DRUG INTERACTIONS -(summary)

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

• Moderate CYP3A Inhibitors: Reduce TRUQAP dose.

 • Strong and Moderate CYP3A Inducers: Avoid concomitant use.

BRIEF SUMMARY

CAPIVASERIB-(Nov 2023)

Indn-    To treat breast cancer that meets certain disease criteria                                                                           

Comp-   Tablets: 160 mg and 200 mg  • Recommended Dosage: 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off.

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

CI-   Severe hypersensitivity to TRUQAP or any of its components.

WARNINGS -

 • Hyperglycemia: Evaluate blood glucose levels prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. 

 • Diarrhea: TRUQAP caused diarrhea in most patients. Advise patients to increase oral fluids, start antidiarrheal treatment, and consult with a healthcare provider if diarrhea occurs while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. 

Pat Inform- 

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 

================================================================

U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 51

Name-          TRUQAB

Active ingedient-       Capivaserib          

Indication              To treat breast cancer that meets certain disease criteria

Date  of approval       11/16/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                           TRUQAP safely and effectively.

See full prescribing information for TRUQAP. TRUQAP™ (capivasertib) tablets, for oral use

Initial U.S. Approval: 2023 -

 INDICATIONS AND USAGE -

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

 ADVERSE REACTIONS-

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

CONTRAINDICATIONS -

 Severe hypersensitivity to TRUQAP or any of its components.

WARNINGS AND PRECAUTIONS -

 • Hyperglycemia: Evaluate blood glucose levels prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. 

 • Diarrhea: TRUQAP caused diarrhea in most patients. Advise patients to increase oral fluids, start antidiarrheal treatment, and consult with a healthcare provider if diarrhea occurs while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity.

 • Cutaneous Adverse Reactions: Monitor for signs and symptoms of cutaneous adverse reactions. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity.

 • Embryo-Fetal Toxicity: TRUQAP can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.-

DOSAGE AND ADMINISTRATION-

 • 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

 • Recommended Dosage: 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off.

 DOSAGE FORMS AND STRENGTHS -

 Tablets: 160 mg and 200 mg 

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

Lactation-                                                                                                                   Advise women to not breastfeed during treatment with TRUQAP

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 prior to swallowing. 

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

Take the next dose at the usual time. 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.

Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 TRUQAP is a trademark of the AstraZeneca group of companies. ©AstraZeneca 2023

 CLINICAL PHARMACOLOGY

1. 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).

2, Pharmacodynamics -                                                                                             Exposure-Response Relationships The exposure-response relationship and time course of pharmacodynamic response for the effectiveness of capivasertib have not been fully characterized. 

Cardiac Electrophysiology-                                                                                             At the recommended TRUQAP dose, a mean increase in the QTc interval > 20 ms was not observed.

3. Pharmacokinetics-                                                                                              Capivasertib pharmacokinetic parameters are presented as the mean [%coefficient of variation (%CV)], unless otherwise specified.

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.

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%.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.

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.

2. 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 

 Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TRUQAP.

3. Females and Males of Reproductive Potential-                                                       TRUQAP is used in combination with fulvestrant.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 do

4. Pediatric Use-                                                                                                                 The safety and effectiveness of TRUQAP have not been established in pediatric patients.

5. 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.