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Precautions of Capivasertib

Capatertinib is contraindicated in patients with severe hypersensitivity to capatertinib or any of its components.

Hyperglycemia

Severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes, may occur in patients receiving capatertinib treatment (n=355).

Among patients treated with capatertinib, 37% experienced an increase in fasting blood glucose from baseline, including 11% of patients with grade 2 events (fasting blood glucose >160 to 250 mg/dL), 2% with grade 3 events (fasting blood glucose >250 to 500 mg/dL), and 1.1% with grade 4 events (fasting blood glucose >500 mg/dL). The median time to first onset of hyperglycemia was 15 days (range: 1 to 367 days). Dose reduction due to hyperglycemia was required in 0.6% of patients, and permanent discontinuation was needed in 0.6% of patients. Diabetic ketoacidosis occurred in 0.3% of patients, and diabetic metabolic decompensation occurred in 0.6% of patients.

In the CAPItello-291 study, 12% of patients (43/355) receiving capatertinib initiated or switched antihyperglycemic medications during the study period, including 4.8% (17/355) of patients who received insulin therapy.

The safety of capatertinib in patients with type 1 diabetes mellitus or diabetes mellitus requiring insulin has not been established. The CAPItello-291 study excluded patients with insulin-dependent diabetes mellitus.

Prior to initiating capatertinib treatment, fasting blood glucose levels (fasting plasma glucose or fasting blood glucose) and hemoglobin A1C (HbA1C) levels should be measured, and fasting blood glucose should be optimized. After starting capatertinib, monitor or self-monitor fasting blood glucose levels on day 3 or 4 of the 1st, 2nd, 4th, 6th, and 8th treatment weeks; thereafter, monitor monthly during capatertinib treatment and as clinically indicated. Monitor HbA1C levels every 3 months during capatertinib treatment and as clinically indicated. Patients with a history of well-controlled type 2 diabetes mellitus may require intensified antihyperglycemic therapy and close monitoring of fasting blood glucose levels.

For patients who develop hyperglycemia during capatertinib treatment, monitor fasting blood glucose at least twice weekly (regardless of whether it is a capatertinib administration day) until fasting blood glucose returns to baseline levels. During treatment with antihyperglycemic medications, monitor fasting blood glucose at least once weekly for 2 months, then every 2 weeks, or as clinically indicated. For patients with risk factors for hyperglycemia or those who develop hyperglycemia, consultation with a healthcare professional specializing in the management of hyperglycemia is recommended, and consideration should be given to initiating home monitoring of fasting blood glucose. Inform patients of the signs and symptoms of hyperglycemia and provide guidance on lifestyle modifications.

Immediately withhold capatertinib if ketoacidosis is suspected. Permanently discontinue capatertinib if ketoacidosis is confirmed. Withhold, reduce the dose of, or permanently discontinue capatertinib based on the severity of hyperglycemia.

Diarrhea

Severe diarrhea associated with dehydration occurred in patients receiving capatertinib treatment (n=355).

Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first onset was 8 days (range: 1 to 519 days). Among the 257 patients who developed diarrhea, 59% required antidiarrheal medications for symptom management. Dose reduction was needed in 8% of patients, and permanent discontinuation of capatertinib due to diarrhea was required in 2% of patients. Among patients with grade ≥2 diarrhea (n=93), those who achieved at least grade 1 improvement (n=89) had a median time from first event to improvement of 4 days (range: 1 to 154 days).

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluid intake and initiate antidiarrheal treatment at the first sign of diarrhea during capatertinib administration. Withhold, reduce the dose of, or permanently discontinue capatertinib based on the severity of diarrhea.

Cutaneous Adverse Reactions

Cutaneous adverse reactions, which may be severe, occurred in patients receiving capatertinib treatment (n=355), including erythema multiforme, palmar-plantar erythrodysesthesia syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients treated with capatertinib. Erythema multiforme occurred in 1.7% of patients, and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients, and permanent discontinuation of capatertinib due to cutaneous adverse reactions was needed in 7% of patients.

Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, reduce the dose of, or permanently discontinue capatertinib based on the severity of cutaneous adverse reactions.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, capatertinib may cause fetal harm when administered to pregnant women. Inform pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with capatertinib and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capatertinib and for 4 months after the last dose.

Capatertinib is used in combination with fulvestrant. See the full prescribing information for fulvestrant for additional information on pregnancy and contraception.

from FDA，2024.09