BRIEF SUMMARY

TRANSTUMAB- (Dec 2019)

Indn-       To treat metastatic breast cancer

Comp.

ADR-

CI-

Pat Infrm-

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  47.

CONTRAINDICATIONS-

The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

 • Management of adverse reactions (ILD, neutropenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of EN

 DOSAGE FORMS AND STRENGTHS -

­ For injection: 100 mg lyophilized powder in a single-dose via

CONTRAINDICATIONS------------------------------­ None. (4) ----------------------- 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. (2.2, 5.2) • 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). (2.2, 5.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ The most common adverse reactions (=20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Lactation: Advise not to breastfeed. (8.2) • Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. (

 DOSAGE AND ADMINISTRATION-

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 [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.3)]. 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 [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months after the last dose [see Use in Specific Populations (8.3)]. • 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 [see Use in Specific Populations (8.3)]. Lactation • Advise women not to breastfeed during treatment and for 7 months after the last dose of ENHERTU [see Use in Specific Populations (8.2)]. Infertility • Advise males of reproductive potential that ENHERTU may impair fertility [see Use in Specific Populations (8.3)].

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. 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. 12.2 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. 12.3 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). At the recommended dosage of ENHERTU, the geometric mean (coefficient of variation [CV]%) Cmax of famtrastuzumab deruxtecan-nxki and DXd were 122 µg/mL (20%) and 4.4 ng/mL (40%), respectively, and the AUC of famtrastuzumab deruxtecan-nxki and DXd were 735 µg·day/mL (31%) and 28 ng·day/mL (38%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 35% at steady state (Cycle 3). 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 11 Reference ID: 4537820 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with fam-trastuzumab deruxtecan-nxki. The topoisomerase inhibitor component of fam-trastuzumab deruxtecan-nxki, DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay. Fertility studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In a six-week repeat-dose toxicity study in rats, intravenous administratio

USE IN SPECIFIC POPULATIONS 8.1 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 8 Reference ID: 4537820 8 during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data]. Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. 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 [see Clinical Considerations]. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ENHERTU during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received a HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped. Animal Data There were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki. 8.2 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. 8.3 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 [see Use in Specific Populations (8.1)]. 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 [see Nonclinical Toxicology (13.1)]. Infertility 9 Reference ID: 4537820 Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of ENHERTU have not been established in pediatric patients. 8.5 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%). 8.6 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 [see Clinical Pharmacology (12.3)]. No data are available in patients with severe renal impairment. 8.7 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 [see Dosage and Administration (2.2)]. No data are available in patients with severe (total bilirubin >3 to 10 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].

11 DESCRIPTION Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody and topoisomerase inhibitor conjugate. Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate (ADC) composed of three components: 1) a humanized anti-HER2 IgG1 monoclonal antibody (mAb), covalently linked to 2) a topoisomerase inhibitor, via 3) a tetrapeptide-based cleavable linker. Deruxtecan is composed of a protease-cleavable maleimide tetrapeptide linker and the topoisomerase inhibitor, DXd, which is an exatecan derivative.