Capivasertib (Monograph)

Brand name: Truqap(https://www.truqap.com)
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a kinase inhibitor.

Uses for Capivasertib

Breast Cancer

Used in combination with fulvestrant for treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor type 2 (HER2)-negative, locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN-alterations as detected by an FDA-approved test following progression on ≥1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

Guidelines recommend capivasertib in combination with fulvestrant as a second- or third-line treatment option in patients with HR-positive, HER2-negative metastatic breast cancer with PIK3CA or AKT1 mutation or PTEN inactivation.

Capivasertib Dosage and Administration

General

Pretreatment Screening

Confirm presence of ≥1 genetic alteration (PIK3CA, AKT1,or PTEN) in tumor tissue by an FDA-approved diagnostic test prior to initiating therapy with capivasertib.
Assess fasting plasma glucose and HbA_1c prior to initiating capivasertib; optimize serum glucose levels prior to treatment.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor fasting plasma glucose at least every 2 weeks for the first month and at least once a month starting with the second month, prior to the scheduled dose of capivasertib. Monitor fasting plasma glucose more frequently in patients with a history of diabetes mellitus and in patients with risk factors for hyperglycemia (e.g., obesity [BMI ≥30 kg/m²], elevated fasting glucose >160 mg/dL, HbA_1c at or above ULN, concomitant use of systemic corticosteroids, or intercurrent infections).
Monitor HbA_1c every 3 months.
Monitor for signs or symptoms of hyperglycemia. Closely monitor patients with diabetes.
If hyperglycemia occurs following initiation of capivasertib, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with antihyperglycemic medication(s), continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks, and as clinically indicated.
Monitor for signs or symptoms of diarrhea.
Monitor for signs or symptoms of cutaneous adverse reactions.

Other General Considerations

Consult manufacturer’s labeling for information on dosage adjustments, adverse effects, and contraindications of other antineoplastic agents (e.g., fulvestrant, luteinizing hormone-releasing hormone [LHRH] agonist) used in combination regimens.
For premenopausal and perimenopausal women, administer LHRH agonist in accordance with current clinical practice guidelines. For men, consider administering a LHRH agonist according to current clinical practice guidelines.

Administration

Oral Administration

Available as tablets containing 160 mg or 200 mg of the drug.

Administer orally with or without food. Swallow tablets whole; do not split, crush, or chew prior to swallowing. Do not take tablets that are broken, cracked, or otherwise not intact.

If a dose is missed within 4 hours of the scheduled time, take missed dose. If more than 4 hours has passed, skip missed dose and take next dose at regularly scheduled time.

If vomiting occurs after taking dose, do not take an extra dose; take next dose at regularly scheduled time.

Dosage

Adults

Breast Cancer

Oral

400 mg (two 200-mg tablets) twice daily (approximately 12 hours apart) for 4 days followed by 3 days off. Use in combination with fulvestrant.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.

If dosage modification required, reduce dosage of capivasertib as outlined in Table 1. See Table 2 for recommended capivasertib dosage modifications for adverse reactions.

Permanently discontinue capivasertib if unable to tolerate the second dose reduction.

Table 1. Recommended Dosage Reductions of Capivasertib for Adverse Reactions.1
Dose Reduction	Capivasertib Dose and Schedule
First dose reduction	320 mg twice daily for 4 days followed by 3 days off
Second dose reduction	200 mg twice daily for 4 days followed by 3 days off

Table 2. Recommended Dosage Modifications of Capivasertib for Adverse Reactions.1
Adverse Reaction	Severity	Dosage Modification
Hyperglycemia	Fasting glucose (FG) greater than ULN to 160 mg/dL or FG greater than ULN to 8.9 mmol/L or HbA_1c>7%	Consider initiation or intensification of oral diabetes treatment
Hyperglycemia	FG 161–250 mg/dL or FG 9–13.9 mmol/L	Withhold capivasertib until FG decrease ≤160 mg/dL (or ≤8.9 mmol/L) If recovery occurs in ≤28 days, resume capivasertib at same dose If recovery occurs in >28 days, resume capivasertib at one lower dose
Hyperglycemia	FG 251–500 mg/dL or FG 14–27.8 mmol/L	Withhold capivasertib until FG decrease ≤160 mg/dL (or ≤8.9 mmol/L) If recovery occurs in ≤28 days, resume capivasertib at one lower dose If recovery occurs in >28 days, permanently discontinue capivasertib
Hyperglycemia	FG >500 mg/dL or FG >27.8 mmol/L or Life-threatening sequelae of hyperglycemia at any FG level	For life-threatening sequelae of hyperglycemia or if FG persists at ≥500 mg/dL after 24 hours, permanently discontinue capivasertib If FG ≤500 mg/dL (or ≤27.8 mmol/L) within 24 hours, then follow the guidance in the table for the relevant grade
Diarrhea	Grade 2	Withhold capivasertib until recovery to grade 1 or lower If recovery occurs in ≤28 days, resume capivasertib at same dose or one lower dose as clinically indicated If recovery occurs in >28 days, resume at one lower dose as clinically indicated For recurrence, reduce capivasertib by one lower dose
Diarrhea	Grade 3	Withhold capivasertib until recovery to grade 1 or lower If recovery occurs in ≤28 days, resume capivasertib at same dose or one lower dose as clinically indicated If recovery occurs in >28 days, permanently discontinue capivasertib
Diarrhea	Grade 4	Permanently discontinue
Cutaneous adverse reactions	Grade 2	Withhold capivasertib until recovery to grade 1 or lower; resume capivasertib at the same dose Persistent or recurrent reactions: reduce capivasertib by one lower dose
Cutaneous adverse reactions	Grade 3	Withhold capivasertib until recovery to grade 1 or lower If recovery occurs in ≤28 days, resume capivasertib at same dose If recovery occurs in >28 days, resume at one lower dose For recurrent grade 3 reactions, permanently discontinue capivasertib
Cutaneous adverse reactions	Grade 4	Permanently discontinue
Other adverse reactions	Grade 2	Withhold capivasertib until recovery to grade 1 or lower Resume capivasertib at the same dose
Other adverse reactions	Grade 3	Withhold capivasertib until recovery to grade 1 or lower If recovery occurs in ≤28 days, resume capivasertib at same dose If recovery occurs in >28 days, resume at one lower dose
Other adverse reactions	Grade 4	Permanently discontinue

Dosage Modification for Concomitant Use with CYP3A4 Inhibitors

When used concomitantly with a moderate CYP3A inhibitor, reduce dosage to 320 mg twice daily for 4 days followed by 3 days off; monitor for adverse reactions.

Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use is necessary, reduce dosage of capivasertib to 320 mg orally twice daily for 4 days followed by 3 days off; monitor for adverse reactions.

After discontinuation of a strong or moderate CYP3A inhibitor, resume the capivasertib dosage (after 3–5 half-lives of the inhibitor) that was taken prior to initiating the strong or moderate CYP3A inhibitor.

Special Populations

Hepatic Impairment

Mild hepatic impairment (bilirubin ≤ULN and AST >ULN, or bilirubin >1–1.5 times ULN and any AST): no dosage modification recommended.

Moderate hepatic impairment (bilirubin >1.5–3 times ULN and any AST): monitor for adverse reactions due to potential increased capivasertib exposure.

Severe hepatic impairment (bilirubin >3 times ULN and any AST): not studied.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): no dosage modification recommended.

Severe renal impairment (Cl_cr 15–29 mL/minute): not studied.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Capivasertib

Contraindications

Severe hypersensitivity to capivasertib or any of its components.

Warnings/Precautions

Hyperglycemia

Severe hyperglycemia associated with ketoacidosis (including grade 3 and 4 events) reported. Safety not established in patients with type 1 diabetes or diabetes requiring insulin.

Assess fasting blood glucose and HbA_1c, and optimize blood glucose prior to treatment.

Before initiating capivasertib, inform patients about its potential to cause hyperglycemia and to immediately contact their clinician if hyperglycemia symptoms occur.

Monitor fasting blood glucose at least every 2 weeks during the first month and at least once monthly starting from the second month, prior to the scheduled dose of capivasertib. Monitor HbA_1c every 3 months. Monitor fasting glucose more frequently if history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (body mass index ≥30), elevated fasting glucose of >160 mg/dL (>8.9 mmol/L), HbA_1c at or above ULN, use of concomitant systemic corticosteroids, or intercurrent infections.

If hyperglycemia occurs, asess fasting blood glucose as clinically indicated and at least twice weekly until fasting glucose decreases to normal levels. During treatment with antihyperglycemic medication(s), continue monitoring fasting glucose at least once weekly for 8 weeks, followed by once every 2 weeks and as clinically indicated.

Consider consultation with a clinician with expertise in the management of hyperglycemia. Counsel patients on lifestyle changes.

Temporary interruption, dosage reduction, or treatment discontinuance of capivasertib may be necessary based on severity.

Diarrhea

Diarrhea, sometimes severe and resulting in dehydration, reported.

Monitor for diarrhea; advise patients to increase oral fluids and start antidiarrheal treatment at first sign of diarrhea.

Temporary interruption, dosage reduction, or treatment discontinuance of capivasertib may be necessary based on severity.

Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (e.g., erythema multiforme, drug reaction with eosinophilia and systemic symptoms [DRESS], palmar-plantar erythrodysesthesia) reported, including grade 3 and 4 events.

Monitor for signs and symptoms. Early consultation with a dermatologist recommended.

Temporary interruption, dosage reduction, or treatment discontinuance of capivasertib may be necessary based on severity.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on drug mechanism of action and findings from animal studies. Embryofetal mortality and reduced fetal weights observed in animals.

Verify pregnancy status in females of reproductive potential prior to initiating capivasertib. Apprise pregnant women and females of reproductive potential of the potential hazard 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 males with female partners of reproductive potential to use effective contraception during treatment with capivasertib and for 4 months after the last dose.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and findings from animal studies.

Human data on capivasertib use during pregnancy not available. Maternal toxicities and adverse developmental outcomes demonstrated in animals.

Verify pregnancy status in females of reproductive potential prior to initiating capivasertib. Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus.

Lactation

Unknown whether capivasertib or its metabolites distribute into human milk or affect breast-fed infants or milk production.

Advise women not to breast-feed during treatment with capivasertib.

Females and Males of Reproductive Potential

May cause fetal harm. May impair male fertility based on findings in animal studies; effects on female fertility not studied in animals.

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

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No overall differences in efficacy observed between geriatric patients ≥65 years of age and younger adults; however, increased incidence of grade 3–5 adverse reactions, dosage reductions, dose interruptions, and permanent discontinuations observed in geriatric patients.

Hepatic Impairment

No clinically important differences in capivasertib pharmacokinetics observed in mild hepatic impairment (bilirubin ≤ULN and AST >ULN, or bilirubin >1–1.5 times ULN).

Effects of moderate hepatic impairment (bilirubin >1.5–3 times ULN and any AST) not fully characterized; monitor for adverse reactions due to potential increased capivasertib exposure.

Not studied in severe hepatic impairment (bilirubin >3 times ULN and any AST).

Renal Impairment

No clinically important differences in capivasertib pharmacokinetics observed in mild or moderate renal impairment (Cl_cr 30–89 mL/minute).

Not studied in severe renal impairment (Cl_cr 15–29 mL/minute).

Common Adverse Effects

Most common adverse effects (incidence ≥20%): 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, stomatitis.

Drug Interactions

Primarily metabolized by CYP3A4 and UDP-glycosyltransferase (UGT) 2B7.

Substrate of CYP3A.

In vitro, inhibits breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 3, multidrug and toxin extrusion (MATE) transporter 1, MATE2-K, and organic cation transporter (OCT) 2.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increases capivasertib exposure, which may increase risk of adverse reactions.

Avoid concomitant use with a strong CYP3A inhibitor.

If concomitant use cannot be avoided, reduce dose of capivasertib to 320 mg orally twice daily for 4 days followed by 3 days off; monitor for adverse reactions. After discontinuation of a strong CYP3A inhibitor, resume capivasertib dosage (after 3–5 half-lives of the inhibitor) that was taken prior to initiating the strong CYP3A inhibitor.

Moderate CYP3A Inhibitors

Concomitant use with a moderate CYP3A inhibitor increases capivasertib exposure, which may increase risk of capivasertib adverse reactions.

When concomitantly used with a moderate CYP3A inhibitor, reduce dose of capivasertib to 320 mg orally twice daily for 4 days followed by 3 days off; monitor for adverse reactions. After discontinuation of a moderate CYP3A inhibitor, resume the capivasertib dosage (after 3–5 half-lives of the inhibitor) that was taken prior to initiating the moderate CYP3A inhibitor.

Strong or Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreases capivasertib exposure, which may reduce effectiveness of capivasertib.

Avoid concomitant use with strong or moderate CYP3A inducers.

Specific Drugs

Drug	Interaction	Comments
Desipramine	Concomitant administration expected to increase desipramine (CYP2D6 substrate) AUC by up to 2.1-fold on day 4
Efavirenz	Concomitant administration with efavirenz (moderate CYP3A inducer) expected to decrease capivasertib AUC by 60% and peak plasma concentration by 50%	Avoid concomitant use
Erythromycin	Concomitant administration with erythromycin (moderate CYP3A inhibitor) expected to increase capivasertib AUC by up to 1.5-fold and peak plasma concentration by up to 1.3-fold	Reduce capivasertib dosage and monitor for adverse reactions
Itraconazole	Concomitant administration with itraconazole (strong CYP3A inhibitor) expected to increase capivasertib AUC up to 1.7-fold and peak plasma concentration by up to 1.4-fold	Avoid concomitant use; if concomitant use cannot be avoided, reduce capivasertib dosage and monitor for adverse reactions
Midazolam	Concomitant administration expected to increase midazolam (CYP3A substrate) AUC by 1.8-fold on day 4 and by 1.2-fold on day 7
Probenecid	No clinically important differences in capivasertib pharmacokinetics predicted when used concomitantly with probenecid (UGT2B7 inhibitor)
Rabeprazole	No clinically important differences observed with concomitant use of capivasertib and rabeprazole
Raltegravir	Concomitant administration expected to increase raltegravir (UGT1A1 substrate) AUC by up to 1.7-fold on day 4
Rifampicin	Concomitant administration with rifampicin (strong CYP3A inducer) expected to decrease capivasertib AUC by 70% and peak plasma concentration by 60%	Avoid concomitant use
Verapamil	Concomitant administration with verapamil (moderate CYP3A inhibitor) expected to increase capivasertib AUC by up to 1.5-fold and peak plasma concentration by up to 1.3-fold	Reduce capivasertib dosage and monitor for adverse reactions
Warfarin	No clinically important differences in pharmacokinetics of warfarin (CYP2C9 substrate) predicted

Capivasertib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability: 29%.

Time to peak plasma concentration: approximately 1–2 hours.

Time to steady-state concentrations: 3rd and 4th dosing day of each week, starting week 2.

Plasma concentrations 0.5–15% of steady-state peak plasma concentrations during off-dosing days.

AUC and peak plasma concentrations dose-proportional over dosage range of 80–800 mg.

Food

No clinically important differences in pharmacokinetics observed when administered with a high-fat or low-fat meal.

Special Populations

Mild hepatic impairment (bilirubin ≤ULN and AST >ULN, or bilirubin >1–1.5 times ULN): no clinically important differences in capivasertib pharmacokinetics observed.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): no clinically important differences in capivasertib pharmacokinetics observed.

Distribution

Extent

Unknown whether capivasertib or its metabolites distribute into human milk.

Plasma Protein Binding

22%.

Plasma-to-blood ratio: 0.71.

Elimination

Metabolism

Primary pathways: CYP3A4, UGT2B7.

Elimination Route

Feces (50%), urine (45%).

Half–life

8.3 hours.

Special Populations

No clinically important differences in pharmacokinetics observed based on age (26–87 years), sex (88% females), race/ethnicity (white, Asian, Black, American Indian or Alaskan Native, and Native Hawaiian or Other Pacific Islander), or body weight (32–150 kg).

Stability

Storage

Oral

Tablets, Film-Coated

20–25ºC (excursions permitted between 15–30ºC).

Actions

Inhibits serine/threonine kinase AKT (AKT1, AKT2, AKT3) and 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, 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 patients 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 clinician for signs and symptoms of hyperglycemia.
Advise patients that capivasertib can cause diarrhea and to start antidiarrheal treatment, increase oral fluids, and notify their clinician if diarrhea occurs while taking capivasertib.
Advise patients that capivasertib can cause cutaneous adverse reactions and to contact their clinician immediately to report new or worsening rash, erythematous and exfoliative skin reactions.
Advise females to inform their clinician of a known or suspected pregnancy. Apprise pregnant women and females of reproductive potential of the potential hazard 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 males with female partners of reproductive potential to use effective contraception during treatment with capivasertib and for 4 months after the last dose.
Advise women to not breast-feed during treatment with capivasertib.
Instruct patients to take capivasertib 2 times each day, at about the same time each day, for 4 days on and 3 days off, with or without food. Instruct patients to swallow the tablet(s) whole with water, and to not chew, crush, or split the tablets prior to swallowing.
Instruct patients that if a dose of capivasertib is missed, it can be taken within 4 hours after the time it is usually taken. If more than 4 hours has passed, instruct patients to skip the dose and take the next dose at the usual time.
Instruct patients that if a dose of capivasertib is vomited, they should not take an additional dose; instead, they should take the next dose at the usual time.
Advise patients that grapefruit may interact with capivasertib. Instruct patients to not consume grapefruit products while taking capivasertib.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Capivasertib is available through specialty pharmacies and specialty distributors. Consult the Truqapwebsite ([Web]) for specific availability information.