Alpelisib

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 )

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.

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 < 6 50 mg a Not applicable b 6 to < 18 50 mg a 125 mg 2.2 VIJOICE Dosage Form Overview VIJOICE is available in two dosage forms: tablets and oral granules. Prescribe the most appropriate dosage form of VIJOICE according to the dose required and patient needs. VIJOICE Tablets (50 mg, 125 mg, and 200 mg) may be administered as: Whole tablets: For patients who can swallow whole tablets. Tablets prepared as an oral suspension: For patients who have difficulty swallowing whole tablets [see Dosage and Administration (2.4)] . VIJOICE Oral Granules (50 mg per packet): For patients who are prescribed a 50 mg daily dose only [see Dosage and Administration (2.1)] . Do not use multiple 50 mg packets or a partial packet of oral granules for patients prescribed a 125 mg or a 250 mg dose [see Clinical Pharmacology (12.3)] . Do not combine VIJOICE tablets and VIJOICE oral granules to achieve the prescribed dose. 2.3 VIJOICE Administration Overview Take VIJOICE with food at approximately the same time each day [see Clinical Pharmacology (12.3)] . If a dose of VIJOICE is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take 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. 2.4 VIJOICE Preparation and Administration Instructions VIJOICE Tablets Swallow VIJOICE tablets whole, or prepare as a suspension to administer orally, or via feeding tubes. VIJOICE Tablets, Whole Swallow VIJOICE tablets whole and take with food. Do not chew, divide, or crush. Do not use broken, cracked, or damaged tablets. VIJOICE Tablets Prepared as a Suspension for Oral use, or Feeding Tubes (Nasogastric or Gastric Tube) Administration For patients who are not able to swallow tablets, or who are using a feeding tube, prepare and administer VIJOICE as a suspension and take with food [see Clinical Pharmacology (12.3)] . To prepare VIJOICE tablets as a suspension for oral use, place VIJOICE tablets in a cup containing 2 to 4 ounces of water. To prepare VIJOICE tablets as a suspension for feeding tubes ad

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

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. ( 2.5 , 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 1 or uncontrolled Type 2 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. ( 2.5 , 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. ( 2.5 , 5.4 ) Diarrhea or Colitis : VIJOICE can cause severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, as well as colitis. Monitor for diarrhea and additional symptoms of colitis, including abdominal pain and mucus or blood in stool. Interrupt, reduce dose, or permanently discontinue VIJOICE based on severity of diarrhea or colitis. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids. ( 2.5 , 5.5 ) Embryo-Fetal Toxicity : VIJOICE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Severe Hypersensitivity Severe hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have occurred in adult patients treated with alpelisib in the oncology setting and in patients treated with VIJOICE [see Adverse Reactions (6.1)] . 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 a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue VIJOICE. If a SCAR is not confirmed, VIJOICE may require dose modifications, topical or systemic corticosteroids, or oral antihistamine treatment as described in Table 4 [see Dosage and Administration (2.5)] . 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 1 or 2 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 2 weeks, then at least once every 4 weeks, and as clinically indicate

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 )

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.