Truqap
(capivasertib)Dosage & Administration
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Truqap Prescribing Information
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.
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.
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)].
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.
TRUQAP dosing schedule for each week is provided in Table 1.
| |||||||
Day | 1 | 2 | 3 | 4 | 5 * | 6 * | 7 * |
Morning | 2 x 200 mg | 2 x 200 mg | 2 x 200 mg | 2 x 200 mg | |||
Evening | 2 x 200 mg | 2 x 200 mg | 2 x 200 mg | 2 x 200 mg | |||
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.
Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are listed in Table 2. Permanently discontinue TRUQAP if unable to tolerate the second dose reduction.
| 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.
| Adverse Reaction | Severity * | TRUQAP Dosage Modification |
|---|---|---|
| ||
Hyperglycemia † (Fasting Glucose [FG]) [see Warnings and Precautions (5.1)] | 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 decrease ≤ 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 decrease ≤ 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 (5.2)] | 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 as clinically indicated. 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 (5.3)] | 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 TRUQAP at one lower dose. For recurrent Grade 3, permanently discontinue TRUQAP. | |
Grade 4 | Permanently discontinue TRUQAP. | |
Other Adverse Reactions [see Adverse Reactions (6.1)] | 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 TRUQAP at one lower dose. | |
Grade 4 | Permanently discontinue TRUQAP. | |
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.
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.
Pregnancy
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 [see Clinical Pharmacology (12.1)]. 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 resulted in reduced litter and pup weights.
Lactation
Risk Summary
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.
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 day 7 to 8 [see Use in Specific Populations (8.1)]. Plasma concentrations in pups were up to 0.6% of concentrations in maternal plasma in the 150 mg/kg/day group.
Females and Males of Reproductive Potential
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 (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating TRUQAP [see Use in Specific Populations (8.1)].
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.
Pediatric Use
The safety and effectiveness of TRUQAP have not been established in pediatric patients.
Geriatric 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.
Renal Impairment
No dosage modification is recommended for patients with mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment [see Clinical Pharmacology (12.3)].
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) [see Clinical Pharmacology (12.3)].
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 (5.1, 5.2, 5.3)].
TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment.
TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.
Hyperglycemia
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 (2.4)].
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). 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 (2.4)].
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 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 (2.4)].
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.