ADR- The most common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia.

 WARNINGS-                                                                                                     •  Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. 

• Left Ventricular Dysfunction: Assess LVEF prior to initiation  and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue  in patients with symptomatic congestive heart failure (CHF

 ADVERSE REACTIONS

The most common adverse reactions (=20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia.                                 

 CONTRAINDICATIONS                                                                                         ­     None. 

 WARNINGS AND PRECAUTIONS

 •  Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. 

• Left Ventricular Dysfunction: Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF). 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Interstitial Lung Disease                                                                                                • Inform patients of the risks of severe or fatal ILD. Advise patients to contact their healthcare provider immediately for any of the following: cough, shortness of breath, fever, or other new or worsening respiratory symptoms 

Neutropenia                                                                                                                    • Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection 

Left Ventricular Dysfunction                                                                                           • Advise patients to contact their healthcare provider immediately for any of the following: new onset or worsening shortness of breath, cough, fatigue, swelling of ankles/legs, palpitations, sudden weight gain, dizziness, loss of consciousness 

Embryo-Fetal Toxicity                                                                                                    • Inform female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider of a known or suspected pregnancy 

• Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months after the last dose

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose 

Lactation                                                                                                                           • Advise women not to breastfeed during treatment and for 7 months after the last dose of ENHERTU 

Infertility                                                                                                                          • Advise males of reproductive potential that ENHERTU may impair fertility 

Manufactured by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 U.S. License No. 2128 Marketed by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 and AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 ENHERTU® is a registered trademark of Daiichi Sankyo Company, Ltd. © 2019 Daiichi Sankyo Co., Ltd. USPI-XXX-CX-XXXX-rXXX

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1.

Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. 

2. Pharmacodynamics                                                                                       Cardiac Electrophysiology The administration of multiple doses of ENHERTU (6.4 mg/kg every 3 weeks, which is 1.2 times the recommended dosage) did not show large mean effect (i.e. >20 ms) on the QTc interval in an open label, single-arm study in 51 patients with HER2-expressing metastatic breast cancer.

3. Pharmacokinetics                                                                                                 The pharmacokinetics of fam-trastuzumab deruxtecan-nxki was evaluated in patients with cancer. Following a single dose, exposures (Cmax and AUC) of fam-trastuzumab deruxtecan-nxki and released topoisomerase inhibitor (DXd) increased proportionally over a dose range of 3.2 mg/kg to 8 mg/kg (approximately 0.6 to 1.5 times the recommended dose).

Distribution                                                                                                            Based on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki was 2.77 L. For humans, DXd plasma protein binding is approximately 97% and the blood to plasma ratio is approximately 0.6, in vitro.

Elimination                                                                                                                 The median elimination half-life (t1/2) of fam-trastuzumab deruxtecan-nxki was approximately 5.7 days. Based on population pharmacokinetic analysis, the estimated systemic clearance of fam-trastuzumab deruxtecan-nxki was 0.42 L/day.

The median apparent elimination half-life (t1/2) of DXd was approximately 5.8 days. Based on population pharmacokinetic analysis, the estimated apparent systemic clearance of DXd was 19.2 L/h.

Metabolism                                                                                                                The humanized HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. In vitro, DXd is primarily metabolized by CYP3A4.

Specific Populations                                                                                                   No clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (23-96 years), race (Asian [n=291] and non-Asian [n=221]), sex, body weight (34.6-125.4 kg), mild (total bilirubin =ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST, n=215) hepatic impairment, mild (creatinine  clearance [CLcr] =60 and <90 mL/min, n=206) or moderate (CLcr =30 and <60 mL/min; n=58) renal impairment based on population pharmacokinetic analysis.

The pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr <30 mL/min) is unknown.

Drug Interaction Studies                                                                                     Clinical Studies Effect of CYP3A Inhibitors on DXd: Coadministration of itraconazole, a strong CYP3A inhibitor, with multiple doses of ENHERTU increased steady state AUC0-17 days of fam-trastuzumab deruxtecan-nxki by 11% and DXd by 18%. The impact of these changes is not clinically meaningful.

Effect of OATP Inhibitors on DXd: Coadministration of ritonavir, a dual inhibitor of OATP1B/CYP3A, with multiple doses of ENHERTU increased steady state AUC0-17 days of fam-trastuzumab deruxtecan-nxki by 19% and DXd by 22%. The impact of these changes is not clinically meaningful.

In Vitro Studies Effects of DXd on CYP Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A nor induce CYP1A2, CYP2B6, or CYP3A.

Effects of DXd on Transporters: At clinically relevant concentrations (steady-state Cmax of ~0.2 µmol/L), DXd has a low potential to inhibit OAT1 (IC50 value of 12.7 µmol/L), OAT3, OCT1, OCT2, OATP1B1 (IC50 value of 14.4 µmol/L), OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.

Effects of Other Drugs on DXd: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP. 1

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman.

There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death 

Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15­ 20%, respectively. . 

2. Lactation Risk Summary                                                                                          There is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production. 

Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

3. Females and Males of Reproductive Potential Pregnancy Testing                   Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.

Contraception Females ENHERTU can cause fetal harm when administered to a pregnant woman 

Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose.

Males                                                                                                                                 Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose

Infertility Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility 

4. Pediatric Use                                                                                                          Safety and effectiveness of ENHERTU have not been established in pediatric patients.

5 Geriatric Use                                                                                                             Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were 65 years or older and 5% were 75 years or older. No overall differences in efficacy were observed between patients =65 years of age compared to younger patients.

There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (53%) as compared to younger patients (42%).

6. Renal Impairment                                                                                                    No dose adjustment of ENHERTU is required in patients with mild (creatinine clearance (CLcr) =60 and <90 mL/min) or moderate (CLcr =30 and <60 mL/min) renal impairment  No data are available in patients with severe renal impairment.

7. Hepatic Impairment                                                                                                 No dose adjustment of ENHERTU is required in patients with mild (total bilirubin =ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment.

In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd 

No data are available in patients with severe (total bilirubin >3 to 10 times ULN and any AST) hepatic impairment