ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)] Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)] Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] The most common adverse reactions (>=20%) in patients with:breast cancer were nausea, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, fatigue, vomiting, alopecia, aspartate aminotransferase increased, alanine aminotransferase increased, platelet count decreased, constipation, decreased appetite, anemia, diarrhea, hypokalemia, and cough. (6.1)gastric cancer were hemoglobin decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia. (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.. breast cancer were nausea, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, fatigue, vomiting, alopecia, aspartate aminotransferase increased, alanine aminotransferase increased, platelet count decreased, constipation, decreased appetite, anemia, diarrhea, hypokalemia, and cough. (6.1). gastric cancer were hemoglobin decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Metastatic Breast CancerThe safety of ENHERTU was evaluated in pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.7 to 31).In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an ECOG performance status of (58%) or (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, fatigue, vomiting, alopecia, aspartate aminotransferase increased, alanine aminotransferase increased, platelet count decreased, constipation, decreased appetite, anemia, diarrhea, hypokalemia, and cough.Tables and summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients.Table 3: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101Adverse ReactionsENHERTU 5.4 mg/kg N=234All Grades %Grades or %Events were graded using NCI CTCAE version 4.03. = number of patients exposed; PT preferred term. Percentages were calculated using the number of patients in the Safety Analysis Set as the denominator.Gastrointestinal Disorders Nausea797 Vomiting473.8 Constipation350.9 Diarrhea291.7 Abdominal painGrouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and abdominal pain upper. 191.3 StomatitisGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). 140.9 Dyspepsia120General Disorders and Administration Site Conditions FatigueGrouped term of fatigue includes PTs of fatigue and asthenia. 596Skin and Subcutaneous Tissue Disorders Alopecia460.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2. RashGrouped term of rash includes PTs of rash, rash pustular, and rash maculo-papular. 100Metabolism and Nutrition Disorders Decreased appetite321.3Blood and Lymphatic System Disorders AnemiaGrouped term of anemia includes PTs of anemia, hemoglobin decreased, hematocrit decreased, and red blood cell count decreased. 317Respiratory, Thoracic and Mediastinal Disorders Cough200 Dyspnea131.3 Epistaxis130 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 92.6All events had fatal outcomes (n=6). Nervous System Disorders HeadacheGrouped term of headache includes PTs of headache, sinus headache, and migraine. 190 Dizziness100Infections and Infestation Upper respiratory tract infectionGrouped term of upper respiratory tract infection includes PTs of influenza, influenza-like illness, and upper respiratory tract infection. 150Eye Disorders Dry eye110.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3. Other clinically relevant adverse reactions reported in less than 10% of patients were:Injury, Poisoning and Procedural Complications: infusion-related reactions (2.6%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Table 4: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTULaboratory ParameterENHERTU 5.4 mg/kg N=234All Grades %Grades or %Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyWhite blood cell count decreased707Hemoglobin decreased707Neutrophil count decreased6216Platelet count decreased373.4ChemistryAspartate aminotransferase increased410.9Alanine aminotransferase increased380.4Hypokalemia263. Injury, Poisoning and Procedural Complications: infusion-related reactions (2.6%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Locally Advanced or Metastatic Gastric CancerThe safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.2)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, white blood cell decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia.Tables and summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.Table 5: Adverse Reactions in >=10% All Grades or >=2% Grades or of Patients Receiving ENHERTU in DESTINY-Gastric01ENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62Adverse ReactionsAll Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03. = number of patients exposed; PT preferred term.Percentages were calculated using the number of patients in the Safety Analysis Set as the denominator.Gastrointestinal DisordersNausea634.8471.6Diarrhea322.4321.6Vomiting26080Constipation240230Abdominal painGrouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and abdominal pain upper. 140.8153.2StomatitisGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering. 111.64.80Metabolism and Nutrition DisordersDecreased appetite60174513Dehydration62.43.21.6Blood and Lymphatic System DisordersAnemiaGrouped term of anemia includes PTs of anemia, hemoglobin decreased, red blood cell count decreased, and hematocrit decreased. 58383123Febrile neutropenia4.84.83.23.2General Disorders and Administration Site ConditionsFatigueGrouped term of fatigue includes PTs of fatigue, asthenia, and malaise. 559444.8Pyrexia240160Edema peripheral10000Skin and Subcutaneous Tissue DisordersAlopecia220150Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseInterstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 102.400Hepatobiliary DisordersHepatic function abnormal83.21.61.6Other clinically relevant adverse reactions reported in less than 10% of patients were:Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%)Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%)Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01Laboratory ParameterENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyHemoglobin decreased75385523White blood cell count decreased74295313Neutrophil count decreased72514523Lymphocyte count decreased70285312Platelet count decreased6812125ChemistryAspartate aminotransferase increased589328Blood alkaline phosphatase increased5483410Alanine aminotransferase increased479171.7Hypokalemia304.8188Blood bilirubin increased24753.4. Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%). Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%). 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to ENHERTU in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Treatment-induced anti-fam-trastuzumab deruxtecan-nxki antibodies (ADA) developed in 1.7% (14/807) patients who received ENHERTU across all doses. Due to the limited number of patients who tested positive for ADA, no conclusions can be drawn concerning potential effect of immunogenicity on efficacy or safety. In addition, neutralizing activity of anti-ENHERTU antibodies has not been assessed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fam-trastuzumab deruxtecan-nxki is HER2-directed antibody-drug conjugate. The antibody is humanized anti-HER2 IgG1. The small molecule, DXd, is topoisomerase inhibitor attached to the antibody by 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 ElectrophysiologyThe administration of multiple doses of ENHERTU 6.4 mg/kg every weeks 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 metastatic HER2-positive cancer.. 12.3 Pharmacokinetics. The pharmacokinetics of fam-trastuzumab deruxtecan-nxki was evaluated in patients with cancer. Following single dose, exposures (Cmax and AUC) of fam-trastuzumab deruxtecan-nxki and released topoisomerase inhibitor (DXd) increased proportionally over dose range of 3.2 mg/kg to mg/kg (approximately 0.6 to 1.5 times the recommended dose).. Metastatic Breast CancerAt the recommended dosage of ENHERTU for patients with HER2-positive breast cancer, the geometric mean (coefficient of variation [CV]%) Cmax of fam-trastuzumab deruxtecan-nxki and DXd were 122 ug/mL (20%) and 4.4 ng/mL (40%), respectively, and the AUC of fam-trastuzumab deruxtecan-nxki and DXd were 735 ugday/mL (31%) and 28 ngday/mL (38%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 35% at steady-state (Cycle 3).. Locally Advanced or Metastatic Gastric CancerAt the recommended dosage of ENHERTU for patients with HER2-positive gastric cancer, the geometric mean Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 126 ug/mL (18%) and 5.2 ng/mL (42%), respectively, and the AUCss of fam-trastuzumab deruxtecan-nxki and DXd were 743 ugday/mL (26%) and 33 ngday/mL (43%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 39% at steady-state (Cycle 3).. DistributionBased on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki was 2.78 L.For humans, DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6, in vitro.. EliminationThe median elimination half-life (t1/2) of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive metastatic breast cancer and gastric cancer was approximately 5.7-5.8 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 in patients with HER2-positive metastatic breast cancer and gastric cancer was approximately 5.5-5.8 days. Based on population pharmacokinetic analysis, the estimated apparent systemic clearance of DXd was 19.6 L/h.. MetabolismThe 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 PopulationsNo clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (23-96 years), race (Asian [n=563] and non-Asian [n=245]), sex, body weight (27.3-125.4 kg), mild (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST, n=312) hepatic impairment, mild (creatinine clearance [CLcr] >=60 and <90 mL/min, n=292) or moderate (CLcr >=30 and <60 mL/min, n=54) 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, 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, 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 umol/L), DXd has low potential to inhibit OAT1 (IC50 value of 12.7 umol/L), OAT3, OCT1, OCT2, OATP1B1 (IC50 value of 14.4 umol/L), OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.. Effects of Other Drugs on DXd: DXd is substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Metastatic Breast Cancer. The efficacy of ENHERTU was evaluated in study DESTINY-Breast01 (NCT03248492), multicenter, single-arm, trial that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients were excluded for history of treated ILD or current ILD at screening. Patients were also excluded for history of clinically significant cardiac disease, active brain metastases, and ECOG performance status >1. HER2 expression was based on archival tissue tested at central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.Patients received ENHERTU 5.4 mg/kg by intravenous infusion every weeks until unacceptable toxicity or disease progression. Tumor imaging was obtained every weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. The major efficacy outcomes were confirmed objective response rate (ORR) assessed by independent central review (ICR) using RECIST v1.1 and duration of response (DOR).The median age was 55 years (range: 28-96); 76% of patients were <65 years. All 184 patients were female, and the majority were White (55%) or Asian (38%). Patients had an ECOG performance status of (55%) or (44%) at baseline. Ninety-two percent had visceral disease, 29% had bone metastases, and 13% had brain metastases. Fifty-three percent were hormone receptor positive. Sum of diameters of target lesions were <5 cm in 42%, and >=5 cm in 50% (not evaluable by central review in 8% of patients).The median number of prior cancer regimens in the locally advanced/metastatic setting was (range: 2-17). All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab.Efficacy results are summarized in Table 7.Table 7: Efficacy Results by Independent Central Review in DESTINY-Breast01Efficacy ParameterDESTINY-Breast01 N=184ORR 95% CI calculated using Clopper-Pearson methodConfirmed Objective Response Rate (95% CI)60.3% (52.9, 67.4)Complete Response4.3%Partial Response56.0%Duration of ResponseDOR is based on median duration of follow-up of 11.1 months. Median, months (95% CI)Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method14.8 (13.8, 16.9). 14.2Locally Advanced or Metastatic Gastric Cancer. The efficacy of ENHERTU was evaluated in study DESTINY-Gastric01 (NCT03329690), multicenter, open-label, randomized trial conducted in Japan and South Korea that enrolled 188 adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH positive), locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy. HER2 expression was determined by central lab on tissue obtained either before or after prior trastuzumab treatment. Patients were excluded for history of treated or current ILD, history of clinically significant cardiac disease, active brain metastases, or ECOG performance status >1.Patients were randomized 2:1 to receive ENHERTU (N=126) 6.4 mg/kg intravenously every weeks or physicians choice of chemotherapy: irinotecan monotherapy (N=55) 150 mg/m2 intravenously every weeks or paclitaxel monotherapy (N=7) 80 mg/m2 intravenously weekly. Randomization was stratified by HER2 status (IHC 3+ or IHC 2+/ISH+), ECOG performance status (0 or 1), and region (Japan or South Korea). Tumor imaging assessments were performed at screening and every weeks from the first treatment dose. Treatment was administered until unacceptable toxicity or disease progression. The major efficacy outcomes were ORR assessed by ICR according to RECIST v1.1 and overall survival (OS) in the intent-to-treat population. Additional efficacy outcomes were progression-free survival (PFS) and DOR.The median age was 66 years (range 28 to 82); 76% were male; and 100% were Asian. All patients received trastuzumab product. Patients had an ECOG performance status of either (49%) or (51%); 87% had gastric adenocarcinoma and 13% had GEJ adenocarcinoma; 76% were IHC 3+ and 23% were IHC 2+/ISH+; 65% had inoperable advanced cancer; 35% had postoperative recurrent cancer; 54% had liver metastases; 29% had lung metastases; 45% had three or more prior regimens in the locally advanced or metastatic setting. total of 30% of patients were identified as HER2-positive using tissue obtained following prior treatment with trastuzumab product.Efficacy results are summarized in Table 8, and the Kaplan-Meier curve for OS is shown in Figure 1.Table 8: Efficacy Results in DESTINY-Gastric01Efficacy ParameterENHERTUN=126Irinotecan or PaclitaxelN=62CI confidence interval; NR not reachedOverall Survival (OS)OS was evaluated following statistically significant outcome of ORR. Median, months (95% CI)Median based on Kaplan-Meier estimate; 95% CI for median calculated using Brookmeyer-Crowley method 12.5 (9.6, 14.3)8.4 (6.9,10.7)Hazard ratio (95% CI)Based on the stratified Cox proportional hazards regression model (stratified by region) 0.59 (0.39, 0.88)p-valueBased on the stratified log-rank test (stratified by region) 0.0097Progression-Free Survival (PFS)Assessed by independent central review Median, months (95% CI) 5.6 (4.3, 6.9)3.5 (2.0, 4.3)Hazard ratio (95% CI) 0.47 (0.31, 0.71)Confirmed Objective Response Rate (ORR) (%)51 (40.5)7 (11.3)95% CI95% exact binomial confidence interval (31.8, 49.6)(4.7, 21.9)p-valueBased on the stratified Cochran-Mantel-Haenszel test (stratified by region) <0.0001Complete Response (%)10 (7.9)0 (0.0)Partial Response (%)41 (32.5)7 (11.3)Duration of Response (DOR) Median, months (95% CI) 11.3 (5.6, NR)3.9 (3.0, 4.9)Figure 1: Kaplan-Meier Plot of Overall Survival Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Metastatic Breast CancerThe safety of ENHERTU was evaluated in pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was months (range: 0.7 to 31).In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an ECOG performance status of (58%) or (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were nausea, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, fatigue, vomiting, alopecia, aspartate aminotransferase increased, alanine aminotransferase increased, platelet count decreased, constipation, decreased appetite, anemia, diarrhea, hypokalemia, and cough.Tables and summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients.Table 3: Common Adverse Reactions (>=10% All Grades or >=2% Grades or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101Adverse ReactionsENHERTU 5.4 mg/kg N=234All Grades %Grades or %Events were graded using NCI CTCAE version 4.03. = number of patients exposed; PT preferred term. Percentages were calculated using the number of patients in the Safety Analysis Set as the denominator.Gastrointestinal Disorders Nausea797 Vomiting473.8 Constipation350.9 Diarrhea291.7 Abdominal painGrouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and abdominal pain upper. 191.3 StomatitisGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). 140.9 Dyspepsia120General Disorders and Administration Site Conditions FatigueGrouped term of fatigue includes PTs of fatigue and asthenia. 596Skin and Subcutaneous Tissue Disorders Alopecia460.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2. RashGrouped term of rash includes PTs of rash, rash pustular, and rash maculo-papular. 100Metabolism and Nutrition Disorders Decreased appetite321.3Blood and Lymphatic System Disorders AnemiaGrouped term of anemia includes PTs of anemia, hemoglobin decreased, hematocrit decreased, and red blood cell count decreased. 317Respiratory, Thoracic and Mediastinal Disorders Cough200 Dyspnea131.3 Epistaxis130 Interstitial lung diseaseInterstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 92.6All events had fatal outcomes (n=6). Nervous System Disorders HeadacheGrouped term of headache includes PTs of headache, sinus headache, and migraine. 190 Dizziness100Infections and Infestation Upper respiratory tract infectionGrouped term of upper respiratory tract infection includes PTs of influenza, influenza-like illness, and upper respiratory tract infection. 150Eye Disorders Dry eye110.4This Grade event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3. Other clinically relevant adverse reactions reported in less than 10% of patients were:Injury, Poisoning and Procedural Complications: infusion-related reactions (2.6%)Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)Table 4: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTULaboratory ParameterENHERTU 5.4 mg/kg N=234All Grades %Grades or %Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyWhite blood cell count decreased707Hemoglobin decreased707Neutrophil count decreased6216Platelet count decreased373.4ChemistryAspartate aminotransferase increased410.9Alanine aminotransferase increased380.4Hypokalemia263. Injury, Poisoning and Procedural Complications: infusion-related reactions (2.6%). Blood and Lymphatic System Disorders: febrile neutropenia (1.7%). Locally Advanced or Metastatic Gastric CancerThe safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.2)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.The most common (>=20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, white blood cell decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia.Tables and summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.Table 5: Adverse Reactions in >=10% All Grades or >=2% Grades or of Patients Receiving ENHERTU in DESTINY-Gastric01ENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62Adverse ReactionsAll Grades%Grades or 4%All Grades%Grades or 4%Events were graded using NCI CTCAE version 4.03. = number of patients exposed; PT preferred term.Percentages were calculated using the number of patients in the Safety Analysis Set as the denominator.Gastrointestinal DisordersNausea634.8471.6Diarrhea322.4321.6Vomiting26080Constipation240230Abdominal painGrouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and abdominal pain upper. 140.8153.2StomatitisGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering. 111.64.80Metabolism and Nutrition DisordersDecreased appetite60174513Dehydration62.43.21.6Blood and Lymphatic System DisordersAnemiaGrouped term of anemia includes PTs of anemia, hemoglobin decreased, red blood cell count decreased, and hematocrit decreased. 58383123Febrile neutropenia4.84.83.23.2General Disorders and Administration Site ConditionsFatigueGrouped term of fatigue includes PTs of fatigue, asthenia, and malaise. 559444.8Pyrexia240160Edema peripheral10000Skin and Subcutaneous Tissue DisordersAlopecia220150Respiratory, Thoracic and Mediastinal DisordersInterstitial lung diseaseInterstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 102.400Hepatobiliary DisordersHepatic function abnormal83.21.61.6Other clinically relevant adverse reactions reported in less than 10% of patients were:Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%)Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%)Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01Laboratory ParameterENHERTU 6.4 mg/kgN=125Irinotecan or PaclitaxelN=62All Grades%Grades or 4%All Grades%Grades or 4%Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities.HematologyHemoglobin decreased75385523White blood cell count decreased74295313Neutrophil count decreased72514523Lymphocyte count decreased70285312Platelet count decreased6812125ChemistryAspartate aminotransferase increased589328Blood alkaline phosphatase increased5483410Alanine aminotransferase increased479171.7Hypokalemia304.8188Blood bilirubin increased24753.4. Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)] Infections and Infestations: pneumonia (6%). Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. (2.2, 2.4)For intravenous infusion only. Do not administer as an intravenous push or bolus. Do not use Sodium Chloride Injection, USP. (2.4)The recommended dosage of ENHERTU for breast cancer is 5.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity. (2.2, 2.3)The recommended dosage of ENHERTU for gastric cancer is 6.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity. (2.2, 2.3)Management of adverse reactions (ILD, neutropenia, thrombocytopenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU. (2.3). Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine. (2.2, 2.4). For intravenous infusion only. Do not administer as an intravenous push or bolus. Do not use Sodium Chloride Injection, USP. (2.4). The recommended dosage of ENHERTU for breast cancer is 5.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity. (2.2, 2.3). The recommended dosage of ENHERTU for gastric cancer is 6.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity. (2.2, 2.3). Management of adverse reactions (ILD, neutropenia, thrombocytopenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU. (2.3). 2.1Patient Selection for Locally Advanced or Metastatic Gastric Cancer. Select patients with locally advanced or metastatic gastric cancer based on HER2 protein overexpression or HER2 gene amplification. Reassess HER2 status if it is feasible to obtain new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification in gastric cancer is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage and Schedules. Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.First infusion: Administer infusion over 90 minutes.Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.Permanently discontinue ENHERTU in case of severe infusion reactions.. Recommended Dosage for Metastatic Breast CancerThe recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity.. Recommended Dosage for Locally Advanced or Metastatic Gastric CancerThe recommended dosage of ENHERTU is 6.4 mg/kg given as an intravenous infusion once every weeks (21-day cycle) until disease progression or unacceptable toxicity.. 2.3Dose Modifications. Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables and 2.. Do not re-escalate the ENHERTU dose after dose reduction is made.If planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.Table 1: Dose Reduction ScheduleDose Reduction ScheduleBreast CancerGastric CancerRecommended starting dose5.4 mg/kg6.4 mg/kgFirst dose reduction4.4 mg/kg5.4 mg/kgSecond dose reduction3.2 mg/kg4.4 mg/kgRequirement for further dose reductionDiscontinue treatment.Discontinue treatment.Table 2: Dose Modifications for Adverse ReactionsAdverse ReactionSeverityTreatment ModificationToxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v.4.03).Interstitial Lung Disease (ILD)/PneumonitisAsymptomatic ILD/pneumonitis (Grade 1)Interrupt ENHERTU until resolved to Grade 0, then:if resolved in 28 days or less from date of onset, maintain dose.if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 1).consider corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)]. Symptomatic ILD/pneumonitis (Grade or greater)Permanently discontinue ENHERTU.Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)].NeutropeniaGrade (less than 1.0 to 0.5 109/L)Interrupt ENHERTU until resolved to Grade or less, then maintain dose.Grade (less than 0.5 109/L)Interrupt ENHERTU until resolved to Grade or less.Reduce dose by one level (see Table 1).Febrile NeutropeniaAbsolute neutrophil count of less than 1.0 109/L and temperature greater than 38.3C or sustained temperature of 38C or greater for more than one hourInterrupt ENHERTU until resolved.Reduce dose by one level (see Table 1).ThrombocytopeniaGrade (platelets less than 50 to 25 109/L)Interrupt ENHERTU until resolved to Grade or less, then maintain dose.Grade (platelets less than 25 109/L)Interrupt ENHERTU until resolved to Grade or less.Reduce dose by one level (see Table 1).Left Ventricular DysfunctionLVEF greater than 45% and absolute decrease from baseline is 10% to 20%Continue treatment with ENHERTU.LVEF 40% to 45%And absolute decrease from baseline is less than 10% Continue treatment with ENHERTU.Repeat LVEF assessment within weeks.And absolute decrease from baseline is 10% to 20%Interrupt ENHERTU.Repeat LVEF assessment within weeks.If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose.LVEF less than 40% or absolute decrease from baseline is greater than 20%Interrupt ENHERTU.Repeat LVEF assessment within weeks.If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.Symptomatic congestive heart failure (CHF)Permanently discontinue ENHERTU.. if resolved in 28 days or less from date of onset, maintain dose.. if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 1).. consider corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)].. Permanently discontinue ENHERTU.. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)].. Interrupt ENHERTU until resolved to Grade or less, then maintain dose.. Interrupt ENHERTU until resolved to Grade or less.. Reduce dose by one level (see Table 1).. Interrupt ENHERTU until resolved.. Reduce dose by one level (see Table 1).. Interrupt ENHERTU until resolved to Grade or less, then maintain dose.. Interrupt ENHERTU until resolved to Grade or less.. Reduce dose by one level (see Table 1).. Continue treatment with ENHERTU.. Continue treatment with ENHERTU.. Repeat LVEF assessment within weeks.. Interrupt ENHERTU.. Repeat LVEF assessment within weeks.. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose.. Interrupt ENHERTU.. Repeat LVEF assessment within weeks.. If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.. Permanently discontinue ENHERTU.. 2.4Preparation for Administration. In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (fam-trastuzumab deruxtecan-nxki) and not trastuzumab or ado-trastuzumab emtansine.Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.ENHERTU (fam-trastuzumab deruxtecan-nxki) is cytotoxic drug. Follow applicable special handling and disposal procedures.1 ReconstitutionReconstitute immediately before dilution.More than one vial may be needed for full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].Reconstitute each 100 mg vial by using sterile syringe to slowly inject mL of Sterile Water for Injection, USP into each vial to obtain final concentration of 20 mg/mL.Swirl the vial gently until completely dissolved. Do not shake.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.If not used immediately, store the reconstituted ENHERTU vials in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.The product does not contain preservative. Discard unused ENHERTU after 24 hours refrigerated.. Reconstitute immediately before dilution.. More than one vial may be needed for full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].. Reconstitute each 100 mg vial by using sterile syringe to slowly inject mL of Sterile Water for Injection, USP into each vial to obtain final concentration of 20 mg/mL.. Swirl the vial gently until completely dissolved. Do not shake.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.. If not used immediately, store the reconstituted ENHERTU vials in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.. The product does not contain preservative. Discard unused ENHERTU after 24 hours refrigerated.. DilutionDilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. Do not use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).Gently invert the infusion bag to thoroughly mix the solution. Do not shake.Cover the infusion bag to protect from light.If not used immediately, store at room temperature for up to hours including preparation and infusion, or in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours, protected from light. Do not freeze.Discard any unused portion left in the vial.. Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. Do not use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).. Gently invert the infusion bag to thoroughly mix the solution. Do not shake.. Cover the infusion bag to protect from light.. If not used immediately, store at room temperature for up to hours including preparation and infusion, or in refrigerator at 2C to 8C (36F to 46F) for up to 24 hours, protected from light. Do not freeze.. Discard any unused portion left in the vial.. AdministrationIf the prepared infusion solution was stored refrigerated (2C to 8C [36F to 46F]), allow the solution to reach room temperature prior to administration.Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene and 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer as an intravenous push or bolus.Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.. If the prepared infusion solution was stored refrigerated (2C to 8C [36F to 46F]), allow the solution to reach room temperature prior to administration.. Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene and 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer as an intravenous push or bolus.. Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Interstitial Lung DiseaseInform 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)].. 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)].. NeutropeniaAdvise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)].. Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop fever, particularly in association with any signs of infection [see Warnings and Precautions (5.2)].. Left Ventricular DysfunctionAdvise 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)].. 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 ToxicityInform female patients of the potential risk to fetus. Advise female patients to contact their healthcare provider of 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 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 months after the last dose [see Use in Specific Populations (8.3)].. Inform female patients of the potential risk to fetus. Advise female patients to contact their healthcare provider of 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 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 months after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment and for months after the last dose of ENHERTU [see Use in Specific Populations (8.2)].. Advise women not to breastfeed during treatment and for months after the last dose of ENHERTU [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential that ENHERTU may impair fertility [see Use in Specific Populations (8.3)].. Advise males of reproductive potential that ENHERTU may impair fertility [see Use in Specific Populations (8.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of fam-trastuzumab deruxtecan-nxki was evaluated in patients with cancer. Following single dose, exposures (Cmax and AUC) of fam-trastuzumab deruxtecan-nxki and released topoisomerase inhibitor (DXd) increased proportionally over dose range of 3.2 mg/kg to mg/kg (approximately 0.6 to 1.5 times the recommended dose).. Metastatic Breast CancerAt the recommended dosage of ENHERTU for patients with HER2-positive breast cancer, the geometric mean (coefficient of variation [CV]%) Cmax of fam-trastuzumab deruxtecan-nxki and DXd were 122 ug/mL (20%) and 4.4 ng/mL (40%), respectively, and the AUC of fam-trastuzumab deruxtecan-nxki and DXd were 735 ugday/mL (31%) and 28 ngday/mL (38%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 35% at steady-state (Cycle 3).. Locally Advanced or Metastatic Gastric CancerAt the recommended dosage of ENHERTU for patients with HER2-positive gastric cancer, the geometric mean Cmax,ss of fam-trastuzumab deruxtecan-nxki and DXd were 126 ug/mL (18%) and 5.2 ng/mL (42%), respectively, and the AUCss of fam-trastuzumab deruxtecan-nxki and DXd were 743 ugday/mL (26%) and 33 ngday/mL (43%), respectively, based on population pharmacokinetic analysis. Accumulation of fam-trastuzumab deruxtecan-nxki was approximately 39% at steady-state (Cycle 3).. DistributionBased on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki was 2.78 L.For humans, DXd plasma protein binding is approximately 97% and the blood-to-plasma ratio is approximately 0.6, in vitro.. EliminationThe median elimination half-life (t1/2) of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive metastatic breast cancer and gastric cancer was approximately 5.7-5.8 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 in patients with HER2-positive metastatic breast cancer and gastric cancer was approximately 5.5-5.8 days. Based on population pharmacokinetic analysis, the estimated apparent systemic clearance of DXd was 19.6 L/h.. MetabolismThe 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 PopulationsNo clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (23-96 years), race (Asian [n=563] and non-Asian [n=245]), sex, body weight (27.3-125.4 kg), mild (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST, n=312) hepatic impairment, mild (creatinine clearance [CLcr] >=60 and <90 mL/min, n=292) or moderate (CLcr >=30 and <60 mL/min, n=54) 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, 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, 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 umol/L), DXd has low potential to inhibit OAT1 (IC50 value of 12.7 umol/L), OAT3, OCT1, OCT2, OATP1B1 (IC50 value of 14.4 umol/L), OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.. Effects of Other Drugs on DXd: DXd is substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1 and BCRP.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 01/2021Medication GuideENHERTU(R) (en-HER-too) (fam-trastuzumab deruxtecan-nxki) for injectionWhat is the most important information should know about ENHERTU ENHERTU can cause serious side effects, including: Lung problems that may be severe, life-threatening or that may lead to death. If you develop lung problems your healthcare provider may treat you with corticosteroid medicines. Tell your healthcare provider right away if you get any of the following signs and symptoms: coughtrouble breathing or shortness of breathfeverother new or worsening breathing symptoms (e.g., chest tightness, wheezing) Low white blood cell count (neutropenia). Low white blood cell counts are common with ENHERTU and can sometimes be severe. Your healthcare provider will check your white blood cell counts before starting ENHERTU and before starting each dose. Tell your healthcare provider right away if you develop any signs or symptoms of an infection or have fever or chills during treatment with ENHERTU. Heart problems that may affect your hearts ability to pump blood. Your healthcare provider will check your heart function before starting treatment with ENHERTU. Tell your healthcare provider right away if you get any of the following signs and symptoms:new or worsening shortness of breathcoughingfeeling tiredswelling of your ankles or legsirregular heartbeatsudden weight gaindizziness or feeling light-headedloss of consciousnessYour healthcare provider will check you for these side effects during your treatment with ENHERTU. Your healthcare provider may reduce your dose, delay treatment or completely stop treatment with ENHERTU if you have severe side effects.Harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ENHERTU. If you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ENHERTU.Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for at least months after the last dose.Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for at least months after the last dose.See What are the possible side effects of ENHERTU for more information about side effects.What is ENHERTUENHERTU is prescription medicine used in adults to treat human epidermal growth factor receptor (HER2)-positive breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic), and who have received two or more prior anti-HER2 breast cancer treatments.stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that has spread to areas near your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received prior trastuzumab-based regimen.It is not known if ENHERTU is safe and effective in children.Before you receive ENHERTU, tell your healthcare provider about all of your medical conditions, including if you:have lung or breathing problems.have signs or symptoms of an infection.have or have had any heart problems.are breastfeeding or plan to breastfeed. It is not known if ENHERTU passes into your breast milk. Do not breastfeed during treatment with ENHERTU and for months after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive ENHERTUYou will receive ENHERTU into your vein through an intravenous (IV) line by your healthcare provider.ENHERTU is given time every three weeks (21-day treatment cycle).Your healthcare provider will decide how many treatments you need.Your healthcare provider may slow down or temporarily stop your infusion of ENHERTU if you have an infusion-related reaction, or permanently stop ENHERTU if you have severe infusion reactions.If you miss planned dose of ENHERTU, call your healthcare provider right away to schedule an appointment. Do not wait until the next planned treatment cycle.What are the possible side effects of ENHERTU ENHERTU can cause serious side effects. See What is the most important information should know about ENHERTU The most common side effects of ENHERTU, when used in people with breast cancer, include:nausealow white blood cell countslow red blood cell countsfeeling tiredvomitinghair lossincreased liver function testslow platelet countsconstipationdecreased appetitediarrhealow levels of blood potassiumcoughThe most common side effects of ENHERTU, when used in people with stomach cancer, include:low red blood cell countslow white blood cell countslow platelet countsnauseadecreased appetiteincreased liver function testsfeeling tireddiarrhealow levels of blood potassiumvomitingconstipationfeverhair lossENHERTU may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of ENHERTU. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ENHERTU.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about ENHERTU that is written for healthcare professionals.What are the ingredients in ENHERTUActive Ingredient: fam-trastuzumab deruxtecan-nxki. Inactive Ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose. 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(R) is registered trademark of Daiichi Sankyo Company, Ltd. (C) 2021 Daiichi Sankyo Co., Ltd. USMG-ENH-C4-0121-r002For more information, call 1-877-437-7763 or go to https://www.ENHERTU.com. cough. trouble breathing or shortness of breath. fever. other new or worsening breathing symptoms (e.g., chest tightness, wheezing). new or worsening shortness of breath. coughing. feeling tired. swelling of your ankles or legs. irregular heartbeat. sudden weight gain. dizziness or feeling light-headed. loss of consciousness. If you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ENHERTU.. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for at least months after the last dose.. Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with ENHERTU and for at least months after the last dose.. breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic), and who have received two or more prior anti-HER2 breast cancer treatments.. stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that has spread to areas near your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received prior trastuzumab-based regimen.. have lung or breathing problems.. have signs or symptoms of an infection.. have or have had any heart problems.. are breastfeeding or plan to breastfeed. It is not known if ENHERTU passes into your breast milk. Do not breastfeed during treatment with ENHERTU and for months after the last dose.. You will receive ENHERTU into your vein through an intravenous (IV) line by your healthcare provider.. ENHERTU is given time every three weeks (21-day treatment cycle).. Your healthcare provider will decide how many treatments you need.. Your healthcare provider may slow down or temporarily stop your infusion of ENHERTU if you have an infusion-related reaction, or permanently stop ENHERTU if you have severe infusion reactions.. If you miss planned dose of ENHERTU, call your healthcare provider right away to schedule an appointment. Do not wait until the next planned treatment cycle.. nausea. low white blood cell counts. low red blood cell counts. feeling tired. vomiting. hair loss. increased liver function tests. low platelet counts. constipation. decreased appetite. diarrhea. low levels of blood potassium. cough. low red blood cell counts. low white blood cell counts. low platelet counts. nausea. decreased appetite. increased liver function tests. feeling tired. diarrhea. low levels of blood potassium. vomiting. constipation. fever. hair loss.

USE IN SPECIFIC POPULATIONS SECTION.

8 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. (8.3). Lactation: Advise not to breastfeed. (8.2). Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. (8.3). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ENHERTU can cause fetal harm when administered to pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of HER2-directed antibody 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 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 fetus.There are clinical considerations if ENHERTU is used in pregnant women, or if patient becomes pregnant within 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 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 ReactionsMonitor women who received ENHERTU during pregnancy or within 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 DataThere are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving 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 HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of HER2-directed antibody was stopped.. Animal DataThere were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.. 8.2 Lactation. Risk SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with ENHERTU and for months after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.. Contraception. FemalesENHERTU can cause fetal harm when administered to 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 months following the last dose.. MalesBecause 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 months following the last dose [see Nonclinical Toxicology (13.1)].. InfertilityBased 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 higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (53%) as compared to younger patients (42%).Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients.. 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 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 (2.3)]. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 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. (2.3, 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). (2.3, 5.3). 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. (2.3, 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). (2.3, 5.3). 5.1Interstitial Lung Disease/Pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU [see Adverse Reactions (6.1)]. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with pulmonologist. For asymptomatic (Grade 1) ILD, consider corticosteroid treatment (e.g., >=0.5 mg/kg/day prednisolone or equivalent). Withhold ENHERTU until recovery [see Dosage and Administration (2.3)]. In cases of symptomatic ILD (Grade or greater), promptly initiate systemic corticosteroid treatment (e.g., >=1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least weeks. Permanently discontinue ENHERTU in patients who are diagnosed with symptomatic (Grade or greater) ILD [see Dosage and Administration (2.3)].. Metastatic Breast CancerIn clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).. Locally Advanced or Metastatic Gastric CancerIn DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).. 5.2Neutropenia. Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction [see Dosage and Administration (2.3)].. Metastatic Breast CancerIn clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade or decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: to 547). Febrile neutropenia was reported in 1.7% of patients.. Locally Advanced or Metastatic Gastric CancerIn DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade or decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: to 187). Febrile neutropenia was reported in 4.8% of patients.. 5.3Left Ventricular Dysfunction. Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade decrease in LVEF.Treatment with ENHERTU has not been studied in patients with history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF) [see Dosage and Administration (2.3)].. 5.4Embryo-Fetal Toxicity. Based on its mechanism of action, ENHERTU can cause fetal harm when administered to pregnant woman. In postmarketing reports, use of HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to pregnant woman because it is genotoxic and targets actively dividing cells [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Advise patients of the potential risks to fetus.Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least months after the last dose of ENHERTU [see Use in Specific Populations (8.1, 8.3)].