VIJOICE

Dosage and Administration, VIJOICE Preparation and Administration Instructions ( 2.4 ) 7/2025 Warnings and Precautions, Severe Hypersensitivity ( 5.1 ) 7/2025

1 INDICATIONS AND USAGE VIJOICE is indicated for the treatment of adult and pediatric patients 2 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 a confirmatory trial(s). VIJOICE is a kinase inhibitor indicated for the treatment of adult and pediatric patients 2 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 a confirmatory trial(s). ( 1 )

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 ) Administration: Swallow tablets whole. Do not chew, divide, or crush. ( 2.4 ) For patients who cannot swallow tablets whole, use tablets or oral granules to create a suspension or a mixture. ( 2.4 ) VIJOICE suspension made with water can be administered orally or via a nasogastric or gastric tube. ( 2.4 ) See full prescribing information for preparation and administration instructions. 2.1 Recommended Dosage Adult Patients The recommended dosage of VIJOICE in adult patients is 250 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2, 2.3, 2.4)] 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, 2.3, 2.4)] until disease progression or unacceptable toxicity. Consider a dose increase to 125 mg once daily in pediatric patients ≥ 6 years old for response optimization (clinical/radiological) after 24 weeks of treatment with VIJOICE at 50 mg once daily. When a pediatric patient turns 18 years old, consider a 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 Dose can be administered as VIJOICE tablets or VIJOICE oral granules. b A recommended increased dose has not been established. Patient age (years) Initial dose Dose increase 2 to 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 increased Grade ≥ 3 rash recurs Grade 4 (e.g., severe bullous, blistering or exfoliating skin conditions) (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences) Permanently discontinue VIJOICE. Hyperglycemia 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 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Warnings and Precautions (5.3)] . Table 5: Dosage Modification and Management for Hyperglycemia Abbreviation: ULN, upper limit of normal. a FPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. b Initiate 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 values a Recommendation for adult and p …

3 DOSAGE FORMS AND STRENGTHS Tablets 50 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. Oral Granules 50 mg: White to almost white free flowing mixture of powder and granules in packets. Tablets: 50 mg, 125 mg, and 200 mg ( 3 ) Oral Granules: 50 mg ( 3 )

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 )

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 or Colitis [see Warnings and Precautions (5.5)] Most common adverse reactions (Grades 1 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 Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VIJOICE was evaluated in EPIK-P1 (NCT04285723), a single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use. Fifty-seven patients 2 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 6 months or longer and 79% were exposed for greater than one year. The median age of patients who received VIJOICE was 14 years (range, 2 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 3 or 4 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-P1 Grading according to CTCAE Version 4.03. a Stomatitis: including stomatitis and aphthous ulcer. VIJOICE N = 57 Adverse reactions All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 16 0 Stomatitis a 16 0 Metabolism and nutrition disorders Hyperglycemia 12 0 Skin and subcutaneous tissue disorders Eczema 7 0 Dry skin 7 0 Alopecia 5 0 Nervous system disorders Headache 5 0 Infections and infestations Cellulitis 5 3.5 Clinically 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-P1 Grading according to CTCAE Version 4.03. Abbreviation: N/A, not available. a The denominator used to calculate the rate varied from 9 to 50 based on the number of patients with a baseline value and at least one post-treatment value. b No Grade 4 laboratory abnormalities were reported. c Glucose increase is an expected laboratory abnormality of PI3K inhibition. d No CTCAE grade available. For HbA1c, baseline values increasing post-treatment to a value above the upper limit of the normal range (≥ 5.7%) are considered increased. Laboratory abnormality VIJOICE a N = 57 All Grades …

7 DRUG INTERACTIONS CYP3A4 Inducers : Avoid coadministration of VIJOICE with a strong CYP3A4 inducer. Consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. ( 7.1 ) Breast Cancer Resistance Protein (BCRP) Inhibitors : Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, closely monitor for increased adverse reactions. ( 7.1 ) 7.1 Effect of Other Drugs on VIJOICE CYP3A4 Inducers Avoid coadministration of VIJOICE with strong CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. Alpelisib is metabolized by CYP3A4. Concomitant use of VIJOICE with a 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 a BCRP inhibitor may increase alpelisib exposure [see Clinical Pharmacology (12.3)] , which may increase the risk of adverse reactions.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal data and mechanism of action, VIJOICE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at doses described below ( see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib during the period of organogenesis. In the rat study, animals were dosed at 3, 10, or 30 mg/kg/day from gestation day 6 to 17; and in the rabbit study, animals were dosed at 3, 15, 25, and 30 mg/kg/day from gestation day 7 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 a 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 a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day (approximately 7 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 Summary There 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 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating VIJOICE. Contraception Females VIJOICE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment with VIJOICE and for 1 week after the last dose. Males Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with VIJOICE and for 1 week after the last dose. Infertility Based 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 2 to less than 18 years of age with PROS based on results from a single-arm clinical study of VIJOICE (EPIK-P1) that enrolled 39 pediatric patients: 11 patients aged 2 to 5 years, 12 …

12.1 Mechanism of Action Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models. Activating mutations in PIK3CA have been found to induce a spectrum of overgrowths and malformations comprising a 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), a 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.

11 DESCRIPTION VIJOICE (alpelisib) is a kinase inhibitor. The chemical name of alpelisib is (2 S )- N 1 -[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide. Alpelisib is a white to almost white powder. The molecular formula for alpelisib is C 19 H 22 F 3 N 5 O 2 S and the relative molecular mass is 441.47 g/mol. The pH of a 1.0% (m/V) solution of alpelisib in water/ethanol (50:50 V/V) is approximately 6.2. 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. VIJOICE oral granules are supplied for oral administration with one strength that contains 50 mg of alpelisib. The granules also contain hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. alpelisib structural formula

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.

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 Tablets Daily Dose Blister Packs Daily dose Each carton contains Each child-resistant blister pack contains Appearance of tablet NDC 50 mg daily dose One 28-day supply blister pack 28 tablets: 50 mg alpelisib per tablet Light yellow, unscored, round and curved with beveled edges, debossed with “C7” on one side and “NVR” on the other side NDC 0078-1021-84 125 mg daily dose One 28-day supply blister pack 28 tablets: 125 mg alpelisib per tablet Dark yellow, unscored, ovaloid and curved with beveled edges, debossed with “Y7” on one side and “NVR” on the other side NDC 0078-1028-84 250 mg daily dose Two 14-day supply blister packs (56 tablets total) 14 tablets: 200 mg alpelisib per tablet, and 14 tablets: 50 mg alpelisib per tablet Pale yellow, unscored, ovaloid and curved with beveled edges, debossed with “CL7” on one side and “NVR” on the other side Light yellow, unscored, round and curved with beveled edges, debossed with “C7” on one side and “NVR” on the other side NDC 0078-1035-02 Table 14: VIJOICE Oral Granules Daily dose Each carton contains Each child-resistant packet contains Appearance NDC 50 mg daily dose 28 packets (28-day supply of single-use packets) 50 mg alpelisib White to almost white free flowing mixture of powder and granules NDC 0078-1175-51 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].