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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-(4chlorophenyl)-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. Capivasertib has the following structural formula:
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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.
TRUQAP, in combination with fulvestrant, is indicated 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-alteration 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.
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].
Information on FDA-approved tests for the detection of PIK3CA, AKT1, and PTEN alterations is available at: https://www.fda.gov/CompanionDiagnostics.
Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) prior to starting TRUQAP and at regular intervals during treatment [see Warnings and Precautions].
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.
TRUQAP dosing schedule for each week is provided in Table 1.
Table 1: TRUQAP Dosing Schedule for Each Week
| Day | 1 | 2 | 3 | 4 | 5* | 6* | 7* |
| Morning | 2 × 200 mg | 2 × 200 mg | 2 × 200 mg | 2 × 200 mg | |||
| Evening | 2 × 200 mg | 2 × 200 mg | 2 × 200 mg | 2 × 200 mg | |||
| * No dosing on day 5, 6 and 7. | |||||||
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.
The recommended dose reductions for adverse reactions are listed in Table 2. Permanently discontinue TRUQAP if unable to tolerate the second dose reduction.
Table 2: Recommended Dose Reductions of TRUQAP for Adverse Reactions
| TRUQAP | 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 |
The recommended dosage modifications for adverse reactions are provided in Table 3.
Table 3: Recommended Dosage Modifications of TRUQAP for Adverse Reactions
| Adverse Reaction | Severity* | TRUQAP Dosage Modification |
| Hyperglycemia† (Fasting Glucose [FG]) [see Warnings and Precautions] |
FG > ULN–160 mg/dL or FG > ULN–8.9 mmol/L or HbA1C > 7% |
Consider initiation or intensification of oral anti-diabetic treatment. |
| FG 161–250 mg/dL or FG 9–13.9 mmol/L |
Withhold TRUQAP until FG decreases ≤ 160 mg/dL (or ≤ 8.9 mmol/L). If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume TRUQAP at one lower dose. |
|
| FG 251–500 mg/dL or FG 14–27.8 mmol/L |
Withhold TRUQAP until FG decreases ≤ 160 mg/dL (or ≤ 8.9 mmol/L). If recovery occurs in ≤ 28 days, resume TRUQAP at one lower dose. If recovery occurs in > 28 days, permanently discontinue TRUQAP. |
|
| FG > 500 mg/dL or FG > 27.8 mmol/L or life-threatening sequelae of hyperglycemia at any FG level |
Withhold TRUQAP. For life-threatening sequelae of hyperglycemia or if FG persists at ≥ 500 mg/dL after 24 hours, permanently discontinue TRUQAP. 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 [see Warnings and Precautions] |
Grade 2 |
Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose or one lower dose as clinically indicated. If recovery occurs in > 28 days, resume at one lower dose. For recurrence, reduce TRUQAP by one lower dose. |
| Grade 3 |
Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose or one lower dose as clinically indicated. If recovery occurs in > 28 days, permanently discontinue TRUQAP. |
|
| Grade 4 | Permanently discontinue TRUQAP. | |
| Cutaneous Adverse Reactions [see Warnings and Precautions] |
Grade 2 |
Withhold TRUQAP until recovery to ≤ Grade 1. Resume TRUQAP at the same dose. Persistent or recurrent: reduce TRUQAP by one lower dose. |
| Grade 3 |
Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume at one lower dose. For recurrent Grade 3, permanently discontinue TRUQAP. |
|
| Grade 4 | Permanently discontinue TRUQAP. | |
| Other Adverse Reactions [see Adverse Reactions] |
Grade 2 |
Withhold TRUQAP until recovery to ≤ Grade 1. Resume TRUQAP at the same dose. |
| Grade 3 |
Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume at one lower dose. |
|
| Grade 4 | Permanently discontinue TRUQAP. | |
| *Severity grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. | ||
| †For the management of suspected or confirmed diabetic ketoacidosis (DKA) refer to section Warnings and Precautions). | ||
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].
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.
Tablets:
Table 8: TRUQAP 160 mg and 200 mg Tablets
| Strength | Description | Package Size and Type | NDC Number |
| 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. | Bottle of 64 tablets | 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. | Bottle of 64 tablets | 0310-9501-01 |
| TRUQAP 160 mg | Beige film-coated, round, biconvex tablets debossed with ‘CAV’ above ‘160’ on one side and plain on the reverse supplied in a blister with a child-resistant closure. | Each carton has 4 blister packs (64 tablets total)–each blister pack contains 16 tablets. | 0310-9500-02 |
| TRUQAP 200 mg | Beige film-coated, capsule-shaped, biconvex tablets debossed with ‘CAV 200’ on one side and plain on the reverse supplied in a blister with a child-resistant closure. | Each carton has 4 blister packs (64 tablets total)–each blister pack contains 16 tablets. | 0310-9501-02 |
Store TRUQAP in original packaging to maintain stability at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Dispense bottled TRUQAP tablets either in:
Distributed by:
AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 TRUQAP is a registered trademark of the AstraZeneca group of companies.
The following adverse reactions are also discussed in greater details in other sections of the labeling:
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%).
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]. 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.
Table 4: Adverse Reactions ≥ 10% in Patients who Received TRUQAP with Fulvestrant [with a Difference Between Arms of ≥ 3%] in CAPItello-291
| Adverse Reaction | TRUQAP with Fulvestrant N=155 | Placebo with Fulvestrant N=133 | ||
| All Grades % | Grade 3 or 4 % | All Grades % | Grade 3 or 4 % | |
| Gastrointestinal Disorders | ||||
| Diarrhea | 77 | 12 | 19 | 0.8 |
| Nausea | 35 | 1.3 | 14 | 0.8 |
| Stomatitis* | 25 | 1.9 | 5 | 0 |
| Vomiting | 21 | 1.9 | 7 | 0.8 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Cutaneous adverse reactions† | 56 | 15 | 16 | 0.8 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue* | 38 | 1.9 | 27 | 1.5 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 17 | 0 | 8 | 0.8 |
| Nervous System Disorders | ||||
| Headache* | 17 | 0 | 13 | 0.8 |
| Infections and Infestations | ||||
| Urinary tract infection* | 14 | 0.6 | 5 | 0 |
| Renal and Urinary Disorders | ||||
| Renal injury‡ | 11 | 2.6 | 1.5 | 0.8 |
| *Includes other related terms. | ||||
| †Cutaneous adverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo-papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema and drug eruption. | ||||
| ‡ Renal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine and proteinuria. | ||||
Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included anemia, pyrexia, dysgeusia, dyspepsia, pneumonia, weight decreased, and hypersensitivity (including anaphylactic reaction).
Table 5: Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients who Received TRUQAP with Fulvestrant [With a Difference Between Arms ≥3%] in CAPItello-291
| Laboratory Abnormality | TRUQAP with Fulvestrant* | Placebo with Fulvestrant† | ||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Glucose Metabolism | ||||
| Increased random glucose | 58 | 9 | 17 | 0 |
| Increased fasting glucose | 37 | 0.6 | 29 | 0 |
| Hematology | ||||
| Decreased lymphocytes | 49 | 11 | 14 | 2.3 |
| Decreased hemoglobin | 47 | 2 | 22 | 2.3 |
| Decreased leukocytes | 35 | 0.6 | 23 | 0 |
| Decreased neutrophils | 25 | 1.9 | 16 | 0.8 |
| Decreased platelets | 12 | 1.9 | 6 | 0.8 |
| Other Categories | ||||
| Increased triglycerides | 30 | 0.7 | 22 | 0.9 |
| Increased alanine aminotransferase | 23 | 2.6 | 13 | 0 |
| Electrolytes/Renal | ||||
| Decreased corrected calcium | 19 | 0.6 | 8 | 0 |
| Increased creatinine | 19 | 1.3 | 4.6 | 0.8 |
| Decreased potassium | 17 | 4.5 | 8 | 0 |
| *The denominator used to calculate the rate varied from 129 to 155 based on the number of patients with a baseline value and at least one post-treatment value. | ||||
| †The denominator used to calculate the rate varied from 109 to 131 based on the number of patients with a baseline value and at least one post-treatment value. | ||||
Table 6 describes drug interactions where concomitant use of another drug affects TRUQAP.
Table 6: Drug Interactions with TRUQAP
| Strong CYP3A Inhibitors | |
| Clinical Impact |
|
| Prevention or Management |
|
| Moderate CYP3A Inhibitors | |
| Clinical Impact |
|
| Prevention or Management |
|
| Strong and Moderate CYP3A Inducers | |
| Clinical Impact |
|
| Prevention or Management |
|
Included as part of the PRECAUTIONS section.
Severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes, can occur in patients treated with TRUQAP.
Increased fasting glucose from baseline occurred in 37% of patients treated with TRUQAP, including 11% of patients with Grade 2 (FG > 160 to 250 mg/dL), 2% with Grade 3 (FG > 250 to 500 mg/dL), and 1.1% with Grade 4 (FG > 500 mg/dL) events.
The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367). Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients.
Diabetic ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients.
In CAPItello-291, 12% (43/355) of patients who received TRUQAP had an anti-hyperglycemic medication regimen either initiated or changed during the study, including treatment with insulin in 4.8% (17/355) of patients.
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.
Before initiating treatment with TRUQAP, test fasting glucose levels (FPG or FBG), HbA1C levels, and optimize fasting glucose.
After initiating treatment with TRUQAP, monitor or self-monitor fasting glucose levels on Day 3 or 4 of the dosing week during weeks 1, 2, 4, 6 and 8; then monthly while on treatment with TRUQAP; and as clinically indicated. Monitor HbA1C levels every 3 months during treatment with TRUQAP and as clinically indicated. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of fasting glucose levels.
For patients who experience hyperglycemia during treatment with TRUQAP, monitor fasting glucose at least twice weekly, on days on and off TRUQAP, until fasting glucose decreases to baseline levels. During treatment with anti-diabetic medications, monitor fasting glucose at least once a week for 2 months, followed by once every 2 weeks, or as clinically indicated.
Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and initiation of fasting glucose monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia. Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes.
Withhold TRUQAP immediately when ketoacidosis is suspected. If ketoacidosis is confirmed, permanently discontinue TRUQAP.
Based on the severity of the hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP [see Dosage and Administration].
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). 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 TRUQAP 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 TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration].
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 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 TRUQAP based on severity [see Dosage and Administration].
Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. 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].
TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively). While there were no statistically significant increases in tumors, there was an increase in malignant mesothelioma in the testis of male rats at 30 mg/kg/day, which is considered a rare tumor in the tested rat strain.
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 had no effect on 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.
Oral administration of capivasertib for up to 2 years resulted in islet of Langerhans hypertrophy/ hyperplasia in the pancreas and lens degeneration in rats at doses ≥ 15 mg/kg/day (≥ 0.1 times the human exposure at the recommended dose based on AUC).
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 [see Clinical Pharmacology]. 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.
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 resulted in reduced litter and pup weights.
TRUQAP 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 (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TRUQAP.
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 day 7 to 8 [see Use in Specific Populations]. Plasma concentrations in pups were up to 0.6% of concentrations in maternal plasma in the 150 mg/kg/day group.
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 [see Use in Specific Populations].
Verify pregnancy status of females of reproductive potential prior to initiating TRUQAP [see Use in Specific Populations].
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.
The safety and effectiveness of TRUQAP have not been established in pediatric patients.
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.
No dosage modification is recommended for patients with mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment [see Clinical Pharmacology].
TRUQAP has not been studied in patients with severe (CLcr 15 to 29 mL/min) renal 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) [see Clinical Pharmacology].
Monitor patients with moderate (bilirubin > 1.5 to 3x ULN and any AST) hepatic impairment for adverse reactions due to potential increased capivasertib exposure [see Warnings and Precautions].
TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
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 immediately for signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often, blurred vision, mental confusion, difficulty breathing, or increased appetite with weight loss) or ketoacidosis [see Warnings and Precautions].
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 [see Warnings and Precautions].
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 [see Warnings and Precautions].
Advise women to not breastfeed during treatment with TRUQAP [see Use in Specific Populations]. Refer to the Full Prescribing Information of fulvestrant for lactation information.
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 prior to swallowing. [see Dosage and Administration].
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.
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 [see Dosage and Administration].
Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter medications, vitamins, and herbal products [see Drug Interactions].
Grapefruit may interact with TRUQAP. Patients should not consume grapefruit products while taking TRUQAP.
No information provided
TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.
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.
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).
At the recommended TRUQAP dose, a mean increase in the QTc interval > 20 ms was not observed.
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).
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%).
The steady state oral volume of distribution is 1,847 L (36%). Capivasertib plasma protein binding is 78% and the plasma-to-blood ratio is 0.71.
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.
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 off treatment each week of 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 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 a 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.
Efficacy results for PIK3CA/AKT1/PTEN-altered subgroup are presented in Table 7 and Figure 1. 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).
Table 7: Efficacy Results for CAPItello-291 (Patients with PIK3CA/AKT1/PTEN-Altered Tumors)
| TRUQAP with fulvestrant N=155 | Placebo with fulvestrant N=134 | |
| Investigator-Assessed Progression-Free Survival (PFS) | ||
| Number of events (%) | 121 (78%) | 115 (86%) |
| Median, months (95% CI) | 7.3 (5.5, 9.0) | 3.1 (2.0, 3.7) |
| Hazard ratio (95% CI)* | 0.50 (0.38, 0.65) | |
| p-value† | <0.0001 | |
| Investigator-Assessed Confirmed Objective Response Rate (ORR) | ||
| Patients with measurable disease | 132 | 124 |
| ORR (95% CI) | 26% (19, 34) | 8% (4, 14) |
| Complete response rate | 2.3% | 0 |
| Partial response rate | 23% | 8% |
| Median DoR, months (95% CI) | 10.2 (7.7, NC‡) | 8.6 (3.8, 9.2) |
| *Stratified Cox proportional hazards model stratified by presence of liver metastases (yes vs no), and prior use of CDK4/6 inhibitors (yes vs no). | ||
| †Stratified log-rank test stratified by presence of liver metastases (yes vs no), and prior use of CDK4/6 inhibitors (yes vs no). | ||
| ‡NC = not calculable. | ||
Figure 1: Kaplan-Meier Plot of Progression-Free Survival in CAPItello-291 (Investigator Assessment, Patients with PIK3CA/AKT1/PTEN-Altered Tumors)
 |
TRUQAP® (TRUE-cap)
(capivasertib)
tablets
What is TRUQAP?
TRUQAP is a prescription medicine used in combination with the medicine fulvestrant to treat adults who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that is advanced or that has spread to other parts of the body (metastatic), with an abnormal “PIK3CA”, “AKT1”, or “PTEN” gene, and whose disease has progressed on or after endocrine therapy.
Your healthcare provider will test your cancer for an abnormal “PIK3CA”, “AKT1”, or “PTEN” gene to make sure that TRUQAP is right for you.
It is not known if TRUQAP is safe and effective in children.
Do not take TRUQAP if you:
Have had a severe allergic reaction to TRUQAP or are allergic to any of the ingredients of TRUQAP. See the end of this leaflet for a list of the ingredients in TRUQAP.
Before you take TRUQAP, tell your healthcare provider about all of your medical conditions, including if you:
Females who are able to become pregnant:
Males with female partners who are able to become pregnant should use effective birth control during your treatment with TRUQAP and for 4 months after the last dose. If your female partner becomes pregnant, tell your healthcare provider right away.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRUQAP may affect the way other medicines work, and other medicines may affect how TRUQAP works.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
How should I take TRUQAP?
What are the possible side effects of TRUQAP?
TRUQAP may cause severe side effects, including:
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Your healthcare provider may tell you to decrease your dose, temporarily stop your treatment, or completely stop your treatment with TRUQAP if you get certain serious side effects.
The most common side effects of TRUQAP include:
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These are not all of the possible side effects of TRUQAP. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
What should I avoid while taking TRUQAP?
How should I store TRUQAP?
Keep TRUQAP and all medicines out of the reach of children.
General information about the safe and effective use of TRUQAP.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TRUQAP for a condition for which it was not prescribed. Do not give TRUQAP to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRUQAP that is written for health professionals.
What are the ingredients in TRUQAP?
Active ingredient: capivasertib.
Inactive ingredients: copovidone, croscarmellose sodium, dibasic calcium phosphate, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, polydextrose, polyethylene glycol 3350, and titanium dioxide
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
TRUQAP is a registered trademark of the AstraZeneca group of companies.
©AstraZeneca 2025
For more information, go to https://www.TRUQAP.com or call 1-800-236-9933. If you still have questions, contact your healthcare provider.
