POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience and Other Spontaneous Adverse Reaction Reports. The following adverse reactions have been identified with VIJOICE use in patients with PROS in an expanded access program for compassionate use. Because these reactions are reported 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: Decreased appetite.Skin and subcutaneous tissue disorders: Pruritus, rash (including rash maculo-papular, rash erythematous, rash papular, and rash pruritic), acne (including dermatitis acneiform).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed elsewhere in 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 (Grades to 4, incidence >= 10%) were diarrhea, stomatitis, and hyperglycemia. (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 Trials 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 VIJOICE was evaluated in EPIK-P1 (NCT04285723), single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use. Fifty-seven patients years of age and older with severe or life-threatening PIK3CA-Related Overgrowth Spectrum (PROS) received VIJOICE based on age at dosages ranging from 50 mg to 250 mg orally once daily [see Clinical Studies (14)]. Among patients who received VIJOICE, 95% were exposed for months or longer and 79% were exposed for greater than one year.The median age of patients who received VIJOICE was 14 years (range, to 50); 58% were female; 12% were White and race was not reported for 88%.Serious adverse reactions occurred in 12% of patients who received VIJOICE. Serious adverse reactions occurring in two or more patients included dehydration (n 2) and cellulitis (n 2).Dosage interruption of VIJOICE due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption in two or more patients included dizziness (n 2) and vomiting (n 2). Dose reductions of VIJOICE due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reduction included alopecia, memory impairment, and soft tissue infection.The most common adverse reactions (>= 10%) were diarrhea, stomatitis, and hyperglycemia. The most common Grade or laboratory abnormalities (>= 2%) were increased glucose, decreased hemoglobin, decreased phosphate, increased bilirubin, decreased sodium, and decreased platelets.Adverse reactions and laboratory abnormalities are listed in Table 10 and Table 11, respectively.Table 10: Adverse Reactions (>= 5%) in Patients with PROS Who Received VIJOICE in EPIK-P1Grading according to CTCAE Version 4.03. aStomatitis: including stomatitis and aphthous ulcer.VIJOICEN 57Adverse reactionsAll Grades(%)Grade or 4(%)Gastrointestinal disorders Diarrhea160 Stomatitisa 160Metabolism and nutrition disorders Hyperglycemia120Skin and subcutaneous tissue disorders Eczema70 Dry skin70 Alopecia50Nervous system disorders Headache50Infections and infestations Cellulitis53.5Clinically relevant adverse reactions in 5% of patients who received VIJOICE included nausea, vomiting, dehydration, and mucosal dryness.Table 11: Laboratory Abnormalities Worsening from Baseline in >= 10% of Patients with PROS Who Received VIJOICE in EPIK-P1Grading according to CTCAE Version 4.03.Abbreviation: N/A, not available. aThe denominator used to calculate the rate varied from to 50 based on the number of patients with baseline value and at least one post-treatment value. bNo Grade laboratory abnormalities were reported. cGlucose increase is an expected laboratory abnormality of PI3K inhibition. dNo CTCAE grade available. For HbA1c, baseline values increasing post-treatment to value above the upper limit of the normal range (>= 5.7%) are considered increased. Laboratory abnormalityVIJOICEa = 57All Grades%Grade or 4%ChemistryDecreased calcium (corrected)600Decreased phosphate595b Increased glucosec 5611b Increased glycosylated hemoglobin (HbA1c)d 38d N/Ad Increased creatinine310Increased bilirubin292b Increased potassium240Increased triglycerides190Decreased magnesium180Increased aspartate aminotransferase (AST)170Increased cholesterol130Decreased albumin130Decreased sodium122b Decreased potassium120Increased gamma glutamyl transferase (GGT)110Increased alanine aminotransferase (ALT)100HematologyDecreased leukocyte220Decreased hemoglobin206b Decreased lymphocyte200Decreased neutrophil190Increased lymphocyte170Decreased platelets142b 6.2 Postmarketing Experience and Other Spontaneous Adverse Reaction Reports. The following adverse reactions have been identified with VIJOICE use in patients with PROS in an expanded access program for compassionate use. Because these reactions are reported 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: Decreased appetite.Skin and subcutaneous tissue disorders: Pruritus, rash (including rash maculo-papular, rash erythematous, rash papular, and rash pruritic), acne (including dermatitis acneiform).

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.In fertility and early embryonic development study in rats, female animals were administered alpelisib doses of 3, 10, and 20 mg/kg/day orally. Animals were dosed for 4-weeks prior to pairing, during the mating period, and up to Gestation Day 6. At the dose of 20 mg/kg/day, alpelisib increased pre- and post-implantation losses, leading to reduced numbers of implantation sites and live embryos. These findings were observed at doses approximately 2.4 to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on body surface areas (BSA). In repeated-dose toxicity study in rats, adverse effects in female reproductive organs included vaginal atrophy and estrous cycle variations in rats at doses >= mg/kg/day (approximately 0.7 to 0.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). In male fertility study, alpelisib administered orally at doses of 3, 10 and 20 mg/kg/day for up to 99 days (10-weeks prior to pairing, during mating period and continuing during post-pairing) to male rats, resulted in reduced weights of seminal vesicles and prostate, which correlated with atrophy and/or reduced secretion in prostate and seminal vesicles at >= 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). No adverse effects on male fertility parameters were observed at doses up to 20 mg/kg/day.

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.Activating mutations in PIK3CA have been found to induce spectrum of overgrowths and malformations comprising wide group of clinically recognizable disorders commonly known as PROS.In an inducible mouse model of Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome (CLOVES), phenotype of PROS, alpelisib inhibition of the PI3K pathway resulted in the prevention or improvement of organ abnormalities associated with the disease, depending on when alpelisib treatment was started. These findings were reversed after withdrawal of alpelisib.. 12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of VIJOICE have not been characterized. Cardiac ElectrophysiologyAt dose of 300 mg, alpelisib does not prolong the QT interval to any clinically relevant extent in the oncology setting. VIJOICE is not approved for use in the oncology setting.. 12.3 Pharmacokinetics. The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors and are presented as mean (% CV) under fed conditions unless otherwise specified. Steady-state alpelisib maximum plasma concentration (Cmax) and area under the curve (AUC) increased proportionally over the dose range of 30 mg (0.6 times the lowest approved recommended dosage) to 450 mg (1.8 times the highest 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. 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 alpelisib dose of 300 mg. No clinically relevant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.DistributionThe apparent volume of distribution of alpelisib at steady-state is 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 clearance of alpelisib is 9.2 L/hr (21%) under fed conditions.MetabolismAlpelisib is primarily metabolized by chemical and enzymatic hydrolysis and to lesser extent by CYP3A4, in vitro.ExcretionFollowing single oral dose of 400 mg (1.6 times the highest approved recommended dosage) radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged) and 14% (2% unchanged) 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.Pediatric PatientsThe pharmacokinetics of VIJOICE in pediatric patients have not been evaluated.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesAcid Reducing Agents: No clinically significant differences in the pharmacokinetics of alpelisib were observed when used concomitantly with ranitidine (H2 receptor antagonist) and administered with food as directed.Concomitant use of ranitidine decreased alpelisib AUC approximately 30% and Cmax by 51% with single 300 mg oral dose (1.2 times the highest approved recommended dosage) of alpelisib under the fasted state. In the presence of low-fat low-calorie meal, AUC was decreased by 21% and Cmax by 36% with ranitidine.CYP3A4 Substrates: No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when used concurrently 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.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of VIJOICE have been established in pediatric patients to less than 18 years of age with PROS based on results from single-arm clinical study of VIJOICE (EPIK-P1) that enrolled 39 pediatric patients: 11 patients aged to years, 12 patients aged to 11 years, and 16 patients aged 12 to less than 18 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)].The safety and effectiveness of VIJOICE in pediatric patients below the age of years have not been established.Although there were no new safety signals observed in pediatric patients, there is insufficient data to determine whether VIJOICE has an adverse impact on growth and development in pediatric patients with PROS. Based on the animal toxicity data (described below), regular monitoring of growth and development in pediatric patients treated with VIJOICE is recommended.Animal Toxicity DataIn 4-week general toxicology study, rats administered alpelisib had growth plate thickening and decreased trabeculae of the knee joint, dentin thinning, and degenerative odontoblasts at the dose of 30 mg/kg/day (approximately 2.8 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). Dentin thinning/irregular dentin was also observed in the 13-week toxicology study in rats at the high dose of 20 mg/kg/day (approximately to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of VIJOICE was assessed in EPIK-P1 (NCT04285723), single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use which enrolled patients across seven sites in five countries (France, Spain, US, Ireland and Australia). Eligible patients years of age and older with PIK3CA-Related Overgrowth Spectrum (PROS) who received VIJOICE had clinical manifestations of PROS that were assessed by the treating physician as severe or life-threatening and necessitating systemic treatment and had documented evidence of mutation in the PIK3CA gene. Patients received VIJOICE at dosages based on age ranging from 50 mg to 250 mg orally once daily.The efficacy of VIJOICE was evaluated in total of 37 patients with at least one target lesion identified on imaging performed within 24 weeks prior to receipt of the first dose of VIJOICE. The median age of patients was 14 years (range: to 38); 22% of patients were to years, 22% were to 11 years, 27% were 12 to less than 18 years of age, and 30% were >= 18 years; 57% were female, 11% were White and race was not reported for 89%. Ninety-two percent of patients had congenital overgrowth and 8% had early childhood-onset. Patients had heterogeneous manifestations of PROS, including CLOVES, (81%), Megalencephaly-Capillary Malformation Polymicrogyria (MCAP; 8%), Klippel-Trenaunay Syndrome (KTS; 2.7%), Facial Infiltrating Lipomatosis (FIL; 8%), and Other (5%). Five percent (5%) of patients had concurrent manifestations of CLOVES and MCAP.The major efficacy outcome measure for the study was the proportion of patients with radiological response at Week 24 as determined by blinded independent central review (BICR), defined as >= 20% reduction from baseline in the sum of measurable target lesion volume (1 to lesions) confirmed by at least one subsequent imaging assessment, in the absence of >= 20% increase from baseline in any target lesion, progression of non-target lesions, or appearance of new lesion. An additional efficacy outcome measure was duration of response, defined as the time from the first documented response to the date of the first documented disease progression or death due to any cause.Efficacy results are presented in Table 12.Table 12: Efficacy Results at Week 24 in EPIK-P1Abbreviation: +: censored observation. aConfirmed response as determined by blinded independent central review (BICR). bPatients without any response assessment at Week 24 were considered non-responders.Efficacy parametersAll patientsN 37Response ratea,b Responders, (%) 95% CI10 (27)(14, 44)Duration of response (DOR) Median in months (range)NR (0.9+, 42.9+) >= months70 >= 12 months60.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials 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 VIJOICE was evaluated in EPIK-P1 (NCT04285723), single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use. Fifty-seven patients years of age and older with severe or life-threatening PIK3CA-Related Overgrowth Spectrum (PROS) received VIJOICE based on age at dosages ranging from 50 mg to 250 mg orally once daily [see Clinical Studies (14)]. Among patients who received VIJOICE, 95% were exposed for months or longer and 79% were exposed for greater than one year.The median age of patients who received VIJOICE was 14 years (range, to 50); 58% were female; 12% were White and race was not reported for 88%.Serious adverse reactions occurred in 12% of patients who received VIJOICE. Serious adverse reactions occurring in two or more patients included dehydration (n 2) and cellulitis (n 2).Dosage interruption of VIJOICE due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption in two or more patients included dizziness (n 2) and vomiting (n 2). Dose reductions of VIJOICE due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reduction included alopecia, memory impairment, and soft tissue infection.The most common adverse reactions (>= 10%) were diarrhea, stomatitis, and hyperglycemia. The most common Grade or laboratory abnormalities (>= 2%) were increased glucose, decreased hemoglobin, decreased phosphate, increased bilirubin, decreased sodium, and decreased platelets.Adverse reactions and laboratory abnormalities are listed in Table 10 and Table 11, respectively.Table 10: Adverse Reactions (>= 5%) in Patients with PROS Who Received VIJOICE in EPIK-P1Grading according to CTCAE Version 4.03. aStomatitis: including stomatitis and aphthous ulcer.VIJOICEN 57Adverse reactionsAll Grades(%)Grade or 4(%)Gastrointestinal disorders Diarrhea160 Stomatitisa 160Metabolism and nutrition disorders Hyperglycemia120Skin and subcutaneous tissue disorders Eczema70 Dry skin70 Alopecia50Nervous system disorders Headache50Infections and infestations Cellulitis53.5Clinically relevant adverse reactions in 5% of patients who received VIJOICE included nausea, vomiting, dehydration, and mucosal dryness.Table 11: Laboratory Abnormalities Worsening from Baseline in >= 10% of Patients with PROS Who Received VIJOICE in EPIK-P1Grading according to CTCAE Version 4.03.Abbreviation: N/A, not available. aThe denominator used to calculate the rate varied from to 50 based on the number of patients with baseline value and at least one post-treatment value. bNo Grade laboratory abnormalities were reported. cGlucose increase is an expected laboratory abnormality of PI3K inhibition. dNo CTCAE grade available. For HbA1c, baseline values increasing post-treatment to value above the upper limit of the normal range (>= 5.7%) are considered increased. Laboratory abnormalityVIJOICEa = 57All Grades%Grade or 4%ChemistryDecreased calcium (corrected)600Decreased phosphate595b Increased glucosec 5611b Increased glycosylated hemoglobin (HbA1c)d 38d N/Ad Increased creatinine310Increased bilirubin292b Increased potassium240Increased triglycerides190Decreased magnesium180Increased aspartate aminotransferase (AST)170Increased cholesterol130Decreased albumin130Decreased sodium122b Decreased potassium120Increased gamma glutamyl transferase (GGT)110Increased alanine aminotransferase (ALT)100HematologyDecreased leukocyte220Decreased hemoglobin206b Decreased lymphocyte200Decreased neutrophil190Increased lymphocyte170Decreased platelets142b.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. VIJOICE (alpelisib) is kinase inhibitor. The chemical name of alpelisib is (2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide. Alpelisib is 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:VIJOICE film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 125 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 red (applicable only to 50 mg and 200 mg strengths), iron oxide yellow, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.. alpelisib structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dose:Pediatric patients (2 to less than 18 years of age): 50 mg taken orally once daily with food. (2.1)Adult patients: 250 mg taken orally once daily with food. (2.1). Pediatric patients (2 to less than 18 years of age): 50 mg taken orally once daily with food. (2.1). Adult patients: 250 mg taken orally once daily with food. (2.1). 2.1 Recommended Dosage. Adult PatientsThe recommended dosage of VIJOICE in adult patients is 250 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.Pediatric Patients (2 to less than 18 years of age)The recommended initial dosage of VIJOICE in pediatric patients is 50 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.Consider dose increase to 125 mg once daily in pediatric patients >= years old for response optimization (clinical/radiological) after 24 weeks of treatment with VIJOICE at 50 mg once daily. When pediatric patient turns 18 years old, consider gradual dose increase up to 250 mg. Recommended dose increases by age group are listed in Table 1. Table 1: Recommended Daily VIJOICE Dose Levels for Pediatric Patients (2 to less than 18 years of age)A recommended increased dose has not been established.Patient age (years)Initial doseDose increase2 to 650 mgNot applicable6 to 1850 mg125 mg. 2.2 Administration. Take VIJOICE with food at approximately the same time each day.No tablet should be used if it is broken, cracked, or otherwise damaged at the time of opening the blister pack.Swallow VIJOICE tablets whole. Do not split or chew.If dose of VIJOICE 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 VIJOICE 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.Preparation and Administration for Patients Who Have Difficulty Swallowing TabletsFor patients who are not able to swallow tablets, administer VIJOICE as an oral suspension with food [see Clinical Pharmacology (12.3)].Place VIJOICE tablets in glass containing to ounces of water and let it stand for approximately minutes. Make the suspension with water only.Crush the tablets with spoon and stir until an oral suspension is obtained.Administer the oral suspension immediately after preparation. Discard the oral suspension if it is not administered within 60 minutes after preparation.After administration of the oral suspension, add approximately to tablespoons of water to the same glass. Stir with the same spoon to re-suspend any remaining particles and administer the entire contents of the glass. Repeat if particles remain. For patients who are not able to swallow tablets, administer VIJOICE as an oral suspension with food [see Clinical Pharmacology (12.3)].Place VIJOICE tablets in glass containing to ounces of water and let it stand for approximately minutes. Make the suspension with water only.Crush the tablets with spoon and stir until an oral suspension is obtained.Administer the oral suspension immediately after preparation. Discard the oral suspension if it is not administered within 60 minutes after preparation.After administration of the oral suspension, add approximately to tablespoons of water to the same glass. Stir with the same spoon to re-suspend any remaining particles and administer the entire contents of the glass. Repeat if particles remain. Place VIJOICE tablets in glass containing to ounces of water and let it stand for approximately minutes. Make the suspension with water only.. Crush the tablets with spoon and stir until an oral suspension is obtained.. Administer the oral suspension immediately after preparation. Discard the oral suspension if it is not administered within 60 minutes after preparation.. After administration of the oral suspension, add approximately to tablespoons of water to the same glass. Stir with the same spoon to re-suspend any remaining particles and administer the entire contents of the glass. Repeat if particles remain.. 2.3 Dosage Modifications for Adverse Reactions. The recommended VIJOICE dose reductions for adverse reactions in adult and pediatric patients are listed in Table and Table 3, respectively.Table 2: VIJOICE Dosage Reduction Recommendations for Adverse Reactions in Adult PatientsVIJOICE dose levelDose and scheduleFirst-dose reduction125 mg once dailySecond-dose reduction50 mg once dailyTable 3: VIJOICE Dosage Reduction Recommendations for Adverse Reactions in Pediatric PatientsActionVIJOICE dose prior to dose reduction125 mg once daily50 mg once dailyDose reduction50 mg once dailyNot applicableDiscontinue VIJOICE in adults or pediatric patients who cannot tolerate 50 mg daily.Tables 4, 5, 6, 7, 8, and summarize recommendations for dose interruption, reduction, or discontinuation of VIJOICE in the management of specific adverse reactions.Cutaneous Adverse ReactionsIf severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue VIJOICE. Do not reintroduce VIJOICE in patients who have experienced previous SCAR during VIJOICE treatment [see Warnings and Precautions (5.2)].Table 4: Dosage Modification and Management for Rash and Severe Cutaneous Adverse Reactions (SCARs)aGrading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.bFor all grades of rash, consider consultation with dermatologist.cAntihistamines administered prior to rash onset may decrease incidence and severity of rash.[see Warnings and Precautions (5.1, 5.2)]Gradea,b Recommendation for adult and pediatric patientsc Grade 1(< 10% body surface area (BSA) with active skin toxicity)No VIJOICE dosage modification is required unless the etiology is determined to be SCAR.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 determined to be SCAR, permanently discontinue VIJOICE.Grade 2(10% to 30% BSA with active skin toxicity)No VIJOICE dosage modification is required unless the etiology is determined to be SCAR.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 determined to be SCAR, permanently discontinue VIJOICE.Grade (e.g., severe rash not responsive to medical management)(> 30% BSA with active skin toxicity)Interrupt VIJOICE and initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment.If the etiology is determined to be SCAR, permanently discontinue VIJOICE. For rashes other than SCAR Adult Patients: Upon improvement to Grade <= 1, resume VIJOICE at the next lower dose level. Pediatric Patients: Upon improvement to Grade <= 1, either resume VIJOICE at 50 mg while continuing oral antihistamine treatment or permanently discontinue VIJOICE.Permanently discontinue VIJOICE if:Patient was receiving antihistamines at the time of rash onset and antihistamine dose cannot be increasedGrade >= rash recurs 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 VIJOICE.HyperglycemiaBefore initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with VIJOICE, 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 5: Dosage Modification and Management for HyperglycemiaAbbreviation: ULN, upper limit of normal. aFPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. bInitiate applicable anti-hyperglycemic medications, including metformin in adult and pediatric patients >= 10 years, SGLT2 inhibitors or insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors) in adult patients, and review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines [see Warnings and Precautions (5.3)].[see Warnings and Precautions (5.3)]Fasting plasma glucose (FPG)/Fasting blood glucose valuesa Recommendation for adult and pediatric patientsDose 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 VIJOICE dosage modification is required.Initiate or intensify oral anti-hyperglycemic treatmentb.Grade 2Fasting glucose 160 250 mg/dL or 8.9 13.9 mmol/LNo VIJOICE dosage modification is required.Initiate or intensify oral anti-hyperglycemic treatmentb. Adult Patients: If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatmentb, reduce VIJOICE dose by dose level and follow fasting glucose value specific recommendations. Pediatric Patients: If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatmentb, interrupt VIJOICE until improvement to Grade <= 1, then resume VIJOICE at 50 mg and follow fasting glucose value specific recommendations. Grade 3Fasting glucose 250 500 mg/dL or 13.9 27.8 mmol/LInterrupt VIJOICE.Initiate or intensify oral anti-hyperglycemic treatmentb and consider additional anti-hyperglycemic medications 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). Adult Patients: If fasting glucose decreases to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, resume VIJOICE 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 treatmentb, permanently discontinue VIJOICE. Pediatric Patients: If fasting glucose decreases to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, resume VIJOICE at 50 mg.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 to determine if treatment with VIJOICE should be resumed or permanently discontinued.If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days following appropriate anti-hyperglycemic treatmentb, permanently discontinue VIJOICE.If hyperglycemia recurs at Grade >= 3, consider permanent discontinuation of VIJOICE. Grade 4Fasting glucose 500 mg/dL or >= 27.8 mmol/LInterrupt VIJOICE.Initiate or intensify appropriate oral anti-hyperglycemic treatmentb.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 VIJOICE. PneumonitisTable 6: Dosage Modification for PneumonitisaGrading according to CTCAE Version 5.0.[see Warnings and Precautions (5.4)]Gradea Recommendation for adult and pediatric patientsAny GradeoInterrupt VIJOICE if pneumonitis is suspected.oPermanently discontinue VIJOICE if pneumonitis is confirmed.DiarrheaIn pediatric patients, consider consultation with physician with experience in the treatment of gastrointestinal conditions.Table 7: Dosage Modification and Management for DiarrheaaGrading according to CTCAE Version 5.0.[see Warnings and Precautions (5.5)]Gradea Recommendation for adult and pediatric patientsGrade 1No VIJOICE dosage modification is required.Initiate appropriate medical therapy and monitor as clinically indicated.Grade 2Interrupt VIJOICE dose until improvement to Grade <= 1, then resume VIJOICE at the same dose level.Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients: If diarrhea recurs at Grade >= 2, interrupt VIJOICE dose until improvement to Grade <= 1, then resume VIJOICE at the next lower dose level. Pediatric Patients: If diarrhea recurs at Grade >= 2, interrupt VIJOICE dose until improvement to Grade <= 1, then resume VIJOICE at 50 mg. Grade 3Interrupt VIJOICE dose until improvement to Grade <= 1.Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients: Once improved to Grade <= 1, then resume VIJOICE at the next lower dose level. Pediatric Patients: Once improved to Grade <= 1, either resume VIJOICE at 50 mg or permanently discontinue VIJOICE.If diarrhea recurs at Grade >= 3, consider permanent discontinuation of VIJOICE. Grade 4Permanently discontinue VIJOICE.PancreatitisTable 8: Dosage Modification for PancreatitisaGrading according to CTCAE Version 5.0.Gradea Recommendation for adult and pediatric patientsGrade 2Interrupt VIJOICE dose until improvement to Grade 2. Adult Patients: Resume VIJOICE at the next lower dose level (only one dose reduction is permitted).If pancreatitis recurs, permanently discontinue VIJOICE. Pediatric Patients: Resume VIJOICE at 50 mg.If pancreatitis recurs, permanently discontinue VIJOICE. Grade 3Adult Patients:Interrupt VIJOICE dose until improvement to Grade 2.Resume VIJOICE at the next lower dose level (only one dose reduction is permitted).If pancreatitis recurs, permanently discontinue VIJOICE.Pediatric Patients:Permanently discontinue VIJOICE.Grade 4Permanently discontinue VIJOICE.Other Adverse ReactionsTable 9: Dosage Modification and Management for Other Adverse Reactions (Excluding Rash and Severe Cutaneous Adverse Reactions, Hyperglycemia, Pneumonitis, Diarrhea, and Pancreatitis)aGrading according to CTCAE Version 5.0.bFor Grade total bilirubin elevation in adult patients, interrupt VIJOICE dose until improvement to Grade <= 1. If improvement occurs in <= 14 days, resume at the same dose level. If improvement occurs in 14 days, resume VIJOICE at the next lower dose level. cFor Grade total bilirubin elevation in pediatric patients, interrupt VIJOICE dose until improvement to Grade <= 1. If improvement occurs in <= 14 days, resume at the same dose level. If improvement occurs in 14 days, resume VIJOICE at 50 mg.Gradea Recommendation for adult and pediatric patientsGrade or 2b,c No VIJOICE dosage modification is required.Initiate appropriate medical therapy and monitor as clinically indicatedb,c.Grade 3Interrupt VIJOICE dose until improvement to Grade <= 1.Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients: Once improved to Grade <= 1, then resume VIJOICE at the next lower dose level. Pediatric Patients: Once improved to Grade <= 1, either resume VIJOICE at 50 mg or permanently discontinue VIJOICE.If adverse reaction recurs at Grade >= 3, consider permanent discontinuation of VIJOICE.Consider consultation with qualified physician with specific expertise in the field of the concerned adverse reaction. Grade 4Permanently discontinue VIJOICE.. Upon improvement to Grade <= 1, resume VIJOICE at the next lower dose level.. Upon improvement to Grade <= 1, either resume VIJOICE at 50 mg while continuing oral antihistamine treatment or permanently discontinue VIJOICE.. Permanently discontinue VIJOICE if:Patient was receiving antihistamines at the time of rash onset and antihistamine dose cannot be increasedGrade >= rash recurs Patient was receiving antihistamines at the time of rash onset and antihistamine dose cannot be increased. Grade >= rash recurs. If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatmentb, reduce VIJOICE dose by dose level and follow fasting glucose value specific recommendations.. If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatmentb, interrupt VIJOICE until improvement to Grade <= 1, then resume VIJOICE at 50 mg and follow fasting glucose value specific recommendations.. If fasting glucose decreases to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, resume VIJOICE 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 treatmentb, permanently discontinue VIJOICE.. If fasting glucose decreases to <= 160 mg/dL or 8.9 mmol/L within to days under appropriate anti-hyperglycemic treatment, resume VIJOICE at 50 mg.. 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 to determine if treatment with VIJOICE should be resumed or permanently discontinued.. If fasting glucose does not decrease to <= 160 mg/dL or 8.9 mmol/L within 21 days following appropriate anti-hyperglycemic treatmentb, permanently discontinue VIJOICE.. If hyperglycemia recurs at Grade >= 3, consider permanent discontinuation of VIJOICE.. 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 VIJOICE.. If diarrhea recurs at Grade >= 2, interrupt VIJOICE dose until improvement to Grade <= 1, then resume VIJOICE at the next lower dose level.. If diarrhea recurs at Grade >= 2, interrupt VIJOICE dose until improvement to Grade <= 1, then resume VIJOICE at 50 mg.. Once improved to Grade <= 1, then resume VIJOICE at the next lower dose level.. Once improved to Grade <= 1, either resume VIJOICE at 50 mg or permanently discontinue VIJOICE.. If diarrhea recurs at Grade >= 3, consider permanent discontinuation of VIJOICE.. Resume VIJOICE at the next lower dose level (only one dose reduction is permitted).. If pancreatitis recurs, permanently discontinue VIJOICE.. Resume VIJOICE at 50 mg.. If pancreatitis recurs, permanently discontinue VIJOICE.. Interrupt VIJOICE dose until improvement to Grade 2.. Resume VIJOICE at the next lower dose level (only one dose reduction is permitted).. If pancreatitis recurs, permanently discontinue VIJOICE.. Permanently discontinue VIJOICE.. Once improved to Grade <= 1, then resume VIJOICE at the next lower dose level.. Once improved to Grade <= 1, either resume VIJOICE at 50 mg or permanently discontinue VIJOICE.. If adverse reaction recurs at Grade >= 3, consider permanent discontinuation of VIJOICE.. Consider consultation with qualified physician with specific expertise in the field of the concerned adverse reaction.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 50 mg, 125 mg, and 200 mg alpelisib50 mg: Light yellow, unscored, round and curved with beveled edges film-coated tablet, debossed with C7 on one side and NVR on the other side.125 mg: Dark yellow, unscored, ovaloid and curved with beveled edges film-coated tablet, debossed with Y7 on one side and NVR on the other side.200 mg: Pale yellow, unscored, ovaloid and curved with beveled edges film-coated tablet, debossed with CL7 on one side and NVR on the other side.. Tablets: 50 mg, 125 mg, and 200 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A4 Inducers: Avoid coadministration of VIJOICE with strong CYP3A4 inducer. (7.1)Breast Cancer Resistance Protein (BCRP) Inhibitors: Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, closely monitor for increased adverse reactions. (7.1)CYP2C9 Substrates: Closely monitor when VIJOICE is coadministered with CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce activity. (7.2). CYP3A4 Inducers: Avoid coadministration of VIJOICE with strong CYP3A4 inducer. (7.1). Breast Cancer Resistance Protein (BCRP) Inhibitors: Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, closely monitor for increased adverse reactions. (7.1). CYP2C9 Substrates: Closely monitor when VIJOICE 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 VIJOICE. CYP3A4 InducersAvoid coadministration of VIJOICE with strong CYP3A4 inducers.Alpelisib is metabolized by CYP3A4. Concomitant use of VIJOICE with strong CYP3A4 inducer may decrease alpelisib concentration [see Clinical Pharmacology (12.3)], which may decrease alpelisib activity.Breast Cancer Resistance Protein Inhibitors (BCRP)Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, when VIJOICE is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.Alpelisib is transported by BCRP. Concomitant use of VIJOICE with BCRP inhibitor may increase alpelisib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.. 7.2 Effect of VIJOICE on Other Drugs. CYP2C9 SubstratesClosely monitor CYP2C9 substrates where minimal concentration changes of the CYP2C9 substrate may reduce activity when used concomitantly with VIJOICE.Alpelisib induces CYP2C9. Concomitant use of VIJOICE with CYP2C9 substrates may reduce exposure of these drugs, which may reduce activity [see Clinical Pharmacology (12.3)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status in females of reproductive potential prior to initiating VIJOICE.ContraceptionFemalesVIJOICE 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 VIJOICE 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 VIJOICE and for week after the last dose.InfertilityBased on findings from animal studies, VIJOICE may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. There were no adult patients aged 65 years of age or older who received VIJOICE in EPIK-P1.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. VIJOICE (alpelisib) 50 mg, 125 mg, and 200 mg film-coated tablets are available in blister packs based on daily dose as described in Table 13.Table 13: VIJOICE Daily Dose Blister PacksDaily doseEach child-resistant carton containsEach blister pack containsNDC50 mg daily doseOne 28-day supply blister pack 28 tablets; 50 mg alpelisib per tabletNDC 0078-1021-84125 mg daily doseOne 28-day supply blister pack 28 tablets; 125 mg alpelisib per tabletNDC 0078-1028-84250 mg daily doseTwo 14-day supply blister packs (56 tablets total)14 tablets: 200 mg alpelisib per tablet, and14 tablets: 50 mg alpelisib per tabletNDC 0078-1035-02Store 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. VIJOICE is indicated for the treatment of adult and pediatric patients years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy.This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. VIJOICE is kinase inhibitor indicated for the treatment of adult and pediatric patients years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy.This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and their caregivers to read the FDA-approved patient labeling (Patient Information).Severe HypersensitivityInform patients and their caregivers of the signs and symptoms of hypersensitivity. Advise patients and their caregivers to contact their healthcare provider immediately for signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)].Severe Cutaneous Adverse ReactionsInform patients and their caregivers of the signs and symptoms of severe cutaneous adverse reactions (SCARs). Advise patients and their caregivers to contact their healthcare provider immediately for signs and symptoms of SCARs (e.g., prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy) [see Warnings and Precautions (5.2)].HyperglycemiaAdvise patients and their caregivers of the possibility of developing hyperglycemia and the need to monitor fasting glucose periodically during therapy. Advise patients and their caregivers 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) [see Warnings and Precautions (5.3)].PneumonitisInform patients and their caregivers of the possibility of developing pneumonitis and to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].DiarrheaAdvise patients and their caregivers that VIJOICE may cause diarrhea, which may be severe in some cases. Inform patients and their caregivers to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking VIJOICE [see Warnings and Precautions (5.5)].AlopeciaAdvise patients and caregivers that VIJOICE may cause alopecia [see Adverse Reactions (6.1)].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 VIJOICE 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 VIJOICE and for week after the last dose [see Use in Specific Populations (8.3)]. LactationAdvise women not to breastfeed during treatment with VIJOICE and for week after the last dose [see Use in Specific Populations (8.2)]. InfertilityAdvise males and females of reproductive potential that VIJOICE may impair fertility [see Use in Specific Populations (8.3)].Drug InteractionsAdvise patients and their caregivers to inform their healthcare providers of all concomitant medications, herbal and dietary supplements [see Drug Interactions (7.1, 7.2)].DosingInstruct patients and their caregivers of the following:Take VIJOICE with food at approximately the same time each day [see Dosage and Administration (2.2)].Swallow the tablets whole (tablets should not be chewed or split prior to swallowing) [see Dosage and Administration (2.2)].For patients unable to swallow, advise how to prepare an oral suspension [see Dosage and Administration (2.2)].If dose of VIJOICE 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 VIJOICE at the usual time. Instruct patients not to take doses to make up for missed dose [see Dosage and Administration (2.2)]. If vomiting occurs after taking the dose of VIJOICE, they should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time [see Dosage and Administration (2.2)]. Distributed byNovartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2022-27. 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 VIJOICE 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 VIJOICE and for week after the last dose [see Use in Specific Populations (8.3)]. Take VIJOICE with food at approximately the same time each day [see Dosage and Administration (2.2)].. Swallow the tablets whole (tablets should not be chewed or split prior to swallowing) [see Dosage and Administration (2.2)].. For patients unable to swallow, advise how to prepare an oral suspension [see Dosage and Administration (2.2)].. If dose of VIJOICE 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 VIJOICE at the usual time. Instruct patients not to take doses to make up for missed dose [see Dosage and Administration (2.2)]. If vomiting occurs after taking the dose of VIJOICE, they should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time [see Dosage and Administration (2.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are 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 VIJOICE 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.Activating mutations in PIK3CA have been found to induce spectrum of overgrowths and malformations comprising wide group of clinically recognizable disorders commonly known as PROS.In an inducible mouse model of Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome (CLOVES), phenotype of PROS, alpelisib inhibition of the PI3K pathway resulted in the prevention or improvement of organ abnormalities associated with the disease, depending on when alpelisib treatment was started. These findings were reversed after withdrawal of alpelisib.

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.In fertility and early embryonic development study in rats, female animals were administered alpelisib doses of 3, 10, and 20 mg/kg/day orally. Animals were dosed for 4-weeks prior to pairing, during the mating period, and up to Gestation Day 6. At the dose of 20 mg/kg/day, alpelisib increased pre- and post-implantation losses, leading to reduced numbers of implantation sites and live embryos. These findings were observed at doses approximately 2.4 to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on body surface areas (BSA). In repeated-dose toxicity study in rats, adverse effects in female reproductive organs included vaginal atrophy and estrous cycle variations in rats at doses >= mg/kg/day (approximately 0.7 to 0.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). In male fertility study, alpelisib administered orally at doses of 3, 10 and 20 mg/kg/day for up to 99 days (10-weeks prior to pairing, during mating period and continuing during post-pairing) to male rats, resulted in reduced weights of seminal vesicles and prostate, which correlated with atrophy and/or reduced secretion in prostate and seminal vesicles at >= 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). No adverse effects on male fertility parameters were observed at doses up to 20 mg/kg/day.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is limited experience of overdose with alpelisib in clinical trials.In cases where accidental overdosage of alpelisib was reported in the clinical studies, the adverse reactions associated with the overdose were consistent with the known safety profile of alpelisib 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 VIJOICE.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. Vijoice(TM) (alpelisib) tabletsNDC 0078-1021-8450 mg daily doseTake one 50 mg tablet once dailyRx onlyRecommended Dosage: Take one 50 mg tablet once daily with food.Swallow tablets whole. DO NOT chew, crush, or split tablets.See prescribing information for complete dosage information andinstruction for patients who are unable to swallow whole tablets.28-Day SupplyContains: One blister pack containing 28 tabletsNOVARTIS. PRINCIPAL DISPLAY PANELVijoice(TM)(alpelisib) tabletsNDC 0078-1021-8450 mg daily doseTake one 50 mg tablet once dailyRx onlyRecommended Dosage: Take one 50 mg tablet once daily with food. Swallow tablets whole. DO NOT chew, crush, or split tablets. See prescribing information for complete dosage information and instruction for patients who are unable to swallow whole tablets.28-Day SupplyContains: One blister pack containing 28 tabletsNOVARTIS.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of VIJOICE have not been characterized. Cardiac ElectrophysiologyAt dose of 300 mg, alpelisib does not prolong the QT interval to any clinically relevant extent in the oncology setting. VIJOICE is not approved for use in the oncology setting.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors and are presented as mean (% CV) under fed conditions unless otherwise specified. Steady-state alpelisib maximum plasma concentration (Cmax) and area under the curve (AUC) increased proportionally over the dose range of 30 mg (0.6 times the lowest approved recommended dosage) to 450 mg (1.8 times the highest 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. 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 alpelisib dose of 300 mg. No clinically relevant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.DistributionThe apparent volume of distribution of alpelisib at steady-state is 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 clearance of alpelisib is 9.2 L/hr (21%) under fed conditions.MetabolismAlpelisib is primarily metabolized by chemical and enzymatic hydrolysis and to lesser extent by CYP3A4, in vitro.ExcretionFollowing single oral dose of 400 mg (1.6 times the highest approved recommended dosage) radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged) and 14% (2% unchanged) 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.Pediatric PatientsThe pharmacokinetics of VIJOICE in pediatric patients have not been evaluated.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesAcid Reducing Agents: No clinically significant differences in the pharmacokinetics of alpelisib were observed when used concomitantly with ranitidine (H2 receptor antagonist) and administered with food as directed.Concomitant use of ranitidine decreased alpelisib AUC approximately 30% and Cmax by 51% with single 300 mg oral dose (1.2 times the highest approved recommended dosage) of alpelisib under the fasted state. In the presence of low-fat low-calorie meal, AUC was decreased by 21% and Cmax by 36% with ranitidine.CYP3A4 Substrates: No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when used concurrently 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on animal data and mechanism of action, VIJOICE 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 doses described below (see Data). Advise pregnant women 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 during the period of organogenesis. In the rat study, animals were dosed at 3, 10, or 30 mg/kg/day from gestation day to 17; and in the rabbit study, animals were dosed at 3, 15, 25, and 30 mg/kg/day from gestation day to 20.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 3.6 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). At dose of 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA), 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 (approximately to 2.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients based on BSA) resulted in no viable fetuses (post-implantation loss). Doses >= 15 mg/kg/day (approximately 3.5 to 1.1 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA) resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: April 2022PATIENT INFORMATIONVIJOICE(R) (vi joiz)(alpelisib)tabletsWhat is VIJOICEVIJOICE is prescription medicine used to treat adults and children years of age and older with severe phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA)-Related Overgrowth Spectrum (PROS).It is not known if VIJOICE is safe and effective in children below years of age.Do not take VIJOICE if you have had severe allergic reaction to alpelisib or are allergic to any of the ingredients in VIJOICE.See the end of this Patient Information leaflet for complete list of the ingredients in VIJOICE.See What are the possible side effects of VIJOICE for signs and symptoms of severe allergic reactions. Before you take VIJOICE, tell your healthcare provider about all of your medical conditions, including if you: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. VIJOICE 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 VIJOICE.You should use effective birth control during treatment with VIJOICE 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 VIJOICE and for week after the last dose. If your female partner becomes pregnant, tell your healthcare provider right away.are breastfeeding or plan to breastfeed. It is not known if VIJOICE passes into your breast milk. Do not breastfeed during treatment with VIJOICE and for week after the last dose.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VIJOICE 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 VIJOICETake VIJOICE exactly as your healthcare provider tells you.Do not change your dose or stop taking VIJOICE unless your healthcare provider tells you.Take VIJOICE time each day, at about the same time each day.Take VIJOICE with food.Swallow VIJOICE tablets whole. Do not split or chew the tablets.Do not take VIJOICE tablets that are broken, cracked or that look damaged at the time of opening the blister pack.If you cannot swallow tablets, you can take VIJOICE mixed with water (suspension) as follows:Place VIJOICE tablets into glass that contains to ounces of water and let it stand for about minutes. Use water only. Crush the tablets with spoon and stir to dissolve. The liquid will be cloudy and you may see tablet pieces.Swallow the mixture right away.Next, add about to tablespoons of water to the same glass and stir with the same spoon. Then swallow the entire contents of the glass to ensure the entire dose is consumed. Repeat this step if necessary.Throw away any of the VIJOICE that is not taken within 60 minutes after it is prepared. If you miss dose of VIJOICE, 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 VIJOICE, do not take another dose on that day. Take your next dose at your usual time.If you take too much VIJOICE, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of VIJOICEVIJOICE 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 VIJOICE.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 VIJOICE and can be severe. Your healthcare provider will monitor your sugar levels before you start and during treatment with VIJOICE. Your healthcare provider may monitor your sugar levels more often if you have history of diabetes. Tell your healthcare provider right away if you develop symptoms of hyperglycemia, 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 VIJOICE and can be severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney injury. Tell your healthcare provider right away if you develop diarrhea during treatment with VIJOICE. 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 VIJOICE if you get certain serious side effects. The most common side effects of VIJOICE include: diarrhea high blood sugar dry skin mouth sores (stomatitis) headache hair loss (alopecia)VIJOICE 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 VIJOICE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VIJOICEStore VIJOICE at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F).Keep VIJOICE and all medicines out of the reach of children.General information about the safe and effective use of VIJOICE.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VIJOICE for condition for which it was not prescribed. Do not give VIJOICE 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 VIJOICE that is written for health professionals.What are the ingredients in VIJOICEActive ingredient: alpelisib Inactive ingredients: hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains hypromellose, iron oxide red (applicable only to 50 mg and 200 mg strengths), iron oxide yellow, 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.VIJOICE.com or call 1-888-VIJOICE (1-888-845-6423).T2022-22. See the end of this Patient Information leaflet for complete list of the ingredients in VIJOICE.. See What are the possible side effects of VIJOICE 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. VIJOICE 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 VIJOICE.You should use effective birth control during treatment with VIJOICE 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 VIJOICE and for week after the last dose. If your female partner becomes pregnant, tell your healthcare provider right away.. Your healthcare provider will check to see if you are pregnant before you start treatment with VIJOICE.. You should use effective birth control during treatment with VIJOICE 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 VIJOICE passes into your breast milk. Do not breastfeed during treatment with VIJOICE and for week after the last dose.. Take VIJOICE exactly as your healthcare provider tells you.. Do not change your dose or stop taking VIJOICE unless your healthcare provider tells you.. Take VIJOICE time each day, at about the same time each day.. Take VIJOICE with food.. Swallow VIJOICE tablets whole. Do not split or chew the tablets.. Do not take VIJOICE tablets that are broken, cracked or that look damaged at the time of opening the blister pack.. If you cannot swallow tablets, you can take VIJOICE mixed with water (suspension) as follows:Place VIJOICE tablets into glass that contains to ounces of water and let it stand for about minutes. Use water only. Crush the tablets with spoon and stir to dissolve. The liquid will be cloudy and you may see tablet pieces.Swallow the mixture right away.Next, add about to tablespoons of water to the same glass and stir with the same spoon. Then swallow the entire contents of the glass to ensure the entire dose is consumed. Repeat this step if necessary.Throw away any of the VIJOICE that is not taken within 60 minutes after it is prepared. Place VIJOICE tablets into glass that contains to ounces of water and let it stand for about minutes. Use water only. Crush the tablets with spoon and stir to dissolve. The liquid will be cloudy and you may see tablet pieces.. Swallow the mixture right away.. Next, add about to tablespoons of water to the same glass and stir with the same spoon. Then swallow the entire contents of the glass to ensure the entire dose is consumed. Repeat this step if necessary.. Throw away any of the VIJOICE that is not taken within 60 minutes after it is prepared.. If you miss dose of VIJOICE, 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 VIJOICE, do not take another dose on that day. Take your next dose at your usual time.. If you take too much VIJOICE, 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 VIJOICE.. 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 VIJOICE and can be severe. Your healthcare provider will monitor your sugar levels before you start and during treatment with VIJOICE. Your healthcare provider may monitor your sugar levels more often if you have history of diabetes. Tell your healthcare provider right away if you develop symptoms of hyperglycemia, 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 VIJOICE and can be severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney injury. Tell your healthcare provider right away if you develop diarrhea during treatment with VIJOICE. Your healthcare provider may tell you to drink more fluids or take medicines to treat diarrhea.. Store VIJOICE at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F).

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Adult PatientsThe recommended dosage of VIJOICE in adult patients is 250 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.Pediatric Patients (2 to less than 18 years of age)The recommended initial dosage of VIJOICE in pediatric patients is 50 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.Consider dose increase to 125 mg once daily in pediatric patients >= years old for response optimization (clinical/radiological) after 24 weeks of treatment with VIJOICE at 50 mg once daily. When pediatric patient turns 18 years old, consider gradual dose increase up to 250 mg. Recommended dose increases by age group are listed in Table 1. Table 1: Recommended Daily VIJOICE Dose Levels for Pediatric Patients (2 to less than 18 years of age)A recommended increased dose has not been established.Patient age (years)Initial doseDose increase2 to 650 mgNot applicable6 to 1850 mg125 mg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on animal data and mechanism of action, VIJOICE 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 doses described below (see Data). Advise pregnant women 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 during the period of organogenesis. In the rat study, animals were dosed at 3, 10, or 30 mg/kg/day from gestation day to 17; and in the rabbit study, animals were dosed at 3, 15, 25, and 30 mg/kg/day from gestation day to 20.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 3.6 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). At dose of 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA), 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 (approximately to 2.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients based on BSA) resulted in no viable fetuses (post-implantation loss). Doses >= 15 mg/kg/day (approximately 3.5 to 1.1 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA) resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head. 8.2 Lactation. Risk SummaryThere are 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 VIJOICE and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status in females of reproductive potential prior to initiating VIJOICE.ContraceptionFemalesVIJOICE 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 VIJOICE 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 VIJOICE and for week after the last dose.InfertilityBased on findings from animal studies, VIJOICE may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of VIJOICE have been established in pediatric patients to less than 18 years of age with PROS based on results from single-arm clinical study of VIJOICE (EPIK-P1) that enrolled 39 pediatric patients: 11 patients aged to years, 12 patients aged to 11 years, and 16 patients aged 12 to less than 18 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)].The safety and effectiveness of VIJOICE in pediatric patients below the age of years have not been established.Although there were no new safety signals observed in pediatric patients, there is insufficient data to determine whether VIJOICE has an adverse impact on growth and development in pediatric patients with PROS. Based on the animal toxicity data (described below), regular monitoring of growth and development in pediatric patients treated with VIJOICE is recommended.Animal Toxicity DataIn 4-week general toxicology study, rats administered alpelisib had growth plate thickening and decreased trabeculae of the knee joint, dentin thinning, and degenerative odontoblasts at the dose of 30 mg/kg/day (approximately 2.8 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). Dentin thinning/irregular dentin was also observed in the 13-week toxicology study in rats at the high dose of 20 mg/kg/day (approximately to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). 8.5 Geriatric Use. There were no adult patients aged 65 years of age or older who received VIJOICE in EPIK-P1.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Severe Hypersensitivity: Permanently discontinue VIJOICE. Promptly initiate appropriate treatment. (5.1)Severe Cutaneous Adverse Reactions (SCARs): VIJOICE 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 VIJOICE for signs or symptoms of SCARs. Permanently discontinue VIJOICE if SCARs are confirmed. (2.3, 5.2)Hyperglycemia: VIJOICE can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. The safety of VIJOICE in patients with Type or uncontrolled Type diabetes has not been established. Before initiating treatment with VIJOICE, 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 VIJOICE if severe hyperglycemia occurs. (2.3, 5.3)Pneumonitis: VIJOICE can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Permanently discontinue VIJOICE if pneumonitis occurs. (2.3, 5.4)Diarrhea: VIJOICE can cause severe diarrhea, dehydration, and acute kidney injury. Interrupt, reduce dose, or permanently discontinue VIJOICE based on severity. (2.3, 5.5)Embryo-Fetal Toxicity: VIJOICE can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). Severe Hypersensitivity: Permanently discontinue VIJOICE. Promptly initiate appropriate treatment. (5.1). Severe Cutaneous Adverse Reactions (SCARs): VIJOICE 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 VIJOICE for signs or symptoms of SCARs. Permanently discontinue VIJOICE if SCARs are confirmed. (2.3, 5.2). Hyperglycemia: VIJOICE can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. The safety of VIJOICE in patients with Type or uncontrolled Type diabetes has not been established. Before initiating treatment with VIJOICE, 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 VIJOICE if severe hyperglycemia occurs. (2.3, 5.3). Pneumonitis: VIJOICE can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Permanently discontinue VIJOICE if pneumonitis occurs. (2.3, 5.4). Diarrhea: VIJOICE can cause severe diarrhea, dehydration, and acute kidney injury. Interrupt, reduce dose, or permanently discontinue VIJOICE based on severity. (2.3, 5.5). Embryo-Fetal Toxicity: VIJOICE can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). 5.1 Severe Hypersensitivity. Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.Permanently discontinue VIJOICE in the event of severe hypersensitivity [see Contraindications (4)].. 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), have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.If signs or symptoms of SCARs occur, interrupt VIJOICE until the etiology of the reaction has been determined. Consultation with dermatologist is recommended.If SCAR is confirmed, permanently discontinue VIJOICE.If SCAR is not confirmed, VIJOICE may require dose modifications, topical corticosteroids, or oral antihistamine treatment, as described in Table [see Dosage and Administration (2.3)].. 5.3 Hyperglycemia. Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or fatal cases of ketoacidosis, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.In the EPIK-P1 study, Grade or hyperglycemia was reported in 12% of patients treated with VIJOICE [see Adverse Reactions (6.1)].Before initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with VIJOICE, 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 VIJOICE 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 VIJOICE, 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 VIJOICE in patients with Type and uncontrolled Type diabetes has not been established. Patients with history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes.Interrupt, reduce the dose, or permanently discontinue VIJOICE based on the severity as decribed in Table [see Dosage and Administration (2.3)].. 5.4 Pneumonitis. Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt VIJOICE 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 VIJOICE in all patients with confirmed pneumonitis [see Dosage and Administration (2.3)].. 5.5 Diarrhea. Severe diarrhea, including cases resulting in dehydration and acute kidney injury, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.In the EPIK-P1 study, 16% of patients experienced Grade diarrhea during treatment with VIJOICE [see Adverse Reactions (6.1)].Interrupt, reduce the dose or permanently discontinue VIJOICE based on severity [see Dosage and Administration (2.3)].. 5.6 Embryo-Fetal Toxicity. Based on findings in animals and its mechanism of action, VIJOICE can cause fetal harm when administered to pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant animals during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at doses that were approximately equivalent to the recommended pediatric and adult doses. 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 VIJOICE 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 VIJOICE and for week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Dose Modifications for Adverse Reactions (2.3)11/2022Warnings and Precautions, Severe Hypersensitivity (5.1)11/2022Warnings and Precautions, Diarrhea or Colitis (5.5)11/2022.