Alpelisib Dose Adjustments in Special Populations
1. Renal Impairment Adjustments
(1) Mild to moderate renal impairment: No dose adjustment required.
(2) Severe renal impairment : Data not available.
2. Hepatic Impairment Adjustments
No dose adjustment of alpelisib is required.
3. Dialysis
Data not available.
Alpelisib Dose Adjustments for Adverse Reactions in Breast Cancer Treatment
1. General Dose Reduction Principles
(1) Starting dose: 300 mg orally once daily.
(2) First dose reduction: 250 mg orally once daily.
(3) Second dose reduction: 200 mg orally once daily.
(4) Discontinuation: If further dose reduction below 200 mg/day is required, discontinue treatment.
Note: For pancreatitis, only one dose reduction is allowed.
2. Dose Adjustments for Hyperglycemia (Based on Fasting Plasma Glucose FPG / Fasting Glucose Grade)
(1) Grade 1 (FPG >ULN to ≤160 mg/dL or >ULN to ≤8.9 mmol/L): No dose adjustment; initiate or intensify antihyperglycemic therapy (*2).
(2) Grade 2 (FPG >160 to 250 mg/dL or >8.9 to 13.9 mmol/L): No dose adjustment; initiate or intensify antihyperglycemic therapy (*2). If FPG does not decrease to ≤160 mg/dL or ≤8.9 mmol/L within 21 days on antihyperglycemic therapy, reduce alpelisib by one dose level and follow specific FPG recommendations.
(3) Grade 3 (FPG >250 to 500 mg/dL or >13.9 to 27.8 mmol/L): Withhold alpelisib; initiate or intensify antihyperglycemic therapy (*2) and consider adding other antihyperglycemic agents (*3) for 1-2 days until hyperglycemia improves. Administer IV fluids and consider treatment (e.g., intervention for electrolytes/ketoacidosis/hyperosmolar state). If FPG decreases to ≤160 mg/dL or ≤8.9 mmol/L within 3-5 days on antihyperglycemic therapy, resume alpelisib at one dose level lower. If FPG does not decrease to ≤160 mg/dL or ≤8.9 mmol/L within 3-5 days on antihyperglycemic therapy, consult a hyperglycemia specialist. If FPG does not decrease to ≤160 mg/dL or ≤8.9 mmol/L within 21 days on antihyperglycemic therapy (*2), permanently discontinue alpelisib.
(4) Grade 4 (FPG >500 mg/dL or >27.8 mmol/L): Withhold alpelisib; initiate or intensify antihyperglycemic therapy (*2) and consider other antihyperglycemic therapy (administer IV fluids and consider treatment such as intervention for electrolytes/ketoacidosis/hyperosmolar state); recheck FPG within 24 hours and as clinically needed. If FPG decreases to ≤500 mg/dL or ≤27.8 mmol/L, follow specific recommendations for Grade 3 hyperglycemia. If FPG remains confirmed >500 mg/dL or >27.8 mmol/L, permanently discontinue alpelisib.
Notes:
FPG/glucose/grading reflect CTCAE hyperglycemia grading.
Initiate applicable antihyperglycemic agents, including metformin and insulin sensitizers (e.g., thiazolidinediones or DPP-4 inhibitors), and refer to respective prescribing information for dosing and titration recommendations, including local diabetes treatment guidelines. In the SOLAR-1 trial, metformin was recommended with the following guidance: Start metformin 500 mg once daily. Based on tolerability, metformin dose may be increased to 500 mg twice daily, then 500 mg with breakfast and 1000 mg with dinner, and further to 1000 mg twice daily if needed.
As recommended in the SOLAR-1 trial, insulin may be used for 1-2 days until hyperglycemia resolves; however, given alpelisib's short half-life and expected normalization of glucose after withholding alpelisib, insulin may not be necessary in most cases of alpelisib-induced hyperglycemia.
3. Dose Adjustments for Rash
(1) Grade 1 : No dose adjustment; initiate topical corticosteroids; consider adding oral antihistamines for symptom control.
(2) Grade 2 (active skin toxicity involving BSA 10%-30%): No dose adjustment; initiate or intensify topical corticosteroids and oral antihistamines; consider low-dose systemic corticosteroids.
(3) Grade 3 (e.g., severe rash unresponsive to medical management) (active skin toxicity involving BSA >30%): Withhold alpelisib; initiate or intensify topical/systemic corticosteroids and oral antihistamines. When improved to Grade 1 or lower, if first occurrence of rash, resume alpelisib at same dose; if second occurrence, resume at one dose level lower.
(4) Grade 4 (e.g., severe bullous, vesicular, or exfoliative dermatological conditions) (any % BSA with extensive superinfection requiring IV antibiotics; life-threatening consequences): Permanently discontinue alpelisib.
Notes:
Grading per CTCAE.
Consider dermatology consultation for all grades of rash.
Use of antihistamines before rash onset may reduce incidence and severity of rash.
4. Dose Adjustments for Diarrhea
(1) Grade 1: No dose adjustment; initiate pharmacotherapy and monitor as clinically indicated.
(2) Grade 2: Initiate or intensify pharmacotherapy and monitor as clinically indicated; withhold alpelisib until recovery to Grade 1 or lower, then resume alpelisib at same dose.
(3) Grade 3 and 4: Initiate or intensify pharmacotherapy and monitor as clinically indicated. Withhold alpelisib until recovery to Grade 1 or lower, then resume alpelisib at one dose level lower.
Note: Grading per CTCAE.
5. Dose Adjustments for Other Toxicities (excluding hyperglycemia, rash, and diarrhea)
(1) Grade 1 or 2: No dose adjustment; initiate pharmacotherapy and monitor as clinically indicated (*2)(*3).
(2) Grade 3: Withhold alpelisib until recovery to Grade 1 or lower, then resume alpelisib at one dose level lower.
(3) Grade 4: Permanently discontinue alpelisib.
Notes:
Grading per CTCAE.
For Grade 2 and 3 pancreatitis, withhold alpelisib until recovery to
For Grade 2 elevated total bilirubin, withhold alpelisib until recovery to Grade 1 or lower; if resolves within 14 days or less, resume at same dose; if resolves after more than 14 days, resume at one dose level lower.
6. Fulvestrant Dose Adjustments
If toxicity occurs, refer to the fulvestrant prescribing information for dose adjustment guidelines.
