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Dosage of Capivasertib

When used in combination with fulvestrant, a dosing schedule of 4 consecutive days of administration followed by 3 days of withdrawal per week can achieve a favorable benefit-risk balance.

The recommended starting dose of capivasertib is 400 mg orally twice daily, approximately 12 hours apart, administered for 4 consecutive days followed by 3 days off per week.

Capivasertib Dosing Instructions

Days 1–4 of each week: Take 200 mg in the morning and 200 mg in the evening.

Days 5–7 of each week: No medication.

Patients should be selected based on the presence of genetic alterations in PIK3CA, AKT1, and PTEN detected by an FDA-approved test method.

Fulvestrant 500 mg Injection

Cycle 1: Administer on Day 1 and Day 15.

Subsequent 28-day cycles: Administer on Day 1 of each cycle.

For the recommended administration information, refer to the fulvestrant prescribing information.

Assess fasting blood glucose and glycated hemoglobin (HbA1c) before initiating capivasertib treatment and periodically during treatment. Verify the pregnancy status of females of reproductive potential prior to starting capivasertib.

Medication Administration Precautions

Blister packs tailored to specific doses help patients track capivasertib treatment.

Easy-to-follow instructions are included to assist patients in adhering to the dosing schedule.

Dose Adjustment

When used in combination with fulvestrant, the recommended dose adjustment schedule for capivasertib in managing adverse reactions (ARs) is as follows. If dose reduction is required, the dosing schedule remains unchanged (4 consecutive days of administration followed by 3 days off per week).

First Dose Reduction

Adjust to 320 mg orally twice daily for 4 consecutive days followed by 3 days off per week.

(Equivalent to two 160 mg tablets per dose, twice daily)

Second Dose Reduction

Adjust to 200 mg orally twice daily for 4 consecutive days followed by 3 days off per week.

(Equivalent to one 200 mg tablet per dose, twice daily)

Warnings and Precautions

1. If the dose after the second reduction is intolerable, permanently discontinue capivasertib.

2. Avoid concomitant use with strong CYP3A inhibitors. If co-administration is unavoidable, reduce the capivasertib dose to 320 mg orally twice daily for 4 consecutive days followed by 3 days off per week.

3. When used concomitantly with moderate CYP3A inhibitors, reduce the capivasertib dose to 320 mg orally twice daily for 4 consecutive days followed by 3 days off per week.

4. After discontinuing a strong or moderate CYP3A inhibitor (following 3–5 half-lives of the inhibitor), resume the capivasertib dose that was used prior to initiating the inhibitor.

5. Avoid concomitant use of capivasertib with strong or moderate CYP3A inducers.

Hyperglycemia Management

1. Fasting blood glucose > upper limit of normal (ULN)–160 mg/dL (or > ULN–8.9 mmol/L) or HbA1c > 7%: Consider initiating or intensifying oral antidiabetic therapy.

2. Fasting blood glucose 161–250 mg/dL (or 9–13.9 mmol/L): Hold capivasertib until fasting blood glucose decreases to ≤ 160 mg/dL (or ≤ 8.9 mmol/L).

3. If recovery occurs within ≤ 28 days, resume capivasertib at the same dose.

4. If recovery occurs after > 28 days, resume capivasertib at a one-dose-level reduction.

5. Fasting blood glucose 251–500 mg/dL (or 14–27.8 mmol/L): Hold capivasertib until fasting blood glucose decreases to ≤ 160 mg/dL (or ≤ 8.9 mmol/L).

6. If recovery occurs within ≤ 28 days, resume capivasertib at a one-dose-level reduction.

7. If recovery occurs after > 28 days, permanently discontinue capivasertib.

8. Fasting blood glucose > 500 mg/dL (or > 27.8 mmol/L) or life-threatening hyperglycemic sequelae at any fasting blood glucose level: Hold capivasertib.

9. If life-threatening hyperglycemic sequelae occur, or fasting blood glucose remains ≥ 500 mg/dL after 24 hours, permanently discontinue capivasertib.

10. If fasting blood glucose decreases to ≤ 500 mg/dL (or ≤ 27.8 mmol/L) within 24 hours, manage according to the guidelines for the corresponding severity level in the table.

11. Before initiating capivasertib, test fasting blood glucose and HbA1c levels and optimize fasting blood glucose control.

12. After starting capivasertib, monitor or self-monitor fasting blood glucose levels on Day 3 or 4 of the dosing week during Weeks 1, 2, 4, 6, and 8; then monitor monthly and as clinically indicated. Monitor HbA1c every 3 months during treatment and as clinically indicated.

13. For patients with risk factors for hyperglycemia or those who develop hyperglycemia, consider consulting a healthcare professional specializing in hyperglycemia management and initiate home fasting blood glucose monitoring.

14. Inform patients of the signs and symptoms of hyperglycemia and provide advice on how dietary and lifestyle modifications can assist in the overall management of treatment-related hyperglycemia. For additional details, refer to the full prescribing information.

15. If ketoacidosis is suspected, immediately hold capivasertib. If ketoacidosis is confirmed, permanently discontinue capivasertib.

Diarrhea Management

Grade 2 Diarrhea

Hold capivasertib until resolution to Grade ≤ 1.

If recovery occurs within ≤ 28 days, resume capivasertib at the same dose or one-dose-level reduction based on clinical judgment.

If recovery occurs after > 28 days, resume capivasertib at a one-dose-level reduction based on clinical judgment.

If diarrhea recurs, reduce the capivasertib dose by one level.

Grade 3 Diarrhea

Hold capivasertib until resolution to Grade ≤ 1.

If recovery occurs within ≤ 28 days, resume capivasertib at the same dose or one-dose-level reduction based on clinical judgment.

If recovery occurs after > 28 days, permanently discontinue capivasertib.

Grade 4 Diarrhea

Permanently discontinue capivasertib.

Inform patients that taking capivasertib with food may reduce the risk of diarrhea. For persistent Grade 1 diarrhea, consider loperamide for secondary prophylaxis.

Cutaneous Adverse Reactions Management

Grade 2 Cutaneous Reactions

Hold capivasertib until resolution to Grade ≤ 1.

Resume capivasertib at the same dose.

If reactions persist or recur, reduce the capivasertib dose by one level.

Grade 3 Cutaneous Reactions

Hold capivasertib until resolution to Grade ≤ 1.

If recovery occurs within ≤ 28 days, resume capivasertib at the same dose.

If recovery occurs after > 28 days, resume capivasertib at a one-dose-level reduction.

If Grade 3 reactions recur, permanently discontinue capivasertib.

Grade 4 Cutaneous Reactions

Permanently discontinue capivasertib.

Monitor for signs and symptoms of cutaneous adverse reactions and advise early consultation with a dermatologist. Depending on the severity, hold treatment, reduce the dose, or permanently discontinue capivasertib. For persistent rash, consider topical corticosteroids and/or non-sedating oral antihistamines for secondary prophylaxis.

Management of Other Adverse Reactions

Grade 2 Adverse Reactions

Hold capivasertib until resolution to Grade ≤ 1.

Resume capivasertib at the same dose.

Grade 3 Adverse Reactions

Hold capivasertib until resolution to Grade ≤ 1.

If recovery occurs within ≤ 28 days, resume capivasertib at the same dose.

If recovery occurs after > 28 days, resume capivasertib at a one-dose-level reduction.

Grade 4 Adverse Reactions

Permanently discontinue capivasertib.

Some patients may require more frequent monitoring. For patients with hepatic impairment, monitor for signs and symptoms of increased capivasertib exposure.

from FDA，2024.09