ADVERSE REACTIONS SECTION.

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 [see Warnings and Precautions (5.5)] 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 [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 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 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 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 and 15, and then at Day 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 ARs. The most frequent ARs 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 ARs occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent ARs 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 listed in Table and Table 7, respectively.Table 6: Adverse Reactions Occurring in >= 10% and >= 2% Higher than Placebo Arm in SOLAR-1 (All Grades)Grading according to CTCAE Version 4.03. 1Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration. 2Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower. 3Fatigue: including fatigue, asthenia. 4Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness. 5Urinary tract infection: including UTI and single case of urosepsis. 6Dysgeusia: including dysgeusia, ageusia, hypogeusia. 7Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic. 8Dry skin: including dry skin, skin fissures, xerosis, xeroderma. No Grade adverse reactions were reported.PIQRAY plus fulvestrantN 284Placebo plus fulvestrantN 287Adverse reactionsAll GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal disorders Diarrhea587 160.3 Nausea452.5 220.3 Stomatitis1 302.5 60 Vomiting270.7 100.3 Abdominal pain2 171.4 111 Dyspepsia110 60 General disorders and administration site conditions Fatigue3 425 291 Mucosal inflammation192.1 10 Edema peripheral150 50.3 Pyrexia140.74.90.3 Mucosal dryness4 120.4 4.20 Infections and infestations Urinary tract infection5 100.7 51 Investigations Weight decreased273.9 2.10 Metabolism and nutrition disorders Decreased appetite360.7 100.3 Nervous system disorders Dysgeusia6 180.4 3.50 Headache180.7 130 Skin and subcutaneous tissue disorders Rash7 5220 70.3 Alopecia200 2.40 Pruritus180.7 60 Dry skin8 180.4 3.80 Among the patients with Grade or rash, the median time to first onset of Grade or rash was 12 days. 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 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.Table 7: Laboratory Abnormalities Occurring in >= 10% of Patients in SOLAR-11Glucose increase is an expected laboratory abnormality of PI3K inhibition.No Grade laboratory abnormalities were reported.PIQRAY plus fulvestrantN 284Placebo plus fulvestrantN 287Laboratory AbnormalityAll GradesGrade 3-4All GradesGrade 3-4%%%%Hematological parameters Lymphocyte count decreased528404.5 Hemoglobin decreased424.2 291 Activated Partial Thromboplastin Time (aPTT) prolonged210.7 160.3 Platelet count decreased141.160 Biochemical parameters Glucose increased1 7939341 Creatinine increased672.8 250.7 Gamma Glutamyl Transferase (GGT) increased52114410 Alanine Aminotransferase (ALT) increased443.5342.4 Lipase increased427256 Calcium (corrected) decreased272.1201.4 Glucose decreased260.4140 Potassium decreased1462.80.7 Albumin decreased140 80 Magnesium decreased110.4 4.20 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of PIQRAY. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).Skin and sub-cutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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 >= 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K. Gain-of-function mutations in the gene encoding the catalytic -subunit of PI3K (PIK3CA) lead to activation of PI3K 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 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.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologySerial ECGs were collected following 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 large effect (i.e., 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant. 12.3 Pharmacokinetics. The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors. Steady-state alpelisib maximum plasma concentration (Cmax) 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 days following daily dosage. In adult patients who received PIQRAY 300 mg once daily in the SOLAR-1 trial, population approach derived mean steady-state alpelisib [coefficient of variation (CV%)] for Cmax was 2480 (23%) ng/mL and AUC0-24hr was 33224 (21%) ngh/mL.AbsorptionThe median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.Effect of foodA high-fat high-calorie meal (985 calories with 58.1 of fat) increased alpelisib AUC by 73% and Cmax by 84%, and low-fat low-calorie meal (334 calories with 8.7 of fat) increased alpelisib AUC by 77% and Cmax by 145% following single dose of PIQRAY. No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.DistributionThe mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 (46%). Protein binding of alpelisib is 89% and is independent of concentration. EliminationThe half-life of alpelisib is predicted to be to hours. The mean (% CV) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.MetabolismAlpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to lesser extent by CYP3A4, in vitro. ExcretionFollowing 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 PopulationsNo 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 StudiesClinical StudiesAcid Reducing Agents: PIQRAY can be coadministered with acid reducing agents, since PIQRAY should be taken with food. Food exhibited 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 single 300 mg oral dose of alpelisib decreased the absorption and overall exposure of alpelisib. In the presence of low-fat low-calorie meal, AUC was decreased on average by 21% and Cmax by 36% with ranitidine. Under the fasted state, AUC was decreased on average by 30% and Cmax 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 StudiesEffect of Alpelisib on CYP Enzymes: Alpelisib inhibits CYP3A4 in time-dependent manner and induces CYP2B6, CYP2C9 and CYP3A4.Effect of Transporter on Alpelisib: Alpelisib is substrate of BCRP.Effect of Alpelisib on Transporters: Alpelisib is an inhibitor of P-gp. Alpelisib has low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. SOLAR-1 (NCT02437318) was randomized, double-blind, placebo-controlled trial of PIQRAY 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 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 CDK4/6 inhibitor.There were 341 patients enrolled by tumor tissue in the cohort with PIK3CA mutation and 231 enrolled in the cohort without PIK3CA mutation. Of the 341 patients in the cohort with PIK3CA mutation, 336 (99%) patients had one or more PIK3CA mutations confirmed in tumor tissue using the FDA-approved therascreen(R) 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(R) 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 PIQRAY (300 mg) or placebo orally once daily on continuous basis, plus fulvestrant (500 mg) administered intramuscularly on Cycle 1, Days and 15, and then on Day of every 28-day cycle. Patients received treatment until radiographic disease progression or unacceptable toxicity. Tumor assessments were performed every 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 (68%) or (32%).Patient demographics for those with PIK3CA-mutated tumors were generally representative of the broader study population. The median duration of exposure to PIQRAY 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 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 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 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 PIK3CA mutation.Efficacy results for the cohort with PIK3CA mutation in tumor tissue are presented in Table and Figure 1. PFS results for the cohort with PIK3CA mutation by investigator assessment were supported by consistent results from 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 PIK3CA tissue mutation (HR 0.85; 95% CI: 0.58, 1.25).Table 8: Efficacy Results in SOLAR-1 (Per Investigator Assessment of Patients with PIK3CA Tumor Mutation)1Both log-rank test and Cox proportional hazards model are stratified by prior CDK4/6 inhibitor usage and presence of lung/liver metastases. P-value was compared to prespecified Haybittle-Peto stopping boundary (two-sided <= 0.0398). 2ORR percentage of patients with confirmed Complete Response or Partial Response with measurable disease at baselinePIQRAY plus fulvestrantPlacebo plus fulvestrantProgression-free survivalN 169N 172 Number of PFS events n (%)103 (61)129 (75) Median PFS months (95% CI)11.0 (7.5, 14.5)5.7 (3.7, 7.4) Hazard ratio (95% CI)0.65 (0.50, 0.85) p-value1 0.0013Overall Response RateN 126N 136 ORR2 (95% CI)35.7 (27.4, 44.7)16.2 (10.4, 23.5)Figure 1: Progression Free Survival in SOLAR-1 (Per Investigator Assessment of Patients with PIK3CA Tumor Mutation). Figure 1: Progression Free Survival in SOLAR-1 (Per Investigator Assessment of Patients with PIK3CA Tumor Mutation).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 and 15, and then at Day 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 ARs. The most frequent ARs 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 ARs occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent ARs 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 listed in Table and Table 7, respectively.Table 6: Adverse Reactions Occurring in >= 10% and >= 2% Higher than Placebo Arm in SOLAR-1 (All Grades)Grading according to CTCAE Version 4.03. 1Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration. 2Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower. 3Fatigue: including fatigue, asthenia. 4Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness. 5Urinary tract infection: including UTI and single case of urosepsis. 6Dysgeusia: including dysgeusia, ageusia, hypogeusia. 7Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic. 8Dry skin: including dry skin, skin fissures, xerosis, xeroderma. No Grade adverse reactions were reported.PIQRAY plus fulvestrantN 284Placebo plus fulvestrantN 287Adverse reactionsAll GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal disorders Diarrhea587 160.3 Nausea452.5 220.3 Stomatitis1 302.5 60 Vomiting270.7 100.3 Abdominal pain2 171.4 111 Dyspepsia110 60 General disorders and administration site conditions Fatigue3 425 291 Mucosal inflammation192.1 10 Edema peripheral150 50.3 Pyrexia140.74.90.3 Mucosal dryness4 120.4 4.20 Infections and infestations Urinary tract infection5 100.7 51 Investigations Weight decreased273.9 2.10 Metabolism and nutrition disorders Decreased appetite360.7 100.3 Nervous system disorders Dysgeusia6 180.4 3.50 Headache180.7 130 Skin and subcutaneous tissue disorders Rash7 5220 70.3 Alopecia200 2.40 Pruritus180.7 60 Dry skin8 180.4 3.80 Among the patients with Grade or rash, the median time to first onset of Grade or rash was 12 days. 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 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.Table 7: Laboratory Abnormalities Occurring in >= 10% of Patients in SOLAR-11Glucose increase is an expected laboratory abnormality of PI3K inhibition.No Grade laboratory abnormalities were reported.PIQRAY plus fulvestrantN 284Placebo plus fulvestrantN 287Laboratory AbnormalityAll GradesGrade 3-4All GradesGrade 3-4%%%%Hematological parameters Lymphocyte count decreased528404.5 Hemoglobin decreased424.2 291 Activated Partial Thromboplastin Time (aPTT) prolonged210.7 160.3 Platelet count decreased141.160 Biochemical parameters Glucose increased1 7939341 Creatinine increased672.8 250.7 Gamma Glutamyl Transferase (GGT) increased52114410 Alanine Aminotransferase (ALT) increased443.5342.4 Lipase increased427256 Calcium (corrected) decreased272.1201.4 Glucose decreased260.4140 Potassium decreased1462.80.7 Albumin decreased140 80 Magnesium decreased110.4 4.20.

CONTRAINDICATIONS SECTION.

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).

DESCRIPTION SECTION.

11 DESCRIPTION. PIQRAY (alpelisib) is 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 white to almost white powder. The molecular formula for alpelisib is C19H22F3N5O2S 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.

DOSAGE & ADMINISTRATION SECTION.

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). 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 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 dose of PIQRAY is missed, it can be taken with food within hours after the time it is usually taken. After more than 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 (ARs) are listed in Table 1. Table 1: PIQRAY Dose Reduction Guidelines for Adverse Reactions1 1Only one dose reduction is permitted for pancreatitis.2If further dose reduction below 200 mg once daily is required, discontinue PIQRAY.PIQRAY Dose LevelDose and ScheduleNumber and Strength of TabletsStarting dose300 mg once dailyTwo 150 mg tabletsFirst-dose reduction250 mg once dailyOne 200 mg tablet and one 50 mg tabletSecond-dose reduction200 mg once daily2 One 200 mg tabletTables 2, 3, 4, and summarize recommendations for dose interruption, reduction, or discontinuation of PIQRAY in the management of specific ARs.Cutaneous Adverse ReactionsIf 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)1Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.2For all grades of rash, consider consultation with dermatologist.3Antihistamines 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)]Grade1,2 Recommendation3 Grade 1(< 10% body surface area (BSA) with active skin toxicity)No PIQRAY dose adjustment required.Initiate topical corticosteroid treatment.Consider adding oral antihistamine to manage symptoms.If active rash is not improved within 28 days of appropriate treatment, add low dose systemic corticosteroid.If the etiology is SCAR, permanently discontinue PIQRAY.Grade 2(10%-30% BSA with active skin toxicity)No PIQRAY dose adjustment required.Initiate or intensify topical corticosteroid and oral antihistamine treatment.Consider low dose systemic corticosteroid treatment.If rash improves to Grade <= within 10 days, systemic corticosteroid may be discontinued.If the etiology is SCAR, permanently discontinue PIQRAY.Grade (e.g., severe rash not responsive to medical management)(> 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 SCAR, interrupt dose until improvement to Grade <= 1, then resume PIQRAY at next lower dose level.Grade (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.HyperglycemiaBefore initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first weeks, then at least once every weeks, and as clinically indicated. Monitor HbA1c every months and as clinically indicated. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Warnings and Precautions (5.3)].Table 3: Dose Modification and Management for HyperglycemiaAbbreviation: ULN, upper limit of normal. 1FPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2Initiate applicable anti-hyperglycemic medications, including metformin, SGLT2 inhibitors or insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500 mg once daily. Based on tolerability, metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1,000 mg with dinner, followed by further increase to 1,000 mg twice daily if needed [see Warnings and Precautions (5.3)]. 3As recommended in the SOLAR-1 trial, insulin may be used for 1-2 days until hyperglycemia resolves. However, this may not be necessary in the majority of PIQRAY-induced hyperglycemia, given the short half-life of PIQRAY and the expectation of glucose levels normalizing after interruption of PIQRAY.[see Warnings and Precautions (5.3)]Fasting Plasma Glucose (FPG)/Fasting Blood Glucose Values1 RecommendationDose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose).Grade 1Fasting glucose ULN -160 mg/dL or ULN -8.9 mmol/LNo PIQRAY dose adjustment required.Initiate or intensify anti-hyperglycemic treatment2.Grade 2Fasting glucose 160-250 mg/dL or 8.9-13.9 mmol/LNo PIQRAY dose adjustment required.Initiate or intensify anti-hyperglycemic treatment2.If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatment2,3, reduce PIQRAY dose by dose level and follow fasting glucose value specific recommendations.Grade 3> 250-500 mg/dL or 13.9-27.8 mmol/LInterrupt PIQRAY.Initiate or intensify oral anti-hyperglycemic treatment2 and consider additional anti-hyperglycemic medications3 for 1-2 days until hyperglycemia improves, as clinically indicated.Administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances).If fasting glucose decreases to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, resume PIQRAY at lower dose level.If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, consultation with physician with expertise in the treatment of hyperglycemia is recommended.If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days following appropriate anti-hyperglycemic treatment2,3, permanently discontinue PIQRAY treatment.Grade 4> 500 mg/dL or >= 27.8 mmol/LInterrupt PIQRAY.Initiate or intensify appropriate anti-hyperglycemic treatment2,3 (administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances)), re-check fasting glucose within 24 hours and as clinically indicated.If fasting glucose decreases to <= 500 mg/dL or 27.8 mmol/L, follow fasting glucose value-specific recommendations for Grade 3.If fasting glucose is confirmed at 500 mg/dL or 27.8 mmol/L, permanently discontinue PIQRAY treatment.DiarrheaTable 4: Dose Modification and Management for Diarrhea1Grading according to CTCAE Version 5.0.[see Warnings and Precautions (5.5)]Grade1 RecommendationGrade 1No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.Grade 2Interrupt PIQRAY dose until improvement to Grade <= 1, then resume PIQRAY at the same dose level.If diarrhea recurs at Grade >= 2, interrupt PIQRAY dose until improvement to Grade <= 1, then resume PIQRAY at the next lower dose level.Initiate or intensify appropriate medical therapy and monitor as clinically indicated.Grade 3Interrupt PIQRAY dose until improvement to Grade <= 1, then resume PIQRAY at the next lower dose level.Initiate or intensify appropriate medical therapy and monitor as clinically indicated.Grade 4Permanently discontinue PIQRAY.Other ToxicitiesTable 5: Dose Modification and Management for Other Toxicities (Excluding Hyperglycemia, Rash and Severe Cutaneous Adverse Reactions, and Diarrhea)1Grading according to CTCAE Version 5.0.2For Grade and pancreatitis, interrupt PIQRAY dose until improvement to Grade 2 and resume at next lower-dose level. Only one dose reduction is permitted. If toxicity reoccurs, permanently discontinue PIQRAY treatment. 3For Grade total bilirubin elevation, interrupt PIQRAY dose until improvement to Grade <= and resume at the same dose if resolved in <= 14 days or resume at the next lower dose level if improved in 14 days.Grade1 RecommendationGrade or 2No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated2,3.Grade 3Interrupt PIQRAY dose until improvement to Grade <= 1, then resume PIQRAY at the next lower dose level.Grade 4Permanently discontinue PIQRAY.Refer to the Full Prescribing Information of fulvestrant for dose modification guidelines in the event of toxicity and for other relevant safety information.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 50 mg, 150 mg, and 200 mg alpelisib50 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A4 Inducers: Avoid coadministration of PIQRAY with strong CYP3A4 inducer. (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)CYP2C9 Substrates: Closely monitor when PIQRAY is coadministered with CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce activity. (7.2). CYP3A4 Inducers: Avoid coadministration of PIQRAY with strong CYP3A4 inducer. (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). CYP2C9 Substrates: Closely monitor when PIQRAY is coadministered with CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce activity. (7.2). 7.1 Effect of Other Drugs on PIQRAY. CYP3A4 InducerCoadministration of PIQRAY with strong CYP3A4 inducer may decrease alpelisib concentration [see Clinical Pharmacology (12.3)], which may decrease alpelisib activity. Avoid coadministration of PIQRAY with strong CYP3A4 inducers.Breast Cancer Resistance Protein InhibitorsCoadministration of PIQRAY with 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.. 7.2 Effect of PIQRAY on Other Drugs. CYP2C9 SubstratesCoadministration of PIQRAY with CYP2C9 substrates (e.g., warfarin) may reduce plasma concentration of these drugs [see Clinical Pharmacology (12.3)]. Closely monitor when PIQRAY is used in combination with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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 TestingVerify the pregnancy status in females of reproductive potential prior to initiating PIQRAY.ContraceptionFemalesPIQRAY can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for week after the last dose.MalesAdvise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for week after the last dose. InfertilityBased on findings from animal studies, PIQRAY may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 284 patients who received PIQRAY in the SOLAR-1 trial, 117 patients were >= 65 years of age and 34 patients were >= 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was 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 PIQRAY 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 Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

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 DoseEach carton containsEach blister pack containsNDC300 mg daily dose2 blister packs (56 tablets total)A 14-day supply of 28 tablets (28 tablets, 150 mg alpelisib per tablet)NDC 0078-0708-02250 mg daily dose2 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 0078-0715-02200 mg daily dose1 blister pack (28 tablets total)A 28-day supply of 28 tablets (28 tablets, 200 mg alpelisib per tablet)NDC 0078-0701-84Store at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PIQRAY is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (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 kinase inhibitor indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor (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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Severe HypersensitivityInform patients of the signs and symptoms of hypersensitivity. Advise patients to contact their healthcare provider immediately for signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)].Severe Cutaneous Adverse ReactionsInform patients of the signs and symptoms of severe cutaneous adverse reactions (SCARs). Advise patients to contact their healthcare provider immediately for signs and symptoms of SCARs [see Warnings and Precautions (5.2)].HyperglycemiaAdvise patients of the possibility of developing hyperglycemia and the need to monitor fasting blood glucose periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia [see Warnings and Precautions (5.3)].PneumonitisInform patients of the possibility of developing pneumonitis and to immediately contact their healthcare provider if they experience respiratory problems [see Warnings and Precautions (5.4)].DiarrheaAdvise patients that PIQRAY may cause diarrhea, which may be severe in some cases. Inform patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY [see Warnings and Precautions (5.5)].Embryo-Fetal ToxicityInform pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for week after the last dose [see Use in Specific Populations (8.3)].Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for week after the last dose [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.LactationAdvise women not to breastfeed during treatment with PIQRAY and for week after the last dose [see Use in Specific Populations (8.2)]. Refer to the Full Prescribing Information of fulvestrant for lactation information.InfertilityAdvise males and females of reproductive potential that PIQRAY may impair fertility [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of fulvestrant for infertility information.Drug InteractionsAdvise patients to avoid the use of strong CYP3A4 inducers in patients treated with PIQRAY. Advise patients to avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions. Advise patients that close monitoring may be required when PIQRAY is coadministered with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs [see Drug Interactions (7.1, 7.2)].DosingInstruct patients to take PIQRAY at approximately the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split prior to swallowing) [see Dosage and Administration (2.2)].Advise patients to take PIQRAY with food [see Clinical Pharmacology (12.3)].Instruct patients that if dose of PIQRAY is missed, it can be taken with food within hours after the time it is usually taken. After more than hours, skip the dose for that day. The next day, take PIQRAY at the usual time. Instruct patients not to take doses to make up for missed dose.Instruct patients that if they vomit after taking the dose of PIQRAY, they should not take an additional dose on that day, and to resume the usual dosing schedule the next day at the usual time [see Dosage and Administration (2.2)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2021-104. Inform pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for week after the last dose [see Use in Specific Populations (8.3)].. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for week after the last dose [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.. Instruct patients to take PIQRAY at approximately the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split prior to swallowing) [see Dosage and Administration (2.2)].. Advise patients to take PIQRAY with food [see Clinical Pharmacology (12.3)].. Instruct patients that if dose of PIQRAY is missed, it can be taken with food within hours after the time it is usually taken. After more than hours, skip the dose for that day. The next day, take PIQRAY at the usual time. Instruct patients not to take doses to make up for missed dose.. Instruct patients that if they vomit after taking the dose of PIQRAY, they should not take an additional dose on that day, and to resume the usual dosing schedule the next day at the usual time [see Dosage and Administration (2.2)].

LACTATION SECTION.

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 week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K. Gain-of-function mutations in the gene encoding the catalytic -subunit of PI3K (PIK3CA) lead to activation of PI3K 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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 >= 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).

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0078-0708-02PIQRAY(R) (alpelisib) tablets300 mg daily doseTake two 150 mg tablets once dailyRx onlyUsual Dosage: Take two 150 mg tablets once daily with food.Swallow tablets whole. DO NOT chew, crush, or split tablets.See prescribing information for complete dosage information.28-Day SupplyContains: Two 14-day blister packs each containing 28 tabletsNOVARTIS. PRINCIPAL DISPLAY PANELNDC 0078-0708-02PIQRAY(R)(alpelisib) tablets300 mg daily doseTake two 150 mg tablets once dailyRx onlyUsual Dosage: Take two 150 mg tablets once daily with food.Swallow tablets whole. DO NOT chew,crush, or split tablets.See prescribing information for complete dosage information.28-Day SupplyContains: Two 14-day blister packs each containing 28 tabletsNOVARTIS.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of PIQRAY in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologySerial ECGs were collected following 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 large effect (i.e., 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors. Steady-state alpelisib maximum plasma concentration (Cmax) 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 days following daily dosage. In adult patients who received PIQRAY 300 mg once daily in the SOLAR-1 trial, population approach derived mean steady-state alpelisib [coefficient of variation (CV%)] for Cmax was 2480 (23%) ng/mL and AUC0-24hr was 33224 (21%) ngh/mL.AbsorptionThe median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.Effect of foodA high-fat high-calorie meal (985 calories with 58.1 of fat) increased alpelisib AUC by 73% and Cmax by 84%, and low-fat low-calorie meal (334 calories with 8.7 of fat) increased alpelisib AUC by 77% and Cmax by 145% following single dose of PIQRAY. No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.DistributionThe mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 (46%). Protein binding of alpelisib is 89% and is independent of concentration. EliminationThe half-life of alpelisib is predicted to be to hours. The mean (% CV) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.MetabolismAlpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to lesser extent by CYP3A4, in vitro. ExcretionFollowing 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 PopulationsNo 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 StudiesClinical StudiesAcid Reducing Agents: PIQRAY can be coadministered with acid reducing agents, since PIQRAY should be taken with food. Food exhibited 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 single 300 mg oral dose of alpelisib decreased the absorption and overall exposure of alpelisib. In the presence of low-fat low-calorie meal, AUC was decreased on average by 21% and Cmax by 36% with ranitidine. Under the fasted state, AUC was decreased on average by 30% and Cmax 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 StudiesEffect of Alpelisib on CYP Enzymes: Alpelisib inhibits CYP3A4 in time-dependent manner and induces CYP2B6, CYP2C9 and CYP3A4.Effect of Transporter on Alpelisib: Alpelisib is substrate of BCRP.Effect of Alpelisib on Transporters: Alpelisib is an inhibitor of P-gp. Alpelisib has low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations.

POSTMARKETING EXPERIENCE SECTION.

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

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPIQRAY 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 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 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.DataAnimal DataIn 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 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At 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 pilot embryo-fetal development study in rabbits, 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 times the exposure achieved at the recommended human dose of 300 mg/day based on AUC.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Dose Modifications for Adverse Reactions (2.3)7/2021Warnings and Precautions, Severe Cutaneous Adverse Reactions (5.2)9/2020Warnings and Precautions, Hyperglycemia (5.3)7/2021.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of severe renal impairment (CLcr 30 mL/min) on alpelisib pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to 90 mL/min).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: July 2021PATIENT INFORMATIONPIQRAY(R) (pik raye)(alpelisib)tabletsWhat is PIQRAYPIQRAY is prescription medicine used in combination with the medicine fulvestrant to treat women who have gone through menopause and men:who have hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced breast cancer or breast cancer that has spread to other parts of the body (metastatic), with an abnormal phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA) gene, and whose disease has progressed on or after endocrine therapy.Your healthcare provider will test your cancer for an abnormal PIK3CA gene to make sure that PIQRAY is right for you.It is not known if PIQRAY is safe and effective in children.Do not take PIQRAY if you have had severe allergic reaction to PIQRAY or are allergic to any of the ingredients in PIQRAY. See the end of this Patient Information leaflet for complete list of the ingredients in PIQRAY.See What are the possible side effects of PIQRAY for signs and symptoms of severe allergic reactions. Before you take PIQRAY, tell your healthcare provider about all of your medical conditions, including if you:have history of diabeteshave history of skin rash, redness of skin, blistering of the lips, eyes or mouth, or skin peelingare pregnant or plan to become pregnant. PIQRAY can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with PIQRAY.You should use effective birth control during treatment with PIQRAY and for week after the last dose. Talk to your healthcare provider about birth control methods that may be right for you during this time.If you become pregnant or think you are pregnant, tell your healthcare provider right away. Males with female partners who are able to become pregnant should use condoms and effective birth control during treatment with PIQRAY and for week after the last dose. If your female partner becomes pregnant, tell your healthcare provider right away.You should also read the Full Prescribing Information of fulvestrant for important pregnancy, contraception, and infertility information. are breastfeeding or plan to breastfeed. It is not known if PIQRAY passes into your breast milk. Do not breastfeed during treatment with PIQRAY and for week after the last dose. You should also read the Full Prescribing Information of fulvestrant for important lactation information.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PIQRAY and other medicines may affect each other causing side effects. Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How should take PIQRAYTake PIQRAY exactly as your healthcare provider tells you.Do not change your dose or stop taking PIQRAY unless your healthcare provider tells you.Take PIQRAY time each day, at about the same time each day.Take PIQRAY with food.Swallow PIQRAY tablets whole. Do not chew, crush or split the tablets.Do not take any PIQRAY tablets that are broken, cracked, or that look damaged.If you miss dose of PIQRAY, you may still take it with food up to hours after the time you usually take it. If it has been more than hours after you usually take your dose, skip the dose for that day. The next day, take the dose at your usual time. Do not take doses to make up for missed dose.If you vomit after taking dose of PIQRAY, do not take another dose on that day. Take your next dose at your usual time.If you take too much PIQRAY, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of PIQRAYPIQRAY may cause serious side effects, including:Severe allergic reactions. Tell your healthcare provider or get medical help right away if you have trouble breathing, flushing, rash, fever, or fast heart rate during treatment with PIQRAY.Severe skin reactions. Tell your healthcare provider or get medical help right away if you get severe rash or rash that keeps getting worse, reddened skin, flu-like symptoms, blistering of the lips, eyes or mouth, blisters on the skin or skin peeling, with or without fever.High blood sugar levels (hyperglycemia). Hyperglycemia is common with PIQRAY and its complications can be severe. Your healthcare provider will monitor your blood sugar levels before you start and during treatment with PIQRAY. Your healthcare provider may monitor your blood sugar levels more often if you have history of Type diabetes. Tell your healthcare provider right away if you develop symptoms of hyperglycemia and its complications, including: excessive thirst dry mouth more frequent urination than usual or higher amount of urine than normal increased appetite with weight loss confusion nausea vomiting fruity odor on breath difficulty breathing dry or flushed skinLung problems (pneumonitis). Tell your healthcare provider right away if you develop new or worsening symptoms of lung problems, including: shortness of breath or trouble breathing cough chest painDiarrhea. Diarrhea is common with PIQRAY and can be severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney problems. If you develop diarrhea during treatment with PIQRAY, tell your healthcare provider right away. Your healthcare provider may tell you to drink more fluids or take medicines to treat diarrhea. Your healthcare provider may tell you to decrease your dose, temporarily stop your treatment, or completely stop your treatment with PIQRAY if you get certain serious side effects.The most common side effects of PIQRAY when used with fulvestrant include: rash nausea tiredness and weakness decreased appetite mouth sores vomiting weight loss hair loss changes in certain blood testsPIQRAY may affect fertility in males and in females who are able to become pregnant. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of PIQRAY.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PIQRAYStore PIQRAY at room temperature between 68F to 77F (20C to 25C). Keep PIQRAY and all medicines out of the reach of children. General information about the safe and effective use of PIQRAY.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use PIQRAY for condition for which it was not prescribed. Do not give PIQRAY to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about PIQRAY that is written for health professionals.What are the ingredients in PIQRAYActive ingredient: alpelisib Inactive ingredients: 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. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936(C) NovartisFor more information, go to www.PIQRAY.com or call 1-833-4-PIQRAY (1-833-474-7729).T2021-105. who have hormone receptor (HR)-positive, human epidermal growth factor receptor (HER2)-negative advanced breast cancer or breast cancer that has spread to other parts of the body (metastatic), with an abnormal phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA) gene, and whose disease has progressed on or after endocrine therapy.. See the end of this Patient Information leaflet for complete list of the ingredients in PIQRAY.. See What are the possible side effects of PIQRAY for signs and symptoms of severe allergic reactions.. have history of diabetes. have history of skin rash, redness of skin, blistering of the lips, eyes or mouth, or skin peeling. are pregnant or plan to become pregnant. PIQRAY can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with PIQRAY.You should use effective birth control during treatment with PIQRAY and for week after the last dose. Talk to your healthcare provider about birth control methods that may be right for you during this time.If you become pregnant or think you are pregnant, tell your healthcare provider right away. Males with female partners who are able to become pregnant should use condoms and effective birth control during treatment with PIQRAY and for week after the last dose. If your female partner becomes pregnant, tell your healthcare provider right away.You should also read the Full Prescribing Information of fulvestrant for important pregnancy, contraception, and infertility information. Your healthcare provider will check to see if you are pregnant before you start treatment with PIQRAY.. You should use effective birth control during treatment with PIQRAY and for week after the last dose. Talk to your healthcare provider about birth control methods that may be right for you during this time.. If you become pregnant or think you are pregnant, tell your healthcare provider right away.. are breastfeeding or plan to breastfeed. It is not known if PIQRAY passes into your breast milk. Do not breastfeed during treatment with PIQRAY and for week after the last dose. You should also read the Full Prescribing Information of fulvestrant for important lactation information.. Take PIQRAY exactly as your healthcare provider tells you.. Do not change your dose or stop taking PIQRAY unless your healthcare provider tells you.. Take PIQRAY time each day, at about the same time each day.. Take PIQRAY with food.. Swallow PIQRAY tablets whole. Do not chew, crush or split the tablets.. Do not take any PIQRAY tablets that are broken, cracked, or that look damaged.. If you miss dose of PIQRAY, you may still take it with food up to hours after the time you usually take it. If it has been more than hours after you usually take your dose, skip the dose for that day. The next day, take the dose at your usual time. Do not take doses to make up for missed dose.. If you vomit after taking dose of PIQRAY, do not take another dose on that day. Take your next dose at your usual time.. If you take too much PIQRAY, call your healthcare provider or go to the nearest hospital emergency room right away.. Severe allergic reactions. Tell your healthcare provider or get medical help right away if you have trouble breathing, flushing, rash, fever, or fast heart rate during treatment with PIQRAY.. Severe skin reactions. Tell your healthcare provider or get medical help right away if you get severe rash or rash that keeps getting worse, reddened skin, flu-like symptoms, blistering of the lips, eyes or mouth, blisters on the skin or skin peeling, with or without fever.. High blood sugar levels (hyperglycemia). Hyperglycemia is common with PIQRAY and its complications can be severe. Your healthcare provider will monitor your blood sugar levels before you start and during treatment with PIQRAY. Your healthcare provider may monitor your blood sugar levels more often if you have history of Type diabetes. Tell your healthcare provider right away if you develop symptoms of hyperglycemia and its complications, including:. Lung problems (pneumonitis). Tell your healthcare provider right away if you develop new or worsening symptoms of lung problems, including:. Diarrhea. Diarrhea is common with PIQRAY and can be severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney problems. If you develop diarrhea during treatment with PIQRAY, tell your healthcare provider right away. Your healthcare provider may tell you to drink more fluids or take medicines to treat diarrhea.

SPL UNCLASSIFIED SECTION.

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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryPIQRAY 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 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 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.DataAnimal DataIn 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 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At 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 pilot embryo-fetal development study in rabbits, 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 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 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 TestingVerify the pregnancy status in females of reproductive potential prior to initiating PIQRAY.ContraceptionFemalesPIQRAY can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for week after the last dose.MalesAdvise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for week after the last dose. InfertilityBased 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 received PIQRAY in the SOLAR-1 trial, 117 patients were >= 65 years of age and 34 patients were >= 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was 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 PIQRAY 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 Warnings and Precautions (5.3)]. 8.6 Renal Impairment. The effect of severe renal impairment (CLcr 30 mL/min) on alpelisib pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to 90 mL/min).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Severe Hypersensitivity: Permanently discontinue PIQRAY. Promptly initiate appropriate treatment. (5.1)Severe Cutaneous Adverse Reactions (SCARs): PIQRAY can cause SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Interrupt PIQRAY for signs or symptoms of SCARs. Permanently discontinue PIQRAY if SCARs are confirmed. (5.2)Hyperglycemia: PIQRAY can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. The safety of PIQRAY in patients with Type or uncontrolled Type diabetes has not been established. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment, monitor periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia occurs. (2.3, 5.3)Pneumonitis: PIQRAY can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs. (2.3, 5.4)Diarrhea: PIQRAY can cause severe cases of diarrhea, including dehydration and acute kidney injury. Most patients experience diarrhea (Grade <= 2) during treatment with PIQRAY. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs. Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea occurs. (2.3, 5.5)Embryo-Fetal Toxicity: PIQRAY can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3) Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.. Severe Hypersensitivity: Permanently discontinue PIQRAY. Promptly initiate appropriate treatment. (5.1). Severe Cutaneous Adverse Reactions (SCARs): PIQRAY can cause SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Interrupt PIQRAY for signs or symptoms of SCARs. Permanently discontinue PIQRAY if SCARs are confirmed. (5.2). Hyperglycemia: PIQRAY can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. The safety of PIQRAY in patients with Type or uncontrolled Type diabetes has not been established. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment, monitor periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia occurs. (2.3, 5.3). Pneumonitis: PIQRAY can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs. (2.3, 5.4). Diarrhea: PIQRAY can cause severe cases of diarrhea, including dehydration and acute kidney injury. Most patients experience diarrhea (Grade <= 2) during treatment with PIQRAY. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs. Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea occurs. (2.3, 5.5). Embryo-Fetal Toxicity: PIQRAY can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3) Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.. 5.1 Severe Hypersensitivity. Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms, including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia.The incidence of Grade and hypersensitivity reactions was 0.7% [see Adverse Reactions (6)].Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.. 5.2 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 PIQRAY. In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively [see Adverse Reactions (6.1)]. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with PIQRAY in the postmarketing setting [see Adverse Reactions (6.2)].If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with dermatologist is recommended.If SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous adverse reactions during PIQRAY treatment.If SCAR is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment as described in Table [see Dosage and Administration (2.3)].Advise patients of the signs and symptoms of SCARs (e.g., prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).. 5.3 Hyperglycemia. Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Some fatal cases of ketoacidosis have occurred in the post marketing setting.Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade (FPG 250 to 500 mg/dL) and Grade (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 >= (FPG 160 to 250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range, 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 >= hyperglycemia with at least grade improvement (n 153), median time to improvement from the first event was days (range, 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 with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first weeks, then at least once every weeks, and as clinically indicated. Monitor HbA1c every months and as clinically indicated. Monitor fasting glucose more frequently for the first few weeks during treatment with PIQRAY 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 Specific Populations (8.5)].If patient experiences hyperglycemia after initiating treatment with PIQRAY, 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 week for weeks, followed by once every weeks and as clinically indicated. Consider consultation with healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.The safety of PIQRAY in patients with Type and uncontrolled Type diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with medical history of controlled Type diabetes were included. Patients with history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes.Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table [see Dosage and Administration (2.3)].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).. 5.4 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 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 PIQRAY in all patients with confirmed pneumonitis.Advise patients to immediately report new or worsening respiratory symptoms.. 5.5 Diarrhea. Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade diarrhea occurred in 7% (n 19) of patients. Among patients with Grade or diarrhea (n 71), the median time to onset was 46 days (range, to 442 days).Dose reductions of PIQRAY were required in 6% of patients and 2.8% of patients permanently discontinued PIQRAY 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, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table [see Dosage and Administration (2.3)].Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY.. 5.6 Embryo-Fetal Toxicity. Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 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 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.