAR, permanently discontinue PIQRAY. If the etiology is not a SCAR, interrupt dose until improvement to Grade ≤ 1, then resume PIQRAY at next lower dose level. Grade 4 (e.g., severe bullous, blistering or exfoliating skin conditions) (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences) Permanently discontinue PIQRAY. Hyperglycemia Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. Consider premedication with metformin prior to the init …

3 DOSAGE FORMS AND STRENGTHS Tablets: 50 mg, 150 mg, and 200 mg alpelisib 50 mg: Light pink, unscored, round and curved with beveled edges film-coated tablet, imprinted with “L7” on one side and “NVR” on the other side. 150 mg: Pale red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “UL7” on one side and “NVR” on the other side. 200 mg: Light red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “YL7” on one side and “NVR” on the other side. Tablets: 50 mg, 150 mg, and 200 mg

4 CONTRAINDICATIONS PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components [see Warnings and Precautions (5.1)] . Severe hypersensitivity to PIQRAY or to any of its components. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Severe Hypersensitivity [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Hyperglycemia [see Warnings and Precautions (5.3)] Pneumonitis [see Warnings and Precautions (5.4)] Diarrhea or Colitis [see Warnings and Precautions (5.5)] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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 PIQRAY 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 Clinical Studies (14)] . Patients received either PIQRAY 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 PIQRAY 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 PIQRAY plus fulvestrant. Serious adverse reactions in > 2% of patients receiving PIQRAY 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 PIQRAY 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 PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and fulvestrant and 21% permanently discontinued PIQRAY alone, due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%). Dose reductions due to adverse reactions occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent adverse reactions leading to dose reduction in > 2% patients receiving PIQRAY 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 liste …

7 DRUG INTERACTIONS CYP3A4 Inducers : Avoid coadministration of PIQRAY with a strong CYP3A4 inducer. Consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. ( 7.1 ) Breast Cancer Resistance Protein (BCRP) Inhibitors : Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions. ( 7.1 ) 7.1 Effect of Other Drugs on PIQRAY CYP3A4 Inducer Coadministration of PIQRAY with a strong CYP3A4 inducer decreases alpelisib concentration [see Clinical Pharmacology (12.3)] , which may reduce alpelisib efficacy. Avoid concomitant use of strong CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. Breast Cancer Resistance Protein Inhibitors Coadministration of PIQRAY with a breast cancer resistance protein (BCRP) inhibitor may increase alpelisib concentration [see Clinical Pharmacology (12.3)] , which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, when PIQRAY is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary PIQRAY 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, PIQRAY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . 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) . 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. 8.2 Lactation PIQRAY 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 PIQRAY and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential PIQRAY 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 PIQRAY. Contraception Females PIQRAY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment with PIQRAY 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 PIQRAY and for 1 week after the last dose. Infertility Based on findings from animal studies, PIQRAY may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use The safety and efficacy of PIQRAY in pediatric patients have not been established. 8.5 Geriatric Use Of 284 patients who receive …

12.1 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.

11 DESCRIPTION PIQRAY (alpelisib) is a kinase inhibitor. The chemical name of alpelisib is (2S)- N 1 -[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 C 19 H 22 F 3 N 5 O 2 S and the relative molecular mass is 441.47 g/mol. The chemical structure of alpelisib is shown below: PIQRAY film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 150 mg and 200 mg of alpelisib. 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. alpelisib structural formula

10 OVERDOSAGE There is limited experience of overdose with PIQRAY in clinical trials. In the clinical studies, PIQRAY was administered at doses up to 450 mg once daily. In cases where accidental overdosage of PIQRAY was reported in the clinical studies, the adverse reactions associated with the overdose were consistent with the known safety profile of PIQRAY 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 PIQRAY.

16 HOW SUPPLIED/STORAGE AND HANDLING PIQRAY (alpelisib) 50 mg, 150 mg, and 200 mg film-coated tablets [see Dosage Forms and Strengths (3)] . Daily dose Each carton contains Each blister pack contains NDC 300 mg daily dose 2 blister packs (56 tablets total) A 14-day supply of 28 tablets (28 tablets, 150 mg alpelisib per tablet) NDC 0078-0708-02 250 mg daily dose 2 blister packs (56 tablets total) A 14-day supply of 28 tablets (14 tablets, 200 mg alpelisib per tablet and 14 tablets, 50 mg alpelisib per tablet) NDC 0078-0715-02 200 mg daily dose 1 blister pack (28 tablets total) A 28-day supply of 28 tablets (28 tablets, 200 mg alpelisib per tablet) NDC 0078-0701-84 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].