Usual Adult Dose for Breast Cancer

300 mg orally once a day with food until disease progression or unacceptable toxicity; when given with this drug, the recommended dose of fulvestrant is 500 mg orally on Days 1, 15, and 29, and once monthly thereafter

Use: In combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CAmutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

Usual Adult Dose for PIK3CA-Related Overgrowth Spectrum

Recommended dosage: 250 mg orally once a day
Duration of therapy: Until disease progression or unacceptable toxicity

Use: Adult patients with PIK3CA- Related Overgrowth Spectrum Disorders (PROS) who require systemic therapy (accelerated approval)

Usual Pediatric Dose for PIK3CA-Related Overgrowth Spectrum

Initial dose: 50 mg orally once a day
Maintenance dose:

• Patients younger than 6 years old: 50 mg orally once a day
• Patients 6 years and older: Increase to 125 mg orally once a day after 24 weeks of 50 mg/day

Maximum dose: 125 mg/day oral
Duration of therapy: Until disease progression or unacceptable toxicity

Comment: When the pediatric patient turns 18 years old, consider gradual dose increase up to 250 mg/day.

Use: Pediatric patients over 2 years old with PIK3CA- Related Overgrowth Spectrum Disorders (PROS) who require systemic therapy (accelerated approval)

Renal Dose Adjustments

Mild to moderate renal impairment (CrCl 30 to less than 90 mL/min): No adjustment recommended.
Severe renal impairment (CrCl less than 30 mL/min): Data not available

Liver Dose Adjustments

No adjustment recommended.

Dose Adjustments

BREAST CANCER INDICATION:
DOSE MODIFICATIONS FOR ADVERSE REACTIONS:

• Starting dose: 300 mg orally once a day
• First dose reduction: 250 mg orally once a day
• Second dose reduction: 200 mg orally once a day
• If further dose reduction below 200 mg once daily is required, discontinue therapy.

NOTE: Only one dose reduction is permitted for pancreatitis.

DOSE MODIFICATIONS FOR HYPERGLYCEMIA:

• GRADE 1 (FPG greater than ULN minus 160 mg/dL or greater than ULN minus 8.9 mmol/L): No adjustment required; initiate or intensify antidiabetic treatment (*2).
• GRADE 2 (FPG greater than 160 to 250 mg/dL or greater than 8.9 to 13.9 mmol/L): No adjustment required; initiate or intensify antidiabetic treatment (*2); if FPG does not decrease to 160 mg/dL or less or 8.9 mmol/L or less within 21 days with antidiabetic treatment, reduce the dose of this drug by 1 dose level and follow FPG value specific recommendations.
• GRADE 3 (greater than 250 to 500 mg/dL or greater than 13.9 to 27.8 mmol/L): Interrupt this drug; initiate or intensify antidiabetic treatment (*2) and consider additional antidiabetic medications (*3) for 1 to 2 days until hyperglycemia improves. Administer IV hydration and consider treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances). If FPG decreases to 160 mg/dL or less or 8.9 mmol/L or less within 3 to 5 days under antidiabetic treatment, resume this drug at 1 lower dose level. If FPG does not decrease to 160 mg/dL or less or 8.9 mmol/L or less within 3 to 5 days under antidiabetic treatment, consultation with a physician with expertise in the treatment of hyperglycemia is recommended. If FPG does not decrease to 160 mg/dL or less or 8.9 mmol/L or less within 21 days following antidiabetic treatment (*2), permanently discontinue this drug.
• GRADE 4 (greater than 500 mg/dL or greater than 27.8 mmol/L): Interrupt this drug; initiate or intensify antidiabetic treatment (*2) and consider additional antidiabetic treatment (administer IV hydration and consider treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances)), re-check FPG within 24 hours and as clinically indicated. If FPG decreases to 500 mg/dL or less or 27.8 mmol/L or less, follow FPG value specific recommendations for Grade 3. If FPG is confirmed at greater than 500 mg/dL or greater than 27.8 mmol/L, permanently discontinue this drug.

NOTE:
(*1) FPG/Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTAE).
(*2) Initiate applicable antidiabetic medications, including metformin and insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local diabetic treatment guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500 mg once daily. Based on tolerability, metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1000 mg with dinner, followed by further increase to 1000 mg twice daily if needed.
(*3) As recommended in the SOLAR-1 trial, insulin may be used for 1 to 2 days until hyperglycemia resolves; however, this may not be necessary in the majority of alpelisib-induced hyperglycemia, given the short half-life of alpelisib and the expectation of glucose levels normalizing after interruption of alpelisib.

DOSE MODIFICATIONS FOR RASH:

• GRADE 1 (less than 10% body surface area [BSA] with active skin toxicity): No adjustment required; initiate topical corticosteroid treatment; consider adding oral antihistamine to manage symptoms
• GRADE 2 (10% to 30% BSA with active skin toxicity): No adjustment required; initiate or intensify topical corticosteroid and oral antihistamine treatment; consider low dose systemic corticosteroid treatment
• GRADE 3 (e.g., severe rash not responsive to medical management) (greater than 30% BSA with active skin toxicity): Interrupt this drug; initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment when improved to Grade 1 or less, resume this drug at the same dose level for first occurrence of rash, or at next lower dose level in case of second occurrence
• 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 this drug.

NOTE:

• Grading according to CTCAE.
• For all grades of rash, consider consultation with a dermatologist.
• Antihistamines administered prior to rash onset may decrease incidence and severity of rash.

DOSE MODIFICATIONS FOR DIARRHEA:

• Grade 1: No adjustment required; initiate medical therapy and monitor as clinically indicated.
• Grade 2: Initiate or intensify medical therapy and monitor as clinically indicated; interrupt this drug until recovery to Grade 1 or less, then resume this drug at same dose level.
• Grade 3 and 4: Initiate or intensify medical therapy and monitor as clinically indicated. Interrupt this drug until recovery to Grade 1 or less, then resume this drug at the next lower dose level.

NOTE:

• Grading according to CTCAE.

DOSE MODIFICATIONS OTHER TOXICITIES (excluding hyperglycemia, rash, and diarrhea):

• Grade 1 or 2: No dose adjustment required; initiate medical therapy and monitor as clinically indicated (*2) (*3).
• Grade 3: Interrupt this drug until recovery to Grade 1 or less, then resume this drug at the next lower dose level.
• Grade 4: Permanently discontinue this drug.

NOTE:
(*1) Grading according to CTCAE.
(*2) For Grade 2 and 3 pancreatitis, interrupt this drug until recovery to less than Grade 2 and resume at next lower dose level; only one dose reduction is permitted; if toxicity reoccurs, permanently discontinue this drug.
(*3) For Grade 2 total bilirubin elevation, interrupt this drug dose until recovery to Grade 1 or less and resume at the same dose if resolved in 14 days or less or resume at the next lower dose level if resolved in greater than 14 days.

Refer to the prescribing information of fulvestrant for dose modification guidelines in the event of toxicity.

PIK3CA- RELATED OVERGROWTH SPECTRUM DISORDERS (PROS) INDICATION
RECOMMENDED DOSE REDUCTION FOR ADVERSE REACTIONS IN ADULT PATIENTS:

• First dose reduction: 125 mg once a day
• Second dose reduction: 50 mg once a day (discontinue if cannot tolerate)

RECOMMENDED DOSE REDUCTION FOR ADVERSE REACTIONS IN PEDIATRIC PATIENTS:

• Dose reduction: Reduce to 50 mg once a day if dose is 125 mg once a day.
• Discontinue in patients that cannot tolerate 50 mg/day.

CUTANEOUS ADVERSE REACTIONS

• Discontinue permanently if a severe cutaneous adverse reaction (SCAR) is confirmed.
• Do not reintroduce in patients with a previous SCAR during therapy.

Rash and SCARs in adult and pediatric patients:
GRADE 1 (less than 10% body surface area (BSA) with active skin toxicity:

• No modification unless the etiology is confirmed to be SCAR.
• Initiate topical corticosteroids and consider adding oral antihistamine to manage symptoms.
• If active rash does not improve within 28 days, add a low dose systemic corticosteroid.
• Permanently discontinue treatment with this drug if etiology is determined to be SCAR.

GRADE 2 (10% to 30% BSA with active skin toxicity):

• No modification unless the etiology is confirmed to be SCAR.
• Initiate or intensify topical corticosteroids and oral antihistamine treatment.
• Consider a low dose systemic corticosteroid that can be discontinued if rash improves to Grade 1 or less within 10 days.
• Permanently discontinue treatment with this drug if etiology is determined to be SCAR.

GRADE 3 (30% or more BSA with active skin toxicity):

• Interrupt this drug and initiate or intensify topical/systemic corticosteroid and antihistamine treatment.
• Permanently discontinue treatment with this drug if etiology is determined to be SCAR.
• For Grade 3 rashes other than SCAR in adults: Resume treatment at the next lower dose upon improvement to Grade 1 or less.
• For Grade 3 rashes other than SCAR in pediatric patients: Upon improvement to Grade 1 or less, either resume treatment at 50 mg/day while continuing oral antihistamine treatment or permanently discontinue this drug. Permanently discontinue if patient was receiving antihistamines at the time of the rash onset and antihistamine dose cannot be increased, or if Grade 3 or greater rash recurs.

GRADE 4 (any % BSA associated with superinfection, with indication of IV antibiotic; life-threatening consequences - e.g., severe bullous, blistering, or exfoliating skin conditions): Permanently discontinue treatment.

HYPERGLYCEMIA (both for adult and pediatric patients)
Should only be based on fasting glucose levels (FPG or fasting blood glucose)
GRADE 1 (FPG greater than ULN 160 mg/dl or greater than ULN 8.9 mmol/L):

• No dosage modification required but initiate or intensify oral anti-hyperglycemic treatment.

GRADE 2 (FPG greater than 160 to 250 mg/dL or 8.9 to 13.9 mmol/L):

• No dosage modification required but initiate or intensify oral anti-hyperglycemic treatment.

Adults: If FPG does not decrease within 21 days under appropriate anti-hyperglycemic treatment, reduce by one dose level, monitor FPG and follow FPG recommendations.
Pediatric: If FPG does not decrease within 21 days under appropriate anti-hyperglycemic treatment, interrupt this drug until improvement to Grade 1 or less, then resume at 50 mg, monitor FPG and follow FPG recommendations.
GRADE 3 (FPG greater than 250 to 500 mg/dL or greater than 13.9 to 27.8 mmol/L):

• Interrupt this drug.
• Initiate or intensify oral antihyperglycemic treatment and consider additional antihyperglycemic medications for 1 to 2 days until FPG improves.
• Administer IV hydration and consider interventions for electrolyte/ketoacidosis/hyperosmolar disturbances.

Adults:

• If FPG decrease to 160 mg/dL or less or 8.9 mmol/L or less within 3 to 5 days, resume this drug at 1 lower dose level.
• If FPG does not decrease within 3 to 5 days, consult with specialist in hyperglycemia.
• If FPG does not decrease within 21 days, permanently discontinue.

Pediatric:

• If FPG decrease to 160 mg/dL or less or 8.9 mmol/L or less within 3 to 5 days, resume this drug at 50 mg/day.
• If FPG does not decrease within 3 to 5 days, consult with specialist in hyperglycemia to determine if treatment should be resumed or discontinued.
• If FPG does not decrease within 21 days, permanently discontinue.
• If hyperglycemia recurs at Grade 3 or greater, consider permanent discontinuation.

GRADE 4 (FPG greater or equal to 500 mg/dl or 27.8 mmol/L):

• Interrupt this drug.
• Initiate or intensify oral antihyperglycemic treatment.
• Administer IV hydration and consider interventions for electrolyte/ketoacidosis/hyperosmolar disturbances.
• Recheck FPG within 24 hours as clinically indicated.
• If FPG decreases to 500 mg/dL (27.8 mmol/L) or less, follow FPG specific recommendations for Grade 3.
• If FPG is confirmed higher than 500 mg/dL (27.8 mmol/L), permanently discontinue treatment.

PNEUMONITIS (both adult and pediatric patients)
Any grade:

• Interrupt treatment if pneumonitis is suspected.
• Permanently discontinue if pneumonitis is confirmed.

DIARRHEA (both adults and pediatric - in children consider consulting with a gastrointestinal specialist)
GRADE 1:

• No modification required, initiate appropriate medical therapy and monitor.

GRADE 2:

• Interrupt treatment until improvement to Grade 1 or less, then resume at same dose.
• Initiate and intensify appropriate medical therapy and monitor.

Adults:

• If diarrhea recurs at grade 2 or higher, interrupt treatment until improvement to Grade 1 or less, then resume at the next lower-level dose.

Pediatric:

• If diarrhea recurs at grade 2 or higher, interrupt treatment until improvement to Grade 1 or less, then resume at 50 mg.

GRADE 3

• Interrupt treatment until improvement to Grade 1 or less.
• Initiate and intensify appropriate medical therapy and monitor.

Adults:

• Once improved to grade 1 or less, resume at the next lower-level dose.

Pediatric:

• Once improved to Grade 1 or less, either resume at 50 mg or permanently discontinue.

If diarrhea recurs at Grade 3 or higher, consider permanent discontinuation.
GRADE 4

• Permanently discontinue.

PANCREATITIS
GRADE 2:

• Interrupt treatment until improvement to Grade less than 2.

Adults:

• Resume at the next lower level (only one dose reduction is permitted).
• If pancreatitis recurs, permanently discontinue.

Pediatric:

• Resume at 50 mg/day.
• Permanently discontinue.

GRADE 3:
Adults:

• Interrupt treatment until improvement to Grade less than 2.
• Resume at the next lower level (only one dose reduction is permitted).
• If pancreatitis recurs, permanently discontinue.

Pediatric:

• Permanently discontinue.

GRADE 4:

• Permanently discontinue.

OTHER ADVERSE REACTIONS:
GRADE 1 or 2:

• No modification is required but initiate appropriate medical therapy and monitor as clinically needed.

GRADE 3:

• Interrupt treatment until improvement to Grade 1 or less.
• Initiate or intensify medical therapy and monitor closely.

Adults:

• Once improved, resume to next lower dose level.

Pediatric:
Once improved, resume at 50 mg/day or permanently discontinue.

• If adverse reaction recurs at Grade 3 or higher, consider permanent discontinuation.
• Consider consultation with a specialist in the field of the concerned adverse reaction.

GRADE 4:

• Permanently discontinue.

Precautions

US FDA requires a medication guide to assure safe use. For additional information: www.fda.gov/drugs/drug-safety-and-availability/medication-guides

CONTRAINDICATIONS

• Hypersensitivity to the active component or any of the ingredients

Breast Cancer indication: Safety and efficacy have not been established in patients younger than 18 years.

PROS indication: Safety and efficacy have not been established in patients younger than 2 years old.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with this drug based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue.
• This drug should be taken at approximately the same time each day with food.
• Swallow tablets whole; do not chew, crush, or split.
• No tablet should be ingested if it is broken, cracked, or otherwise not intact.
• If a dose 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 at the usual time.
• If the patient vomits after taking the dose, they should not take an additional dose on that day and should resume the dosing schedule the next day at the usual time.
• For patients having difficulty swallowing tablets, give as an oral suspension with food:
• Place tablet in a glass with 2 to 4 ounces of water and let stand for 5 minutes (use water only).
• Crush the tablet with a spoon, and drink immediately. After administration, add 2 to 3 tablespoons of water to the same glass and drink entire content. Repeat if particles remain.
• Discard the oral suspension if it is not administered after 1 hour of preparation.

Storage requirements:
Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F).

Monitoring:

• Fasting Plasma Glucose (FPG) and HbA1c at baseline and periodically during treatment.
• Clinical symptoms of pneumonitis or lung radiological changes.
• Growth and development in pediatric patients.

Patient advice:

• Read the Patient Information and Instructions for Use.
• Contact your healthcare provider immediately for signs hypersensitivity or severe cutaneous reactions.
• Monitor blood glucose periodically during therapy and contact your healthcare provider immediately for signs hyperglycemia.
• Contact your healthcare provider if you experience respiratory problems.
• This drug may cause diarrhea, which may be severe in some cases. Start antidiarrheal treatment, increase oral fluids, and notify your healthcare provider if diarrhea occurs.
• This drug can harm a developing fetus.