ALPELISIB: 8,419 Adverse Event Reports & Safety Profile

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

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 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2, 2.3, 2.4)]</span> 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . 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 administration, place VIJOICE tablets in a cup containing 1 to 2 ounces of water. Make the suspension with water only. Let tablets stand in water for approximately 5 minutes. Crush the tablets with a spoon and stir until a suspension is obtained. Immediately after preparation, administer the suspension as directed below. If not administered immediately after preparation, stir the suspension with the same spoon to re-suspend any particles before administration. Discard the suspension if it is not administered within 60 minutes after preparation.

Oral Administration

Administer the suspension from the cup. After administration of the suspension, add approximately 1 to 2 ounces of water to the same cup. Stir with the same spoon to re-suspend any remaining particles and administer the entire contents of the cup orally. Repeat if particles remain.

Feeding Tubes Administration

Administer VIJOICE tablets prepared as a suspension via French size 5 to 12 diameter silicone or polyurethane nasogastric tubes, or via French size 12 to 24 diameter silicone gastric tubes. Withdraw VIJOICE suspension from the cup into an enteral syringe and administer it via the nasogastric or gastric tube. After administration, add approximately 1 to 2 ounces (approximately 30 to 60 mL) of water to the same cup. Stir with the same spoon to re-suspend any remaining particles. Withdraw the contents of the cup into the same enteral syringe and administer it via the nasogastric or gastric tube. Repeat if particles remain.

Vijoice

Oral Granules Administer VIJOICE oral granules directly onto the tongue with water, or prepare as a suspension or a mixture for oral use. To administer via feeding tubes prepare the suspension with water only. Each packet is for single use only. No packet should be used if the packet seal is broken. Do not attempt to use partial quantities of oral granules from 50 mg granules packets to prepare a dose. Do not combine VIJOICE tablets and VIJOICE oral granules to achieve the prescribed dose of 125 mg or 250 mg. For patients for whom a daily dose of 50 mg is prescribed, administer VIJOICE oral granules [see Clinical Pharmacology (12.3)] in one of the following ways: VIJOICE Oral Granules for Direct Oral Administration Pour the contents of one VIJOICE oral granules packet directly onto the tongue and swallow with approximately 2 to 4 ounces of water. If needed, rinse the mouth with additional water and swallow to ensure no particles remain in the mouth.

Vijoice

Oral Granules as a Suspension or a Mixture for Oral administration Pour the contents of one VIJOICE oral granules packet into a cup.

Add

1 to 3 teaspoons (about 0.5 ounces) of a beverage (water, milk, or apple juice) or soft food (applesauce or yogurt) and stir with a spoon, then administer the suspension or the mixture immediately. Rinse the cup with up to 2 ounces of a beverage (water, milk or apple juice) and administer the rinse immediately to ensure the entire dose is administered. If particles remain, repeat until the full dose is administered. If not administered immediately after preparation, stir the suspension or the mixture with the same spoon to re-suspend any particles before administration. Discard the oral granules mixed with water, milk, apple juice, applesauce, or yogurt if they are not administered within 60 minutes after preparation.

Vijoice

Oral Granules Suspension for Feeding Tubes Administration For patients who are not able to swallow VIJOICE orally, administer VIJOICE via feeding tubes. Administer VIJOICE granules via French size 8 to 12 diameter silicone or polyurethane nasogastric tubes or via French size 12 to 24 diameter silicone gastric tubes. Pour the contents of one VIJOICE granules packet into a cup.

Add

4 teaspoons (about 0.7 ounces or 20 mL) of water and stir gently with a spoon until a suspension is obtained. Make the suspension with water only. Immediately after preparation, withdraw the suspension from the cup into an enteral syringe and administer it via the nasogastric or gastric tube. After administration, add 4 teaspoons (about 0.7 ounces or 20 mL) of water to the same cup. Stir with the same spoon to re-suspend any remaining particles. Withdraw the contents of the cup into the same enteral syringe and administer it via the nasogastric or gastric tube. Repeat if particles remain. If not administered immediately after preparation, stir the suspension with the same spoon to re-suspend any particles before withdrawing into an enteral syringe for administration. Discard the suspension if it is not administered within 60 minutes after preparation.

2.5 Dosage Modifications for Adverse Reactions The recommended VIJOICE dose reductions for adverse reactions in adult and pediatric patients are listed in Table 2 and Table 3, respectively.

Table

2: VIJOICE Dosage Reduction Recommendations for Adverse Reactions in Adult Patients a Dose can be administered as VIJOICE tablets or VIJOICE oral granules. VIJOICE dose level Dose and schedule First-dose reduction 125 mg once daily Second-dose reduction 50 mg once daily a Table 3: VIJOICE Dosage Reduction Recommendations for Adverse Reactions in Pediatric Patients a Dose can be administered as VIJOICE tablets or VIJOICE oral granules. Action VIJOICE dose prior to dose reduction 125 mg once daily 50 mg once daily Dose reduction 50 mg once daily a Not applicable Discontinue VIJOICE in adults or pediatric patients who cannot tolerate 50 mg daily.

Tables

4, 5, 6, 7, 8, and 9 summarize recommendations for dose interruption, reduction, or discontinuation of VIJOICE in the management of specific adverse reactions.

Cutaneous Adverse

Reactions If a 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) a Grading according to Common Terminology Criteria for Adverse Events (CTCAE)

Version

5.0. b For all grades of rash, consider consultation with a dermatologist. c Antihistamines administered prior to rash onset may decrease incidence and severity of rash. [see Warnings and Precautions (5.1, 5.2)] Grade a,b Recommendation for adult and pediatric patients c 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 a 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 ≤ 1 within 10 days, systemic corticosteroid may be discontinued. If the etiology is determined to be SCAR, permanently discontinue VIJOICE.

Grade

3 (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 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 pediatric patients Dose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose).

Grade

1 Fasting glucose > ULN -160 mg/dL or > ULN -8.9 mmol/L No VIJOICE dosage modification is required. Initiate or intensify oral anti-hyperglycemic treatment b .

Grade

2 Fasting glucose > 160 - 250 mg/dL or > 8.9 - 13.9 mmol/L No VIJOICE dosage modification is required. Initiate or intensify oral anti-hyperglycemic treatment b .

Adult

Patients: If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatment b , reduce VIJOICE dose by 1 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 treatment b , interrupt VIJOICE until improvement to Grade ≤ 1, then resume VIJOICE at 50 mg and follow fasting glucose value-specific recommendations.

Grade

3 Fasting glucose > 250 - 500 mg/dL or > 13.9 - 27.8 mmol/L Interrupt VIJOICE. Initiate or intensify oral anti-hyperglycemic treatment b 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 3 to 5 days under appropriate anti-hyperglycemic treatment, resume VIJOICE at 1 lower dose level. If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate anti-hyperglycemic treatment, consultation with a 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 treatment b , permanently discontinue VIJOICE.

Pediatric

Patients: If fasting glucose decreases to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 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 3 to 5 days under appropriate anti-hyperglycemic treatment, consultation with a 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 treatment b , permanently discontinue VIJOICE. If hyperglycemia recurs at Grade ≥ 3, consider permanent discontinuation of VIJOICE.

Grade

4 Fasting glucose > 500 mg/dL or > 27.8 mmol/L Interrupt VIJOICE. Initiate or intensify appropriate oral anti-hyperglycemic treatment b . 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.

Pneumonitis Table

6: Dosage Modification for Pneumonitis a Grading according to CTCAE Version 5.0. [see Warnings and Precautions (5.4)] Grade a Recommendation for adult and pediatric patients Any Grade

• Interrupt VIJOICE if pneumonitis is suspected.
• Permanently discontinue VIJOICE if pneumonitis is confirmed. Diarrhea or Colitis In pediatric patients, consider consultation with a physician with experience in the treatment of gastrointestinal conditions.

Table

7: Dosage Modification and Management for Diarrhea or Colitis a Grading according to CTCAE Version 5.0. b For Grade 2 and 3 colitis consider additional treatment, such as enteric-acting and/or systemic steroids. [see Warnings and Precautions (5.5)] Grade a Recommendation for adult and pediatric patients Grade 1 No VIJOICE dosage modification is required. Initiate appropriate medical therapy and monitor as clinically indicated.

Grade

2 Interrupt 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 b .

Adult

Patients: For recurrent Grade ≥ 2, interrupt VIJOICE dose until improvement to Grade ≤ 1, then resume VIJOICE at the next lower dose level.

Pediatric

Patients: For recurrent Grade ≥ 2, interrupt VIJOICE dose until improvement to Grade ≤ 1, then resume VIJOICE at 50 mg.

Grade

3 Interrupt VIJOICE dose until improvement to Grade ≤ 1. Initiate or intensify appropriate medical therapy and monitor as clinically indicated b .

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. For recurrent Grade ≥ 3, consider permanent discontinuation of VIJOICE.

Grade

4 Permanently discontinue VIJOICE.

Pancreatitis Table

8: Dosage Modification for Pancreatitis a Grading according to CTCAE Version 5.0. Grade a Recommendation for adult and pediatric patients Grade 2 Interrupt 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

3 Adult 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

4 Permanently discontinue VIJOICE.

Other Adverse Reactions Table

9: Dosage Modification and Management for Other Adverse Reactions (Excluding Rash and Severe Cutaneous Adverse Reactions, Hyperglycemia, Pneumonitis, Diarrhea or Colitis, and Pancreatitis) a Grading according to CTCAE Version 5.0. b For Grade 2 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. c For Grade 2 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. d If alopecia becomes a concern, consider consulting a dermatologist. Grade a Recommendation for adult and pediatric patients Grade 1 or 2 b,c,d No VIJOICE dosage modification is required. Initiate appropriate medical therapy and monitor as clinically indicated b,c,d .

Grade

3 Interrupt 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 a qualified physician with specific expertise in the field of the concerned adverse reaction.

Grade

4 Permanently discontinue VIJOICE.

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 )

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Severe Hypersensitivity [see Warnings and Precautions (5.1)]

Severe Cutaneous Adverse

Reactions [see Warnings and Precautions (5.2)] Hyperglycemia [see Warnings and Precautions (5.3)] Pneumonitis [see Warnings and Precautions (5.4)] Diarrhea or Colitis [see Warnings and Precautions (5.5)] Most common adverse reactions, including laboratory abnormalities (all Grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation <span class="opacity-50 text-xs">[see Clinical Studies (14)]</span> . Patients received either PIQRAY 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287).

Fulvestrant

500 mg was administered intramuscularly on Cycle 1, Day 1 and 15, and then at Day 1 of each 28-day cycle during treatment phase. Two patients (0.7%) died while on treatment with PIQRAY plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment. Serious adverse reactions occurred in 35% of patients receiving PIQRAY plus fulvestrant. Serious adverse reactions in > 2% of patients receiving PIQRAY plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%). Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the PIQRAY plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK-ligand inhibitor administration. Among patients receiving PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and fulvestrant and 21% permanently discontinued PIQRAY alone, due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%). Dose reductions due to adverse reactions occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent adverse reactions leading to dose reduction in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%). The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia. Adverse reactions and laboratory abnormalities are listed in Table 6 and Table 7, respectively.

Table

6: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher than Placebo Arm in SOLAR-1 (All Grades) Grading according to CTCAE Version 4.03. 1 Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration. 2 Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower. 3 Fatigue: including fatigue, asthenia. 4 Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness. 5 Urinary tract infection: including UTI and single case of urosepsis. 6 Dysgeusia: including dysgeusia, ageusia, hypogeusia. 7 Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic. 8 Dry skin: including dry skin, skin fissures, xerosis, xeroderma. * No Grade 4 adverse reactions were reported. PIQRAY plus fulvestrant N = 284 Placebo plus fulvestrant N = 287 Adverse reactions All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal disorders Diarrhea 58 7 * 16 0.3 * Nausea 45 2.5 * 22 0.3 * Stomatitis 1 30 2.5 * 6 0 * Vomiting 27 0.7 * 10 0.3 * Abdominal pain 2 17 1.4 * 11 1 * Dyspepsia 11 0 * 6 0 * General disorders and administration site conditions Fatigue 3 42 5 * 29 1 * Mucosal inflammation 19 2.1 * 1 0 * Edema peripheral 15 0 * 5 0.3 * Pyrexia 14 0.7 4.9 0.3 * Mucosal dryness 4 12 0.4 * 4.2 0 * Infections and infestations Urinary tract infection 5 10 0.7 * 5 1 * Investigations Weight decreased 27 3.9 * 2.1 0 * Metabolism and nutrition disorders Decreased appetite 36 0.7 * 10 0.3 * Nervous system disorders Dysgeusia 6 18 0.4 * 3.5 0 * Headache 18 0.7 * 13 0 * Skin and subcutaneous tissue disorders Rash 7 52 20 * 7 0.3 * Alopecia 20 0 * 2.4 0 * Pruritus 18 0.7 * 6 0 * Dry skin 8 18 0.4 * 3.8 0 * Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days. A subgroup of 86 patients received premedication, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.

Table

7: Laboratory Abnormalities Occurring in ≥ 10% of Patients in SOLAR-1 1 Glucose increase is an expected laboratory abnormality of PI3K inhibition. * No Grade 4 laboratory abnormalities were reported. PIQRAY plus fulvestrant N = 284 Placebo plus fulvestrant N = 287 Laboratory abnormality All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematological parameters Lymphocyte count decreased 52 8 40 4.5 * Hemoglobin decreased 42 4.2 * 29 1 * Activated partial thromboplastin time (aPTT) prolonged 21 0.7 * 16 0.3 * Platelet count decreased 14 1.1 6 0 * Biochemical parameters Glucose increased 1 79 39 34 1 Creatinine increased 67 2.8 * 25 0.7 * Gamma glutamyl transferase (GGT) increased 52 11 44 10 Alanine aminotransferase (ALT) increased 44 3.5 34 2.4 * Lipase increased 42 7 25 6 Calcium (corrected) decreased 27 2.1 20

1.4 Glucose decreased 26 0.4 14 0 * Potassium decreased 14 6 2.8 0.7 * Albumin decreased 14 0 * 8 0 * Magnesium decreased 11 0.4 * 4.2 0 * Metformin Premedication for Hyperglycemia Adverse Reactions The safety of PIQRAY and endocrine therapy with metformin premedication was evaluated in METALLICA (NCT04300790), a single-arm, two-cohort study in 68 patients with HR-positive, HER2-negative advanced breast cancer harboring PIK3CA mutation(s). The majority of patients (93%) received fulvestrant as endocrine therapy during the study. Cohort A enrolled patients with normal glycemic status (FPG &lt; 100 mg/dl [&lt; 5.6 mmol/L] and HbA1c &lt; 5.7%) and Cohort B enrolled patients with impaired glycemic status (FPG 100–140 mg/dL [5.6–7.8 mmol/L] or HbA1c 5.7%–6.4%). Metformin was administered beginning 7 days prior to treatment with PIQRAY.

On Day

1 to Day 3, metformin 500 mg twice daily was administered orally and then increased up to 1,000 mg twice daily based on tolerability. Hyperglycemia adverse reactions occurred in 33% (16/48) and 70% (14/20 patients) in Cohort A and Cohort B, respectively.

Grade

3-4 hyperglycemia occurred in 2.1% (1/48) of patients in Cohort A and 15% (3/20) of patients in Cohort B. The incidence of nausea, vomiting, and diarrhea adverse reactions, including Grade 3 diarrhea, increases with metformin premedication [see Warnings and Precautions (5.3)] . Serious adverse reactions occurred in 22% of patients in the METALLICA study and serious adverse reactions ≥ 2% included diarrhea (3%), rash (3%) and vomiting (3%). The most common Grade 3-4 adverse reactions (≥ 5%) were rash (16%), diarrhea (13%), and hyperglycemia (6%). Permanent discontinuation of PIQRAY due to adverse reactions in the METALLICA study occurred in 19% of patients, and dose modification or interruption of PIQRAY due to adverse reactions occurred in 56% of patients, of which 28% were dose reductions. The most common adverse reactions (≥ 30%) in the METALLICA study were diarrhea (68%), nausea (68%), fatigue (46%), hyperglycemia (44%), rash (38%), and vomiting (34%).

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

AND PRECAUTIONS Severe Hypersensitivity : Permanently discontinue PIQRAY. Promptly initiate appropriate treatment. ( 5.1 )

Severe Cutaneous Adverse

Reactions (SCARs) : PIQRAY can cause SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Interrupt PIQRAY for signs or symptoms of SCARs. Permanently discontinue PIQRAY if SCARs are confirmed. ( 5.2 ) Hyperglycemia : PIQRAY can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. Consider premedication with metformin prior to the initiation of PIQRAY based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation. Use of metformin premedication prior to the initiation of PIQRAY decreases the incidence and severity of hyperglycemia, but increases the incidence and severity of nausea, vomiting, and diarrhea adverse reactions. After initiating treatment, monitor FPG and HbA1c periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia occurs. ( 2.3 , 5.3 , 6.1 ) Pneumonitis : PIQRAY can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs. ( 2.3 , 5.4 ) Diarrhea or Colitis : PIQRAY causes diarrhea in most patients and may be severe, resulting in dehydration and acute kidney injury. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs. Colitis has been reported in patients treated with PIQRAY. Monitor for diarrhea and additional symptoms of colitis, including abdominal pain and mucus or blood in stool. Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea or colitis occurs. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids. ( 2.3 , 5.5 , 6.2 ) Embryo-Fetal Toxicity : PIQRAY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

5.1 Severe Hypersensitivity Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms, including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia. The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7% <span class="opacity-50 text-xs">[see Adverse Reactions (6)]</span> . Angioedema has been reported in the postmarketing setting in patients treated with PIQRAY <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with PIQRAY. In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with PIQRAY in the postmarketing setting <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous adverse reactions during PIQRAY treatment. If a SCAR is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment as described in Table 2 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)]</span> . Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

5.3 Hyperglycemia Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Fatal cases of ketoacidosis have occurred in the postmarketing setting. Hyperglycemia was reported in 65% of patients treated with PIQRAY.

Grade

3 (FPG > 250 to 500 mg/dL) and Grade 4 (FPG > 500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n = 2) treated with PIQRAY. Among the patients who experienced Grade ≥ 2 (FPG 160 to 250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range, 5 to 517 days). In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-hyperglycemic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-hyperglycemic medication [i.e., insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas]. In patients with Grade ≥ 2 hyperglycemia with at least 1 grade improvement (n = 153), median time to improvement from the first event was 8 days (range, 2 to 65 days). In all patients with elevated FPG who continued fulvestrant treatment after discontinuing PIQRAY (n = 54), 96% (n = 52) of patients had FPG levels that returned to baseline. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. Monitor fasting glucose more frequently for the first few weeks during treatment with PIQRAY in patients with risk factors for hyperglycemia, such as obesity (BMI ≥ 30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥ 75 [see Use in Specific Populations (8.5)] . If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes. The safety of PIQRAY in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of controlled Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes. Consider premedication with metformin prior to the initiation of PIQRAY in combination with fulvestrant based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation. In the METALLICA study, use of metformin starting 7 days prior to the initiation of PIQRAY appeared to decrease the incidence and severity of hyperglycemia events, but increased the incidence and severity of nausea, vomiting, and diarrhea adverse reactions [see Adverse Reactions (6.1)] . Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 3 [see Dosage and Administration (2.3)] . Advise patients of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).

5.4 Pneumonitis Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, can occur in patients treated with PIQRAY. Pneumonitis was reported in 1.8% of patients treated with PIQRAY. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms, such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Permanently discontinue PIQRAY in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.

5.5 Diarrhea or Colitis Severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, can occur in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY.

Grade

3 diarrhea occurred in 7% (n = 19) of patients. Among patients with Grade 2 or 3 diarrhea (n = 71), the median time to onset was 46 days (range, 1 to 442 days). In clinical trials, 63% of patients who experienced diarrhea required antidiarrheal medications (e.g., loperamide) to manage symptoms. Dose reductions of PIQRAY were required in 6% of patients, and 2.8% of patients permanently discontinued PIQRAY due to diarrhea. Colitis has been reported in the postmarketing setting in patients treated with PIQRAY [see Adverse Reactions (6.2)] . Monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Based on the severity of the diarrhea or colitis, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 4 [see Dosage and Administration (2.3)] . Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids.

5.6 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures based on area under the curve (AUC) that were ≥ 0.8 times the exposure in humans at the recommended dose of 300 mg/day. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]</span> . Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> , 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.