Capivasertib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
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Overview
Capivasertib is a kinase inhibitor in combination with fulvestrant that is FDA approved 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.. Common adverse reactions include 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..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
2.1 Patient Selection Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with TRUQAP, based on the presence of one or more of the following genetic alterations in tumor tissue: PIK3CA/AKT1/PTEN [see CLINICAL STUDIES (14)].
Information on FDA-approved tests for the detection of PIK3CA, AKT1, and PTEN alterations is available at: HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS.
2.2 Recommended Evaluation Before Initiating TRUQAP Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) prior to starting TRUQAP and at regular intervals during treatment [see WARNINGS AND PRECAUTIONS (5.1)].
2.3 Recommended Dosage and Administration The recommended dosage of TRUQAP, in combination with fulvestrant, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off. Continue TRUQAP until disease progression or unacceptable toxicity.
Swallow TRUQAP tablets whole. Do not chew, crush, or split tablets prior to swallowing. Do not take tablets that are broken, cracked, or otherwise not intact.
If a patient misses a dose within 4 hours of the scheduled time, instruct the patient to take the missed dose. If a patient misses a dose more than 4 hours of the scheduled time, instruct the patient to skip the dose and take the next dose at its usual scheduled time.
If a patient vomits a dose, instruct the patient not to take an additional dose and take the next dose at its usual scheduled time.
Refer to the fulvestrant Full Prescribing Information for recommended fulvestrant dosing information.
For premenopausal and perimenopausal women, administer a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
For men, consider administering a LHRH agonist according to current clinical practice standards.
2.4 Dosage Modifications for Adverse Reactions Permanently discontinue TRUQAP if unable to tolerate the second dose reduction.
2.5 Dosage Modifications for Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor cannot be avoided, reduce the dosage of TRUQAP to 320 mg orally twice daily for 4 days followed by 3 days off [see DRUG INTERACTIONS (7.1)].
When concomitantly used with a moderate CYP3A inhibitor, reduce the dosage of TRUQAP to 320 mg orally twice daily for 4 days followed by 3 days off.
After discontinuation of a strong or moderate CYP3A inhibitor, resume the TRUQAP dosage (after 3 to 5 half-lives of the inhibitor) that was taken prior to initiating the strong or moderate CYP3A inhibitor.
DOSAGE FORMS AND STRENGTHS
Tablets:
•160 mg: beige film-coated, round, biconvex tablets debossed with ‘CAV’ above ‘160’ on one side and plain on the reverse. •200 mg: beige film-coated, capsule-shaped, biconvex tablets debossed with ‘CAV 200’ on one side and plain on the reverse.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Capivasertib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.
Warnings
Hyperglycemia Severe hyperglycemia, associated with ketoacidosis, occurred in patients treated with TRUQAP. The safety of TRUQAP has not been established in patients with Type I diabetes or diabetes requiring insulin. Patients with insulin-dependent diabetes were excluded from CAPItello-291.
Hyperglycemia occurred in 18% of patients treated with TRUQAP. 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).
Of 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 TRUQAP, 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 before treatment. Before initiating TRUQAP, inform patients about TRUQAP’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, before the scheduled dose of TRUQAP. Monitor HbA1c every three months. Monitor FG more frequently during treatment with TRUQAP in patients with a medical history of diabetes mellitus and 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 TRUQAP, 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 TRUQAP based on severity.
Diarrhea Severe diarrhea associated with dehydration occurred in patients who received TRUQAP.
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). Of 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 TRUQAP due to diarrhea. In patients with Grade ≥ 2 diarrhea (n=93) with at least 1-grade improvement (n=89), the 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 TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP 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 TRUQAP.
Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. 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 TRUQAP 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 reactions (n= 116) with at least 1-grade improvement (n=104), the 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 TRUQAP based on severity.
Embryo-Fetal Toxicity Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1)]. 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 TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose [see USE IN SPECIFIC POPULATIONS (8.1, 8.3)].
TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions are also discussed in greater detail in other sections of the labeling:
•Hyperglycemia •Diarrhea •Cutaneous Adverse Reactions
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients in CAPItello-291 until disease progression or unacceptable toxicity. Among the 355 patients who received TRUQAP, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).
CAPItello-291
The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN-alterations [see CLINICAL STUDIES (14)]. Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year.
Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%).
Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥ 1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each).
Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%).
Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. The most common adverse reaction (≥ 2%) leading to permanent discontinuation of TRUQAP was cutaneous adverse reactions (6%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 39% of patients. Adverse reactions leading to dosage interruption in ≥ 2% of patients included cutaneous adverse reactions (14%), diarrhea (10%), pyrexia (4.5%), vomiting and nausea (3.2% each), and fatigue (2.6%).
Dose reductions of TRUQAP due to adverse reactions occurred in 21% of patients receiving TRUQAP with fulvestrant. Adverse reactions leading to TRUQAP dose reductions in ≥ 2% of patients were diarrhea and cutaneous adverse reactions (8% each).
The most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (77%), increased random glucose (58%), cutaneous adverse reaction (56%), decreased lymphocytes (49%), decreased hemoglobin (47%), fatigue (38%), increased fasting glucose (37%), nausea and decreased leukocytes (35% each), increased triglycerides (30%), stomatitis (25%), decreased neutrophils (25%), and vomiting (21%). Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.
Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included anemia, hypersensitivity (including anaphylactic reaction), dysgeusia, dyspepsia, pneumonia and pyrexia.
Postmarketing Experience
There is limited information regarding Capivasertib Postmarketing Experience in the drug label.
Drug Interactions
Strong CYP3A Inhibitors
Clinical Impact
•Capivasertib is a CYP3A substrate. Strong CYP3A inhibitors increase capivasertib exposure, which may increase the risk of TRUQAP adverse reactions.
Prevention or Management •Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the dose of TRUQAP and monitor patients for adverse reactions.
Moderate CYP3A Inhibitors
Clinical Impact
•Capivasertib is a CYP3A substrate. Moderate CYP3A inhibitors increase capivasertib exposure, which may increase the risk of TRUQAP adverse reactions.
Prevention or Management •When concomitantly used with moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions.
Strong and Moderate CYP3A Inducers
Clinical Impact
•Capivasertib is a CYP3A substrate. Strong and moderate CYP3A inducers decrease capivasertib exposure, which may reduce the effectiveness of TRUQAP.
Prevention or Management
•Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Risk Summary
TRUQAP 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, TRUQAP can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TRUQAP 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 (see Data). 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.
Data
Animal Data
In an embryo-fetal development study, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day during the period of organogenesis. Administration of capivasertib resulted in maternal toxicities (reduced body weight gain and food consumption, increased blood glucose) and adverse developmental outcomes, including embryo-fetal deaths (post-implantation loss), reduced fetal weights, and minor fetal visceral variations at a dose of 150 mg/kg/day (0.7 times the human exposure at the recommended dose of 400 mg twice daily based on AUC).
In a pre-and post-natal assessment, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day from gestation day 6 through at least lactation day 6. Administration of 150 mg/kg/day reduced litter and pup weights.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Capivasertib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Capivasertib during labor and delivery.
Nursing Mothers
Risk Summary
TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.
There is 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 TRUQAP.
Data
Animal Data
In a pre-and post-natal assessment, when capivasertib was administered to maternal rats during the lactation period, capivasertib was detected in plasma of suckling rat pups on lactation days 7 to 8. Plasma concentrations in pups were up to 0.6% of concentrations in maternal plasma in the 150 mg/kg/day group.
Pediatric Use
The safety and effectiveness of TRUQAP have not been established in pediatric patients.
Geriatic Use
Of the 355 patients who received TRUQAP in CAPItello-291, 115 (32%) patients were ≥ 65 years of age and 24 (7%) patients were ≥ 75 years of age. No overall differences in the efficacy of TRUQAP were observed between patients ≥ 65 years of age and younger patients. Analysis of the safety of TRUQAP 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.
Gender
There is no FDA guidance on the use of Capivasertib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Capivasertib with respect to specific racial populations.
Renal Impairment
No dosage modification is recommended for patients with mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment.
TRUQAP has not been studied in patients with severe (CLcr 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.
TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment.
Females of Reproductive Potential and Males
TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.
TRUQAP can cause fetal harm when administered to pregnant women
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating TRUQAP
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose.
Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.
Immunocompromised Patients
There is no FDA guidance one the use of Capivasertib in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Capivasertib Administration in the drug label.
Monitoring
There is limited information regarding Capivasertib Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Capivasertib and IV administrations.
Overdosage
There is limited information regarding Capivasertib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
TRUQAP film-coated tablets are supplied for oral administration with 160 mg or 200 mg capivasertib. The tablets also contain croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, and microcrystalline cellulose. The film coat contains the following inactive ingredients: copovidone, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, medium chain triglycerides, polydextrose, polyethylene glycol 3350, and titanium dioxide.
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.
Structure
TRUQAP (capivasertib) is a kinase inhibitor. The molecular formula for capivasertib is C21H25ClN6O2 and the molecular weight is 428.92 g/mol. The chemical name of capivasertib is 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinecarboxamide. Capivasertib is a white to off-white powder with pH-dependent solubility. It is freely soluble in water at pH values below 1.2 and practically insoluble at pH values above 6.8.
Pharmacodynamics
Exposure-Response Relationships
The exposure-response relationship and time course of pharmacodynamic response for the effectiveness of capivasertib have not been fully characterized. Exposure-response relationships were observed for diarrhea (CTCAE Grade 2 to 4), rash (CTCAE Grade 2 to 4) and hyperglycemia (CTCAE Grades 3 or 4) at doses of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).
Cardiac Electrophysiology
At the recommended TRUQAP dose, a mean increase in the QTc interval > 20 ms was not observed.
Pharmacokinetics
Capivasertib pharmacokinetic parameters are presented as the mean [%coefficient of variation (%CV)], unless otherwise specified. The capivasertib steady-state AUC is 8,069 h·ng/mL (37%) and Cmax is 1,371 ng/mL (30%). Steady-state concentrations are predicted to be attained on the 3rd and 4th dosing day of each week, starting week 2.
Capivasertib plasma concentrations are approximately 0.5% to 15% of the steady state Cmax during the off-dosing days.
Capivasertib AUC and Cmax are proportional with dose over a range of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).
Absorption
Tmax is approximately 1-2 hours. The absolute bioavailability is 29%.
Effect of Food
No clinically meaningful differences in capivasertib pharmacokinetics were observed following administration of TRUQAP with a high-fat meal (approximately 1,000 kcal; fat 60%) or a low-fat meal (approximately 400 kcal; fat 26%).
Distribution
The steady state oral volume of distribution is 1,847 L (36%). Capivasertib plasma protein binding is 22% and the plasma-to-blood ratio is 0.71.
Elimination
The half-life is 8.3 hours and the steady-state oral clearance is 50 L/h (37% CV). Renal clearance was 21% of total clearance.
Metabolism
Capivasertib is primarily metabolized by CYP3A4 and UGT2B7.
Excretion
Following a single radiolabeled oral dose of 400 mg, the mean total recovery was 45% from urine and 50% from feces.
Specific Populations
No clinically significant differences in capivasertib pharmacokinetics were observed based on race/ethnicity (including White, Asian, Black, American Indian or Alaskan Native, and Native Hawaiian or Other Pacific Islander), sex (88% females), body weight (32 to 150 kg), age (26 to 87 years), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN), or mild to moderate renal impairment (CLcr 30 to 89 mL/min).
The effect of moderate (bilirubin > 1.5 to 3x ULN and any AST) hepatic impairment is not fully characterized.
TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15 to 29 mL/min).
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong and Moderate CYP3A Inhibitors on Capivasertib: Itraconazole (strong CYP3A4 inhibitor) is predicted to increase capivasertib AUC by up to 1.7-fold and Cmax by up to 1.4-fold.
Erythromycin and verapamil (moderate CYP3A inhibitors) are predicted to increase capivasertib AUC by up to 1.5-fold and Cmax by up to 1.3-fold.
Effect of Strong and Moderate CYP3A Inducers on Capivasertib: Rifampicin (strong CYP3A4 inducer) is predicted to decrease capivasertib AUC by 70% and Cmax by 60%.
Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib AUC by 60% and Cmax by 50%.
Effect of UGT2B7 Inhibitors on Capivasertib: Probenecid (UGT2B7 inhibitor) is not predicted to have a clinically meaningful effect on capivasertib pharmacokinetics.
Effect of Acid Reducing Agents on Capivasertib: Rabeprazole (gastric acid reducing agent) did not have a clinically meaningful effect on capivasertib pharmacokinetics.
Effect of Capivasertib on CYP3A Substrates: Concomitant use of TRUQAP increased midazolam (CYP3A substrate) AUC by 1.8-fold on day 4 and by 1.2-fold on day 7.
Effect of Capivasertib on CYP2D6 Substrates: TRUQAP is predicted to increase desipramine (CYP2D6 substrate) AUC by up to 2.1-fold on day 4.
Effect of Capivasertib on CYP2C9 Substrates: Concomitant use of TRUQAP with warfarin (CYP2C9 substrate) is not predicted to have a clinically meaningful effect on warfarin pharmacokinetics.
Effect of Capivasertib on UGT1A1 Substrates: TRUQAP is predicted to increase raltegravir (UGT1A1 substrate) AUC by up to 1.7-fold on day 4.
In-Vitro Studies
Capivasertib inhibits BCRP, OATP1B1, OATP1B3, OAT3, MATE1, MATE2-K, and OCT2.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with capivasertib.
Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.
In repeat-dose toxicity studies up to 26 weeks duration in rats and 39 weeks duration in dogs, tubular degeneration in the testes and cellular debris in the epididymides were observed at oral capivasertib doses of 100 mg/kg/day in rats and 15 mg/kg/day in dogs (approximately 1 time the human exposure at the recommended dose of 400 mg twice daily based on AUC). In a male fertility study, capivasertib did not affect fertility in male rats at oral doses up to 100 mg/kg/day following 10 weeks of treatment. Effects of capivasertib on female fertility have not been studied in animals.
Clinical Studies
The efficacy of TRUQAP with fulvestrant was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which 289 patients had tumors with eligible PIK3CA/AKT1/PTEN-alterations. Eligible PIK3CA/AKT1 activating mutations or PTEN loss of function alterations were identified in the majority of FFPE tumor specimens using FoundationOne®CDx next-generation sequencing (n=686). All patients were required to have progression on an aromatase inhibitor (AI) based treatment in the metastatic setting or recurrence on or within 12 months of completing (neo)adjuvant treatment with an AI. Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced (inoperable) or metastatic disease. Patients were excluded if they had clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1, Type 2, requiring insulin treatment, or HbA1c ≥8% (63.9 mmol/mol)).
Patients were randomized (1:1) to receive either 400 mg of TRUQAP (n=355) or placebo (n=353), given orally twice daily for 4 days followed by 3 days of treatment each week of the 28-day treatment cycle. Fulvestrant 500 mg intramuscular injection was administered on cycle 1 days 1 and 15, and then at day 1 of each subsequent 28-day cycle. Patients were treated until disease progression or unacceptable toxicity. Randomization was stratified by the presence of liver metastases (yes vs. no), prior treatment with CDK4/6 inhibitors (yes vs. no), and geographical region (region 1: US, Canada, Western Europe, Australia, and Israel vs region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia).
The major efficacy outcomes were investigator-assessed progression-free survival (PFS) in the overall population and in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alterations evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional efficacy outcome measures were overall survival (OS), investigator-assessed objective response rate (ORR), and duration of response (DoR).
A statistically significant difference in PFS was observed in the overall population and the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration. An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have a PIK3CA/AKT1/PTEN-alteration showed an HR of 0.79 (95% CI: 0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration.
Of the 289 patients whose tumors were PIK3CA/AKT1/PTEN-altered, the median age was 59 years (range 34 to 90); female (99%); White (52%), Asian (29%), Black (1%), American Indian/Alaska Native (0.7%), other races (17%) and 9% were Hispanic/Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (66%) or 1 (34%), and 18% were premenopausal or perimenopausal. Seventy-six percent of patients had an alteration in PIK3CA, 13% had an alteration in AKT1, and 17% had an alteration in PTEN. All patients received prior endocrine-based therapy (100% AI-based treatment and 44% received tamoxifen). Seventy-one percent of patients were previously treated with a CDK4/6 inhibitor and 18% received prior chemotherapy for locally advanced (inoperable) or metastatic disease.
Results from the blinded independent review committee (BICR) assessment were consistent with the investigator-assessed PFS results. Overall survival results were immature at the time of the PFS analysis (30% of the patients died).
How Supplied
TRUQAP 160 mg
Beige film-coated, round, biconvex tablets debossed with ‘CAV’ above ‘160’ on one side and plain on the reverse supplied in HDPE bottle with child-resistant closure. 64 tablets per bottle NDC number: 0310-9500-01
TRUQAP 200 mg
Beige film-coated, capsule-shaped, biconvex, tablets debossed with ‘CAV 200’ on one side and plain on the reverse supplied in HDPE bottle with child-resistant closure.
64 tablets per bottle
NDC number: 0310-9501-01
Storage
Store TRUQAP in original bottle at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F)
Images
Drug Images
{{#ask: Page Name::Capivasertib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
Rx Only NDC 03109500-01
TRUQAP™
(capivasertib) tablets
160mg
64 film-coated tablets
AstraZeneca {{#ask: Label Page::Capivasertib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hyperglycemia
Advise patients that TRUQAP 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
Diarrhea
Advise patients that TRUQAP can cause diarrhea and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking TRUQAP
Cutaneous Adverse Reactions
Advise patients that TRUQAP can cause cutaneous adverse reactions and to contact their healthcare provider immediately to report new or worsening rash, erythematous, and exfoliative skin reactions
Embryo-Fetal Toxicity
•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 TRUQAP and for 1 month after the last dose. •Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose [see USE IN SPECIFIC POPULATIONS (8.3)]. •Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
Lactation
Advise women to not breastfeed during treatment with TRUQAP [see USE IN SPECIFIC POPULATIONS (8.2)]. Refer to the Full Prescribing Information of fulvestrant for lactation information.
Dosing Instructions
Instruct patients to take TRUQAP 2 times each day, at about the same times each day, for four 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 before 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 have passed, skip the dose. Take the next dose at the usual time.
Instruct patients that if they vomit after taking the dose, an additional dose should not be taken. The next dose of TRUQAP should be taken at the usual time.
Drug Interactions
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 TRUQAP. Patients should not consume grapefruit products while taking TRUQAP.
Precautions with Alcohol
Alcohol-Capivasertib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
TRUQAP
Look-Alike Drug Names
There is limited information regarding Capivasertib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.