Capivasertib (Monograph)

Brand name: Truqap
Drug class: Antineoplastic Agents

Introduction

Capivasertib is a kinase inhibitor.

Uses for Capivasertib

Capivasertib has the following uses:

Capivasertib is indicated, in combination with fulvestrant, for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations as detected by an FDA-approved test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

Capivasertib Dosage and Administration

General

Capivasertib is available in the following dosage form(s) and strength(s):

Tablets: 160 mg and 200 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with capivasertib based on the presence of one or more of the following genetic alterations in tumor tissue: PIK3CA/AKT1/PTEN.

• Swallow tablets whole; do not chew, crush, or split tablets prior to swallowing.

• The recommended dosage of capivasertib, in combination with fulvestrant, is 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off. Continue capivasertib until disease progression or unacceptable toxicity occurs. Refer to the fulvestrant Full Prescribing Information for recommended fulvestrant dosing information.

• See Full Prescribing Information for dosage modification recommendations for adverse reactions and concomitant use of CYP3A inhibitors.

Related/similar drugs

Enhertu, Kisqali, Trodelvy, Arimidex, Femara, Xeloda, Herceptin

Cautions for Capivasertib

Contraindications

Severe hypersensitivity to capivasertib or any of its components.

Warnings/Precautions

Hyperglycemia

Severe hyperglycemia, associated with ketoacidosis, occurred in patients treated with capivasertib. The safety of capivasertib has not been established in patients with Type I diabetes or diabetes requiring insulin. Patients with insulin dependent diabetes were excluded from the CAPItello-291 study.

Hyperglycemia occurred in 18% of patients treated with capivasertib. Grade 3 (insulin therapy initiated; hospitalization indicated) or Grade 4 (life-threatening consequences; urgent intervention indicated) hyperglycemia occurred in 2.8% of patients. Diabetic ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients. Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367).

In the 65 patients with hyperglycemia, 45% required treatment with anti-hyperglycemic medication (insulin in 15%, and metformin in 29%). Of the 29 patients who required anti-hyperglycemic medication during treatment with capivasertib, 66% (19/29) remained on these medications at treatment discontinuation or last follow up.

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1c) and optimize blood glucose prior to treatment. Before initiating capivasertib, inform patients about the drug's potential to cause hyperglycemia and to immediately contact their healthcare professional if hyperglycemia symptoms occur (e.g., excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss). Evaluate FG at least every two weeks during the first month and at least once a month starting from the second month, prior to the scheduled dose of capivasertib. Monitor HbA1c every three months. Monitor FG more frequently during treatment with capivasertib in patients with a medical history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (BMI ≥ 30), elevated FG of > 160 mg/dL (> 8.9 mmol/L), HbA1c at or above the upper limit of normal, use of concomitant systemic corticosteroids, or intercurrent infections.

If a patient experiences hyperglycemia after initiating treatment with capivasertib, monitor FG as clinically indicated, and at least twice weekly until FG decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring FG 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.

Withhold, reduce dose, or permanently discontinue capivasertib based on severity.

Diarrhea

Severe diarrhea associated with dehydration occurred in patients who received capivasertib.

Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range 1 to 519). In the 257 patients with diarrhea, 59% required anti-diarrheal medications to manage symptoms. Dose reductions were required in 8% of patients, and 2% of patients permanently discontinued capivasertib due to diarrhea. In patients with Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154).

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking capivasertib. Withhold, reduce dose, or permanently discontinue capivasertib based on severity.

Cutaneous Adverse Reactions

Cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients who received capivasertib.

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving capivasertib. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued capivasertib due to cutaneous adverse reactions.

The median time to onset of cutaneous adverse reactions was 13 days (range 1 to 575 days). Among the 204 patients with cutaneous adverse reactions, 44% (90/204) required corticosteroid treatment. Of these, 37% (76/204) were treated with topical corticosteroids and 19% (39/204) with systemic corticosteroids. In patients with Grade ≥ 2 cutaneous adverse reaction (n= 116) with at least 1 grade improvement (n=104), median time to improvement from the first event was 12 days (range 2 to 544).

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

Embryo-fetal Toxicity

Based on findings from animals and mechanism of action, capivasertib can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dosage of 400 mg twice daily.

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 capivasertib and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capivasertib and for 4 months after the last dose.

Capivasertib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

Specific Populations

Pregnancy

Capivasertib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.

Based on findings in animals and mechanism of action, capivasertib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of capivasertib in pregnant women. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.

Lactation

Capivasertib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.

There are no data on the presence of capivasertib or its metabolites in human milk or their effects on milk production or the breastfed child. Capivasertib was detected in the plasma of suckling rat pups. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with capivasertib.

Females and Males of Reproductive Potential

Capivasertib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.

Capivasertib can cause fetal harm when administered to pregnant women.

Verify pregnancy status of females of reproductive potential prior to initiating capivasertib.

Advise females of reproductive potential to use effective contraception during treatment with capivasertib and for 1 month after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capivasertib and for 4 months after the last dose.

Pediatric Use

The safety and effectiveness of capivasertib have not been established in pediatric patients.

Geriatric Use

Of the 355 patients who received capivasertib in the CAPItello-291 study, 115 (32%) patients were ≥ 65 years of age and 24 (7%) patients were ≥ 75 years of age. No overall differences in the efficacy of capivasertib were observed between patients ≥ 65 years of age and younger patients. Analysis of the safety of capivasertib comparing patients ≥ 65 years of age to younger patients suggest a higher incidence of Grade 3 to 5 adverse reactions (57% versus 36%), dosage reductions (30% versus 15%), dose interruptions (57% versus 30%), and permanent discontinuations (23% versus 8%), respectively.

Renal Impairment

No dosage modification is recommended for patients with mild to moderate (creatinine clearance [Cl_cr] 30 to 89 mL/min) renal impairment.

Capivasertib has not been studied in patients with severe (Cl_cr 15 to 29 mL/min) renal impairment.

Hepatic Impairment

No dosage modification is recommended for patients with mild hepatic impairment (bilirubin ≤ upper limit of normal [ULN] and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST).

Monitor patients with moderate (bilirubin > 1.5 to 3x ULN and any AST) hepatic impairment for adverse reactions due to potential increased capivasertib exposure.

Capivasertib has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment.

Common Adverse Effects

Most common adverse reactions (incidence ≥20%), including laboratory abnormalities, were diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A Inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce capivasertib dose.

• Moderate CYP3A Inhibitors: Reduce capivasertib dose.

• Strong and Moderate CYP3A Inducers: Avoid concomitant use.

Actions

Mechanism of Action

Capivasertib is an inhibitor of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumors is a result of activation of upstream signaling pathways, mutations in AKT1, loss of phosphatase and tensin homolog (PTEN) function and mutations in the catalytic subunit alpha of phosphatidylinositol 3-kinase (PIK3CA).

In vitro, capivasertib reduced growth of breast cancer cell lines including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In vivo, capivasertib alone and in combination with fulvestrant inhibited tumor growth of mouse xenograft models including estrogen receptor positive breast cancer models with alterations in PIK3CA, AKT1, and PTEN.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients that capivasertib can cause hyperglycemia and that they will need to monitor their fasting blood glucose periodically during therapy. Advise patients to contact their healthcare provider for signs and symptoms of hyperglycemia.

• Advise patients that capivasertib can cause diarrhea and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking capivasertib.

• Advise patients that capivasertib can cause cutaneous adverse reactions and to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative skin reactions.

• Advise females to inform their healthcare provider of a known or suspected pregnancy. 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 capivasertib and for 1 month after the last dose.

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capivasertib and for 4 months after the last dose.

• Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

• Advise women to not breastfeed during treatment with capivasertib. Refer to the Full Prescribing Information of fulvestrant for lactation information.

• Instruct patients to take capivasertib 2 times each day, at about the same times each day, for 4 days on and 3 days off, with or without food. Swallow the tablet(s) whole with water. Tablets should not be chewed, crushed, or split prior to swallowing.

• Instruct patients that if the dose is missed, it can be taken within 4 hours after the time it is usually taken. If more than 4 hours has passed, skip the dose. Take the next dose at the usual time.

• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter medications, vitamins, and herbal products.

• Grapefruit may interact with capivasertib. Patients should not consume grapefruit products while taking capivasertib.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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