ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling:Hepatotoxicity [see Warnings and Precautions (5.1)] Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.1)] Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] Most common adverse reactions (>= 20%) are diarrhea, rash, hepatotoxicity, fatigue, nausea, musculoskeletal pain, and upper respiratory tract infection. (6.1)The most common (>= 2%) Grade or laboratory abnormalities were decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma glutamyl transferase, decreased potassium, and decreased neutrophils. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (>= 20%) are diarrhea, rash, hepatotoxicity, fatigue, nausea, musculoskeletal pain, and upper respiratory tract infection. (6.1). The most common (>= 2%) Grade or laboratory abnormalities were decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma glutamyl transferase, decreased potassium, and decreased neutrophils. (6.1). 6.1 Clinical 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 clinical practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to HERNEXEOS in 292 patients with unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS as single agent at 120 mg orally once daily until disease progression or unacceptable toxicity in Beamion LUNG-1 [see Clinical Studies (14)]. Among 292 patients who received HERNEXEOS, 59% of patients were exposed for months or longer and 28% were exposed for greater than one year. In this pooled safety population, the most common (> 20%) adverse reactions were diarrhea (54%), rash (28%), hepatotoxicity (27%), fatigue (25%), nausea (23%), musculoskeletal pain (21%), and upper respiratory tract infection (20%). The most common (>= 2%) Grade or laboratory abnormalities were decreased lymphocytes (10%), increased alanine aminotransferase (6%), increased aspartate aminotransferase (4.5%), increased gamma glutamyl transferase (2.8%), decreased potassium (2.4%), and decreased neutrophils (2.4%).. Beamion LUNG-1The safety of HERNEXEOS was evaluated in Beamion LUNG-1 in 177 patients with unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) mutations; 72 patients had not received prior treatment; 105 patients had received prior platinum-based chemotherapy, and out of those patients, 34 patients had received prior treatment with HER2-directed antibody drug conjugate (ADC) [see Clinical Studies (14)]. Patients received HERNEXEOS as single agent at 120 mg once daily until disease progression or unacceptable toxicity. Among patients who received HERNEXEOS, 74% were exposed for months or longer and 42% were exposed for greater than one year. The median age of patients who received HERNEXEOS was 63 years (range 30 to 88), 61% were female, 41% White, 48% Asian, and 0.6% Black or African American; 11% had unknown race data; 3.4% were of Hispanic or Latino ethnicity; and 38% had an Eastern Cooperative Oncology Group (ECOG) performance score of and 62% had an ECOG performance score of 1.Serious adverse reactions occurred in 36% of patients receiving HERNEXEOS. Serious adverse reactions in >= 2% of patients included pulmonary embolism (4%), dyspnea (3.4%), pneumonia (2.8%), hepatotoxicity, pleural effusion, and pericardial effusion (2.3%). Fatal adverse reactions occurred in one patient (0.6%) who received HERNEXEOS, due to pneumonia.Permanent discontinuation of HERNEXEOS due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of HERNEXEOS were hepatotoxicity, decreased ejection fraction, anemia, increased blood alkaline phosphatase, diarrhea, dyspnea, increased gamma-glutamyl transferase, hemoptysis, pericardial effusion, pneumonitis, and pyrexia.Dosage interruption of HERNEXEOS due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >= 2% of patients were hepatotoxicity, decreased ejection fraction, diarrhea, COVID-19, rash, and vomiting.Dose reductions of HERNEXEOS due to adverse reactions occurred in 9% of patients. Adverse reactions which required dose reductions in >= 1% of patients were hepatotoxicity, decreased ejection fraction, and diarrhea.Tables and summarize adverse reactions and laboratory abnormalities observed in Beamion LUNG-1.Table 3Adverse Reactions (>= 15%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1Adverse ReactionHERNEXEOS = 177All Grades1 %Grade or %Events were graded using NCI CTCAE version 5.0.1No Grade or Grade adverse reactions occurred.Grouped term.Gastrointestinal Disorders Diarrhea562.8 Nausea250.6 Stomatitis210Skin and Subcutaneous Tissue Disorders Rash320.6 Nail disorders210.6 Pruritus150General Disorders Fatigue260.6 Headache160.6Respiratory, Thoracic and Mediastinal Disorders Cough230Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain232.3Infections and Infestations Upper respiratory tract infections230Clinically relevant adverse reactions in 15% of patients who received HERNEXEOS included vomiting, dyspnea, dysgeusia, and dry skin.Table 4Select Laboratory Abnormalities (>= 20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1Laboratory ParameterHERNEXEOS = 177All Grades1 %Grade or %Events were graded using NCI CTCAE version 5.0.1No Grade adverse reactions occurred.Hematology Lymphocytes decreased5612 Hemoglobin decreased371.1 Leukocytes decreased351.1 Activated partial thromboplastin time increased230 Platelets decreased201.1Chemistry Alanine aminotransferase increased417 Aspartate aminotransferase increased355 Creatinine kinase increased281.7 Calcium decreased280.6 Albumin decreased260 Bilirubin increased251.1 Lipase increased250 Triglycerides increased250 Sodium decreased220.6 Bicarbonate decreased220 Magnesium decreased211.1 Potassium decreased211.7 Alkaline phosphate increased201.7.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Zongertinib is kinase inhibitor of human epidermal growth factor receptor (HER2). In vitro, zongertinib inhibited phosphorylation of HER2, downstream signaling of HER2 (phosphorylation of ERK), and proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations. In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations. 12.2 Pharmacodynamics. The exposure-response relationship and time-course of pharmacodynamic response of zongertinib have not been fully characterized.. Cardiac ElectrophysiologyAt 2.6 times the mean maximal concentration provided by the recommended dose of 120 mg, mean increase in the QTc interval 20 ms was not observed.. 12.3 Pharmacokinetics. Zongertinib pharmacokinetics were observed at steady state in patients with advanced or metastatic solid tumors with HER2 aberrations at the approved recommended dosage and are presented as geometric mean (CV%), unless otherwise specified. Zongertinib maximum concentration (Cmax,ss) is 3.0 (37%) umol/L and the total systemic exposure (AUC) is 34 (34%) umolh/L following HERNEXEOS 120 mg orally daily. Zongertinib Cmax and AUC increase in an approximately dose proportional manner across the dose range of 60 mg (0.5 times the approved recommended dosage) to 360 mg (3 times the approved recommended dosage). Zongertinib accumulation is approximately 1.5-fold for AUC and 1.3-fold for Cmax at the approved recommended dosage. Steady state is achieved within 2.5 days. AbsorptionZongertinib median (min, max) time to maximum plasma concentration (Tmax) is approximately hours (min, max: 2, hours). Zongertinib absolute oral bioavailability is 76%.. Effect of FoodNo clinically significant differences in zongertinib Cmax and AUC were observed following administration of single 240 mg dose (2 times the approved recommended dose) with high-fat meal (approximately 1,000 calories, approximately 50% fat). DistributionZongertinib plasma protein binding is 99%. The apparent (oral) volume of distribution is 118 (29%). EliminationZongertinib effective half-life is 12 hours (21%) with an apparent (oral) clearance of 115 mL/min (31%). MetabolismBased on in vitro metabolite profiling, CYP-mediated oxidation pathways represent 48% to 62% (mainly CYP3A4 and CYP3A5), glucuronidation 13% to 25% (mainly UGT1A4), and glutathione conjugation 13% to 26% of total hepatic metabolism. Unchanged zongertinib represented the majority (75%) of total radioactivity in plasma.. ExcretionAfter single oral dose of radiolabeled zongertinib 60 mg to healthy participants, approximately 93% of the dose was recovered in feces (31% unchanged) and 1.3% in urine (0.2% unchanged).. Specific PopulationsThe apparent volume of distribution and clearance of zongertinib increase with increasing body weight (34 to 122 kg).No clinically significant differences in the pharmacokinetics of zongertinib were observed based on age (30 to 88 years), sex, race (36% White, 49% Asian, 1.3% Black/African American), mild renal impairment (eGFR 60 to 90 mL/min) or mild hepatic impairment (AST ULN and total bilirubin <= ULN; or total bilirubin 1 to 1.5x ULN and any AST). The effect of moderate renal impairment (eGFR 30 to 60 mL/min), severe renal impairment (eGFR 15 to 30 mL/min), end-stage renal disease (eGFR 15 mL/min), moderate hepatic impairment (total bilirubin 1.5 to 3x ULN and any AST) or severe hepatic impairment (total bilirubin 3x ULN and any AST) on the pharmacokinetics of zongertinib have not been studied.. Drug Interaction Studies. CYP3A Inducers: Zongertinib AUC decreased by 63% and Cmax decreased by 43% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily for days. The effect of concomitant use of moderate CYP3A inducers on zongertinib Cmax and AUC are unknown.. BCRP Substrates: Rosuvastatin (BCRP substrate) Cmax increased by 3-fold and AUC by 2.3-fold following concomitant use of single dose of zongertinib 120 mg daily for 12 days. Other Drugs: No clinically significant differences in zongertinib pharmacokinetics were observed when used concomitantly with strong CYP3A, P-gp, BCRP inhibitors and rabeprazole (proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following were observed when used concomitantly with zongertinib: midazolam (a CYP3A substrate), dabigatran (a P-gp substrate), metformin (a OCT2 and MATE1/2-K substrate), or repaglinide (a sensitive CYP2C8 substrate).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. HERNEXEOS was evaluated in Beamion LUNG-1 (NCT04886804), single arm, open-label, multi-center, multi-cohort trial. Eligible patients were required to have unresectable or metastatic NSCLC with HER2 (ERBB2) mutations. Patients with stable brain metastases were eligible to enroll. The study excluded patients who had history of non-infectious interstitial lung disease/pneumonitis.Patients received HERNEXEOS 120 mg orally once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by blinded independent central review (BICR).. Previously Untreated Unresectable or Metastatic Non-Squamous NSCLC The efficacy population included 72 patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain (TKD) mutations based on prospective local testing, who had not received prior systemic therapy for advanced disease. Of those, tumor tissue samples from 60% (43/72) of patients were retrospectively tested using Oncomine(TM) Dx Target Test (Life Technologies Corporation, Tissue-test). While 86% (37/43) of samples were positive for HER2 (ERBB2) TKD mutations; 14% (6/43) were unevaluable.The baseline demographic and disease characteristics of the efficacy population were: 67 years (range: 35 to 88); 50% female, 47% Asian, 42% White, 1.4% Black or African American; 10% had unknown race data; 6% were of Hispanic or Latino ethnicity; 44% Eastern Cooperative Oncology Group (ECOG) performance status (PS) and 56% ECOG PS 1; 65% never smoked; 100% had metastatic disease; and 31% had brain metastases.Efficacy results are summarized in Table 5.Table 5Efficacy Results for Beamion LUNG-1 in Previously Untreated Non-Squamous NSCLCEfficacy ParameterHERNEXEOS = 72Abbreviation: CI Confidence Interval, +: Ongoing response.1Based on Wilson confidence interval.2Based on observed duration of response. Objective Response Rate (ORR), (95% CI)1 76 (65, 85) Complete response, %11Partial response, %65Duration of Response (DOR)N 55Range, months1.4, 18+DOR >= months,2 %64DOR >= 12 months,2 %44. Previously Treated Unresectable or Metastatic Non-Squamous NSCLCThe efficacy population included 71 patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) TKD mutations based on prospective local testing. Of those, tumor tissue samples from 52% (37/71) of patients were retrospectively tested using Oncomine(TM) Dx Target Test (Life Technologies Corporation, Tissue-test). While 84% (31/37) of samples were positive for HER2 (ERBB2) TKD mutations, 2.7% (1/37) did not have HER2 (ERBB2) TKD mutations identified, and 13.5% (5/37) were unevaluable.The baseline demographic and disease characteristics of the efficacy population were: 62 years (range: 30 to 80); 70% female, 55% Asian, 35% White, 0% Black or African American; 10% had unknown race data; 1.4% were of Hispanic or Latino ethnicity; 39% Eastern Cooperative Oncology Group (ECOG) performance status (PS) and 61% ECOG PS 1; 65% never smoked; 100% metastatic disease; and 37% with brain metastases. The median number of prior therapies was (range: to 10); 100% of patients had prior platinum therapy and 78% had prior treatment with anti-PD-1/PD-L1 antibody. No patient had received previous treatment with HER2-targeted tyrosine kinase inhibitor (TKI) or HER2-targeted antibody-drug conjugate (ADC).Efficacy results are summarized in Table 6.Table 6Efficacy Results for Beamion LUNG-1 in Previously Treated Non-Squamous NSCLCEfficacy ParameterHERNEXEOS = 71Abbreviation: CI Confidence Interval, +: Ongoing response.1Based on Wilson confidence interval.2Based on observed duration of response. Objective Response Rate (ORR), (95% CI)1 75 (63, 83)Complete response, %6Partial response, %69Duration of Response (DOR)N 53Range, months1.3+, 15+DOR >= months,2 58Among the 71 patients, patients had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within months prior to treatment with HERNEXEOS. Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria per BICR, responses were observed in patients. HERNEXEOS was also evaluated in 34 patients with unresectable or metastatic HER2 (ERBB2) TKD mutation-positive non-squamous NSCLC who had received previous treatment with platinum-based chemotherapy and HER2-targeted ADC. Eligibility criteria were otherwise similar to the efficacy population described above. The median age was 58 years (range: 31 to 85); 65% female, 35% Asian, 50% White, 0% Black or African American; 15% had unknown race data; and 2.9% were of Hispanic or Latino ethnicity. Baseline ECOG performance status was (21%) or (79%); 65% never smoked; 100% of patients had metastatic disease and 74% had brain metastases. The median number of prior therapies was (range: to 8); 100% of patients had prior platinum therapy and 77% had prior treatment with anti-PD-1/PD-L1 antibody; 2.9% of patients had received previous treatment with HER2-targeted TKI. Confirmed ORR by RECIST v1.1 based on BICR was 44% (95% CI 29, 61), with 2.9% of patients having complete response. Median DOR was 5.4 months (95% CI 2.8, not estimable), and 27% of responders had an observed DOR >= months.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 clinical practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to HERNEXEOS in 292 patients with unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS as single agent at 120 mg orally once daily until disease progression or unacceptable toxicity in Beamion LUNG-1 [see Clinical Studies (14)]. Among 292 patients who received HERNEXEOS, 59% of patients were exposed for months or longer and 28% were exposed for greater than one year. In this pooled safety population, the most common (> 20%) adverse reactions were diarrhea (54%), rash (28%), hepatotoxicity (27%), fatigue (25%), nausea (23%), musculoskeletal pain (21%), and upper respiratory tract infection (20%). The most common (>= 2%) Grade or laboratory abnormalities were decreased lymphocytes (10%), increased alanine aminotransferase (6%), increased aspartate aminotransferase (4.5%), increased gamma glutamyl transferase (2.8%), decreased potassium (2.4%), and decreased neutrophils (2.4%).. Beamion LUNG-1The safety of HERNEXEOS was evaluated in Beamion LUNG-1 in 177 patients with unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) mutations; 72 patients had not received prior treatment; 105 patients had received prior platinum-based chemotherapy, and out of those patients, 34 patients had received prior treatment with HER2-directed antibody drug conjugate (ADC) [see Clinical Studies (14)]. Patients received HERNEXEOS as single agent at 120 mg once daily until disease progression or unacceptable toxicity. Among patients who received HERNEXEOS, 74% were exposed for months or longer and 42% were exposed for greater than one year. The median age of patients who received HERNEXEOS was 63 years (range 30 to 88), 61% were female, 41% White, 48% Asian, and 0.6% Black or African American; 11% had unknown race data; 3.4% were of Hispanic or Latino ethnicity; and 38% had an Eastern Cooperative Oncology Group (ECOG) performance score of and 62% had an ECOG performance score of 1.Serious adverse reactions occurred in 36% of patients receiving HERNEXEOS. Serious adverse reactions in >= 2% of patients included pulmonary embolism (4%), dyspnea (3.4%), pneumonia (2.8%), hepatotoxicity, pleural effusion, and pericardial effusion (2.3%). Fatal adverse reactions occurred in one patient (0.6%) who received HERNEXEOS, due to pneumonia.Permanent discontinuation of HERNEXEOS due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of HERNEXEOS were hepatotoxicity, decreased ejection fraction, anemia, increased blood alkaline phosphatase, diarrhea, dyspnea, increased gamma-glutamyl transferase, hemoptysis, pericardial effusion, pneumonitis, and pyrexia.Dosage interruption of HERNEXEOS due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >= 2% of patients were hepatotoxicity, decreased ejection fraction, diarrhea, COVID-19, rash, and vomiting.Dose reductions of HERNEXEOS due to adverse reactions occurred in 9% of patients. Adverse reactions which required dose reductions in >= 1% of patients were hepatotoxicity, decreased ejection fraction, and diarrhea.Tables and summarize adverse reactions and laboratory abnormalities observed in Beamion LUNG-1.Table 3Adverse Reactions (>= 15%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1Adverse ReactionHERNEXEOS = 177All Grades1 %Grade or %Events were graded using NCI CTCAE version 5.0.1No Grade or Grade adverse reactions occurred.Grouped term.Gastrointestinal Disorders Diarrhea562.8 Nausea250.6 Stomatitis210Skin and Subcutaneous Tissue Disorders Rash320.6 Nail disorders210.6 Pruritus150General Disorders Fatigue260.6 Headache160.6Respiratory, Thoracic and Mediastinal Disorders Cough230Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain232.3Infections and Infestations Upper respiratory tract infections230Clinically relevant adverse reactions in 15% of patients who received HERNEXEOS included vomiting, dyspnea, dysgeusia, and dry skin.Table 4Select Laboratory Abnormalities (>= 20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1Laboratory ParameterHERNEXEOS = 177All Grades1 %Grade or %Events were graded using NCI CTCAE version 5.0.1No Grade adverse reactions occurred.Hematology Lymphocytes decreased5612 Hemoglobin decreased371.1 Leukocytes decreased351.1 Activated partial thromboplastin time increased230 Platelets decreased201.1Chemistry Alanine aminotransferase increased417 Aspartate aminotransferase increased355 Creatinine kinase increased281.7 Calcium decreased280.6 Albumin decreased260 Bilirubin increased251.1 Lipase increased250 Triglycerides increased250 Sodium decreased220.6 Bicarbonate decreased220 Magnesium decreased211.1 Potassium decreased211.7 Alkaline phosphate increased201.7.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Select patients for treatment with HERNEXEOS based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations. (2.1)The recommended dosage of HERNEXEOS is based on body weight: (2.2) Patients weighing less than 90 kg: 120 mg (2.2)Patients weighing 90 kg or greater: 180 mg (2.2) Take HERNEXEOS orally once daily with or without food until disease progression or unacceptable toxicity. (2.2). Select patients for treatment with HERNEXEOS based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations. (2.1). The recommended dosage of HERNEXEOS is based on body weight: (2.2) Patients weighing less than 90 kg: 120 mg (2.2)Patients weighing 90 kg or greater: 180 mg (2.2) Patients weighing less than 90 kg: 120 mg (2.2). Patients weighing 90 kg or greater: 180 mg (2.2). Take HERNEXEOS orally once daily with or without food until disease progression or unacceptable toxicity. (2.2). 2.1 Patient Selection. Select patients for treatment of unresectable or metastatic NSCLC based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations in tumor specimens [see Clinical Studies (14)]. Information on FDA-authorized tests for HER2 (ERBB2) tyrosine kinase domain activating mutations is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage and Administration. The recommended dosage of HERNEXEOS is based on body weight:Patients weighing less than 90 kg: 120 mgPatients weighing 90 kg or greater: 180 mgTake HERNEXEOS orally once daily with or without food until disease progression or unacceptable toxicity. Swallow HERNEXEOS tablets whole with water. Do not split, crush, or chew tablets.. Patients weighing less than 90 kg: 120 mg. Patients weighing 90 kg or greater: 180 mg. Missed DoseIf dose is missed within 12 hours, take the dose. If dose is missed by more than 12 hours, skip the missed dose and take the next scheduled dose.. Vomited DoseIf dose is vomited, do not take an additional dose. Take the next dose at the regularly scheduled time.. 2.3 Dosage Modifications for Adverse Reactions. The recommended dose reductions for adverse reactions are presented in Table 1.Table 1Recommended HERNEXEOS Dose Reductions for Adverse ReactionsCurrent HERNEXEOS DoseFirst ReductionSecond Reduction180 mg120 mg60 mg120 mg60 mgPermanently discontinuePermanently discontinue HERNEXEOS in patients who are unable to tolerate 60 mg once daily.The recommended dosage modifications for adverse reactions are presented in Table 2.Table 2Recommended HERNEXEOS Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityDosage ModificationALT alanine aminotransferase; AST aspartate aminotransferase; ULN upper limit of normalBased on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0Hepatotoxicity [see Warnings and Precautions (5.1)] Grade or ALT and/or AST without increased total bilirubinInterrupt HERNEXEOS until recovered to <= Grade or baseline.Resume HERNEXEOS at reduced dose level.Grade total bilirubin Interrupt HERNEXEOS until recovered to <= Grade or baseline.Resume HERNEXEOS at reduced dose level.Grade total bilirubinPermanently discontinue HERNEXEOS.ALT or AST >= 3x ULN with total bilirubin >= 2x ULNPermanently discontinue HERNEXEOS. Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] LVEF 40 to 50% and decrease from baseline of 10 to 19%Interrupt HERNEXEOS until recovered to <= Grade or within 10% from baseline.If recovered to <= Grade in <= weeks, resume HERNEXEOS at the same dose level.If not recovered to <= Grade within weeks, permanently discontinue HERNEXEOS.LVEF 20 to 39% or >= 20% decrease from baselineInterrupt HERNEXEOS until recovered to <= Grade or within 10% from baseline.If recovered to <= Grade in <= weeks, resume HERNEXEOS at the reduced dose level.If not recovered to <= Grade within weeks, permanently discontinue HERNEXEOS.Symptomatic Congestive Heart FailurePermanently discontinue HERNEXEOS.Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] Grade 2Withhold HERNEXEOS until resolution.Resume HERNEXEOS at reduced dose level.Permanently discontinue HERNEXEOS for recurrent ILD/pneumonitis.Grade or Grade 4Permanently discontinue HERNEXEOS.Diarrhea [see Adverse Reactions (6.1)] Grade 2Maintain HERNEXEOS dose.Initiate anti-diarrheal treatment.Grade lasting >= days despite anti-diarrheal treatmentInterrupt HERNEXEOS until recovered to <= Grade 1.Resume HERNEXEOS at reduced dose level.Grade or Grade Interrupt HERNEXEOS until recovered to <= Grade 1.Resume HERNEXEOS at reduced dose level.Permanently discontinue HERNEXEOS if diarrhea does not resolve to <= Grade within 14 days, despite optimal supportive care (including anti-diarrheal treatment) and treatment interruption.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3Interrupt HERNEXEOS until recovered to <= Grade or baseline.Resume HERNEXEOS at reduced dose level.Grade 4Permanently discontinue HERNEXEOS.. Interrupt HERNEXEOS until recovered to <= Grade or baseline.. Resume HERNEXEOS at reduced dose level.. Interrupt HERNEXEOS until recovered to <= Grade or baseline.. Resume HERNEXEOS at reduced dose level.. Permanently discontinue HERNEXEOS.. Permanently discontinue HERNEXEOS. Interrupt HERNEXEOS until recovered to <= Grade or within 10% from baseline.. If recovered to <= Grade in <= weeks, resume HERNEXEOS at the same dose level.. If not recovered to <= Grade within weeks, permanently discontinue HERNEXEOS.. Interrupt HERNEXEOS until recovered to <= Grade or within 10% from baseline.. If recovered to <= Grade in <= weeks, resume HERNEXEOS at the reduced dose level.. If not recovered to <= Grade within weeks, permanently discontinue HERNEXEOS.. Permanently discontinue HERNEXEOS.. Withhold HERNEXEOS until resolution.. Resume HERNEXEOS at reduced dose level.. Permanently discontinue HERNEXEOS for recurrent ILD/pneumonitis.. Permanently discontinue HERNEXEOS.. Maintain HERNEXEOS dose.. Initiate anti-diarrheal treatment.. Interrupt HERNEXEOS until recovered to <= Grade 1.. Resume HERNEXEOS at reduced dose level.. Interrupt HERNEXEOS until recovered to <= Grade 1.. Resume HERNEXEOS at reduced dose level.. Permanently discontinue HERNEXEOS if diarrhea does not resolve to <= Grade within 14 days, despite optimal supportive care (including anti-diarrheal treatment) and treatment interruption.. Interrupt HERNEXEOS until recovered to <= Grade or baseline.. Resume HERNEXEOS at reduced dose level.. Permanently discontinue HERNEXEOS.. 2.4 Dosage Modifications for Drug Interactions. Strong CYP3A InducersAvoid concomitant use of strong CYP3A inducers with HERNEXEOS. If concomitant use cannot be avoided, increase the HERNEXEOS dose based on body weight [see Drug Interactions (7.1)]:Patients weighing less than 90 kg: from 120 mg to 240 mg Patients weighing 90 kg or greater: from 180 mg to 360 mgAfter discontinuing CYP3A inducer, resume the HERNEXEOS dose (7 to 14 days after discontinuing the CYP3A inducer) that was taken prior to initiating the CYP3A inducer.. Patients weighing less than 90 kg: from 120 mg to 240 mg Patients weighing 90 kg or greater: from 180 mg to 360 mg.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose. (7.1) BCRP Substrates: Avoid concomitant use with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies. If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate. (7.2). Strong CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose. (7.1) BCRP Substrates: Avoid concomitant use with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies. If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate. (7.2). 7.1 Effects of Other Drugs on HERNEXEOS. Avoid concomitant use of HERNEXEOS with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose as recommended [see Dosage and Administration (2.4)]. Zongertinib is CYP3A substrate. Strong CYP3A4 inducers decrease zongertinib exposure [see Clinical Pharmacology (12.3)], which may reduce effectiveness of HERNEXEOS.. 7.2 Effects of HERNEXEOS on Other Drugs. BCRP SubstratesAvoid concomitant use of HERNEXEOS with certain BCRP substrates where minimal concentration changes may lead to serious adverse reactions. If coadministration cannot be avoided, monitor for increased adverse reactions and follow recommendations provided in the approved product labeling for the BCRP substrate. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate.Zongertinib is BCRP inhibitor. HERNEXEOS increases exposure of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. HepatotoxicityInform patients that HERNEXEOS can cause severe and life-threatening hepatotoxicity and that they will need to undergo lab tests to monitor liver enzymes during treatment [see Warnings and Precautions (5.1)]. Advise patients to immediately contact their healthcare provider for signs and symptoms of hepatotoxicity. Left Ventricular DysfunctionInform patients that HERNEXEOS can cause severe left ventricular dysfunction. Advise patients to immediately contact their healthcare provider for new or worsening cardiovascular symptoms [see Warnings and Precautions (5.2)]. Interstitial Lung Disease (ILD)/PneumonitisInform patients that HERNEXEOS can cause severe or life-threatening ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.3)]. DiarrheaInform patients that HERNEXEOS can cause diarrhea. Advise patients to immediately contact their healthcare provider for new or worsening diarrhea [see Adverse Reactions (6.1)]. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with HERNEXEOS and for weeks after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].. LactationAdvise women not to breastfeed during treatment with HERNEXEOS and for weeks after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise females and males of reproductive potential that HERNEXEOS may impair fertility [see Use in Specific Populations (8.3)].. Administration InstructionsInstruct patients weighing less than 90 kg to take two 60 mg tablets once daily to achieve complete 120 mg dose and instruct patients weighing 90 kg or greater to take three 60 mg tablets once daily to achieve complete 180 mg dose [see Dosage and Administration (2.2)]. HERNEXEOS film-coated tablets can be taken with or without food [see Clinical Pharmacology (12.3)]. Instruct patients to swallow HERNEXEOS tablets whole with water. Do not split, crush, or chew tablets.Inform patients that if they miss dose of HERNEXEOS within 12 hours, they should take it as soon as they remember. If the next dose is missed by more than 12 hours, the patient should skip the missed dose and wait until the next scheduled dose [see Dosage and Administration (2.2)].If dose is vomited, do not take an additional dose. Take the next dose at the regularly scheduled time.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Zongertinib pharmacokinetics were observed at steady state in patients with advanced or metastatic solid tumors with HER2 aberrations at the approved recommended dosage and are presented as geometric mean (CV%), unless otherwise specified. Zongertinib maximum concentration (Cmax,ss) is 3.0 (37%) umol/L and the total systemic exposure (AUC) is 34 (34%) umolh/L following HERNEXEOS 120 mg orally daily. Zongertinib Cmax and AUC increase in an approximately dose proportional manner across the dose range of 60 mg (0.5 times the approved recommended dosage) to 360 mg (3 times the approved recommended dosage). Zongertinib accumulation is approximately 1.5-fold for AUC and 1.3-fold for Cmax at the approved recommended dosage. Steady state is achieved within 2.5 days. AbsorptionZongertinib median (min, max) time to maximum plasma concentration (Tmax) is approximately hours (min, max: 2, hours). Zongertinib absolute oral bioavailability is 76%.. Effect of FoodNo clinically significant differences in zongertinib Cmax and AUC were observed following administration of single 240 mg dose (2 times the approved recommended dose) with high-fat meal (approximately 1,000 calories, approximately 50% fat). DistributionZongertinib plasma protein binding is 99%. The apparent (oral) volume of distribution is 118 (29%). EliminationZongertinib effective half-life is 12 hours (21%) with an apparent (oral) clearance of 115 mL/min (31%). MetabolismBased on in vitro metabolite profiling, CYP-mediated oxidation pathways represent 48% to 62% (mainly CYP3A4 and CYP3A5), glucuronidation 13% to 25% (mainly UGT1A4), and glutathione conjugation 13% to 26% of total hepatic metabolism. Unchanged zongertinib represented the majority (75%) of total radioactivity in plasma.. ExcretionAfter single oral dose of radiolabeled zongertinib 60 mg to healthy participants, approximately 93% of the dose was recovered in feces (31% unchanged) and 1.3% in urine (0.2% unchanged).. Specific PopulationsThe apparent volume of distribution and clearance of zongertinib increase with increasing body weight (34 to 122 kg).No clinically significant differences in the pharmacokinetics of zongertinib were observed based on age (30 to 88 years), sex, race (36% White, 49% Asian, 1.3% Black/African American), mild renal impairment (eGFR 60 to 90 mL/min) or mild hepatic impairment (AST ULN and total bilirubin <= ULN; or total bilirubin 1 to 1.5x ULN and any AST). The effect of moderate renal impairment (eGFR 30 to 60 mL/min), severe renal impairment (eGFR 15 to 30 mL/min), end-stage renal disease (eGFR 15 mL/min), moderate hepatic impairment (total bilirubin 1.5 to 3x ULN and any AST) or severe hepatic impairment (total bilirubin 3x ULN and any AST) on the pharmacokinetics of zongertinib have not been studied.. Drug Interaction Studies. CYP3A Inducers: Zongertinib AUC decreased by 63% and Cmax decreased by 43% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily for days. The effect of concomitant use of moderate CYP3A inducers on zongertinib Cmax and AUC are unknown.. BCRP Substrates: Rosuvastatin (BCRP substrate) Cmax increased by 3-fold and AUC by 2.3-fold following concomitant use of single dose of zongertinib 120 mg daily for 12 days. Other Drugs: No clinically significant differences in zongertinib pharmacokinetics were observed when used concomitantly with strong CYP3A, P-gp, BCRP inhibitors and rabeprazole (proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following were observed when used concomitantly with zongertinib: midazolam (a CYP3A substrate), dabigatran (a P-gp substrate), metformin (a OCT2 and MATE1/2-K substrate), or repaglinide (a sensitive CYP2C8 substrate).

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information HERNEXEOS(R) (her-nex-ee-ose) (zongertinib tablets)This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: FEB 2026What is HERNEXEOSHERNEXEOS is prescription medicine used to treat adults with type of lung cancer called non-squamous non-small cell lung cancer (NSCLC) that: cannot be removed by surgery or that has spread to other parts of your body (metastatic), and has certain mutation in the human epidermal growth factor receptor (HER2) gene.Your healthcare provider will perform test to make sure HERNEXEOS is right for you. It is not known if HERNEXEOS is safe and effective in children. Before taking HERNEXEOS, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave heart problemshave lung or breathing problems other than lung cancerare pregnant or plan to become pregnant. HERNEXEOS can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before you start treatment with HERNEXEOS. Use an effective form of birth control (contraception) during treatment with HERNEXEOS and for weeks after your last dose.Talk to your healthcare provider about birth control methods that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with HERNEXEOS. are breastfeeding or plan to breastfeed. It is not known if HERNEXEOS passes into your breastmilk. Do not breastfeed during treatment and for weeks after your last dose of HERNEXEOS.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. HERNEXEOS may affect the way other medicines work, and other medicines may affect how HERNEXEOS works. Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine. How should take HERNEXEOSTake HERNEXEOS exactly as your healthcare provider tells you to take it.Your healthcare provider may change your dose if needed. Do not change your dose or stop taking HERNEXEOS unless your healthcare provider tells you to.Take HERNEXEOS time day, with or without food.Swallow HERNEXEOS tablets whole with water. Do not split, crush, or chew tablets.If you miss dose of HERNEXEOS, take it as soon as you remember within 12 hours. If you missed your dose by more than 12 hours, skip the missed dose and take your next dose at your next scheduled time.If you vomit after taking dose of HERNEXEOS, do not take an extra dose. Take your next dose at your regularly scheduled time. If you take too much HERNEXEOS, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of HERNEXEOS HERNEXEOS may cause serious side effects, including:liver problems. Liver problems are common with HERNEXEOS and can be severe and life-threatening. Your healthcare provider will do blood tests to check your liver function before you start taking HERNEXEOS and during your treatment. Tell your healthcare provider right away if you develop any signs and symptoms of liver problems, including:yellowing of your skin or the white part of your eyes (jaundice)dark or brown (tea colored) urinepain on the upper right side of your stomach area (abdomen)bleeding or bruising more easily than normalfeeling very tiredloss of appetitenausea or vomitingheart problems that may affect your hearts ability to pump blood. HERNEXEOS can cause severe heart problems. Your healthcare provider will do tests to check your heart function before you start taking HERNEXEOS and during treatment. Tell your healthcare provider right away if you have any new or worsening symptoms of heart problems, including:feeling like your heart is pounding or racingdizzinesstirednessfeeling lightheadedshortness of breathloss of consciousnesscoughingswelling of your legs, ankles or feetlung problems. HERNEXEOS can cause lung problems that are severe or life-threatening. Tell your healthcare provider right away if you have any new or worsening symptoms of lung problems, including trouble breathing, shortness of breath, cough, or fever.Your healthcare provider may temporarily stop, decrease your dose, or permanently stop treatment with HERNEXEOS if you have serious side effects. The most common side effects of HERNEXEOS include:diarrhea. HERNEXEOS can cause severe diarrhea. Tell your healthcare provider right away if you have new or worsening diarrhea.rashliver problemsfeeling tirednauseamuscle and joint painupper respiratory tract infectionThe most common severe abnormal blood tests include decreased white blood cell count, increased liver function tests and decreased potassium levels. HERNEXEOS may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of HERNEXEOS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store HERNEXEOSStore HERNEXEOS at room temperature between 68F to 77F (20C to 25C).Store HERNEXEOS tablets in the original bottle.Keep the HERNEXEOS bottle tightly closed.The HERNEXEOS bottle contains two desiccants to help keep your tablets dry (protect from moisture). Do not remove the desiccants from the container after opening. Do not eat or swallow the desiccants.HERNEXEOS comes in child-resistant bottle.HERNEXEOS must be used within months of first opening the bottle. Throw away (discard) any unused tablets months after opening the bottle.Keep HERNEXEOS and all medicines out of the reach of children.General information about the safe and effective use of HERNEXEOS. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use HERNEXEOS for any condition for which it was not prescribed. Do not give HERNEXEOS to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HERNEXEOS that is written for health professionals. What are the ingredients in HERNEXEOSActive ingredient: zongertinib Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The film-coating contains ferric oxide (yellow), glycerol mono and dicaprylocaprate, polyvinyl alcohol, sodium lauryl sulfate, talc, and titanium dioxide. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany HERNEXEOS(R) is registered trademark of and used under license from Boehringer Ingelheim International GmbH. Copyright (C) 2026 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED COL13134EB242026 For more information about HERNEXEOS, including the current prescribing information and Patient Information, go to www.hernexeos.com, scan the code, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257. cannot be removed by surgery or that has spread to other parts of your body (metastatic), and has certain mutation in the human epidermal growth factor receptor (HER2) gene.. have liver problems. have heart problems. have lung or breathing problems other than lung cancer. are pregnant or plan to become pregnant. HERNEXEOS can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before you start treatment with HERNEXEOS. Use an effective form of birth control (contraception) during treatment with HERNEXEOS and for weeks after your last dose.Talk to your healthcare provider about birth control methods that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with HERNEXEOS. Your healthcare provider will do pregnancy test before you start treatment with HERNEXEOS. Use an effective form of birth control (contraception) during treatment with HERNEXEOS and for weeks after your last dose.. Talk to your healthcare provider about birth control methods that might be right for you during this time.. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with HERNEXEOS. are breastfeeding or plan to breastfeed. It is not known if HERNEXEOS passes into your breastmilk. Do not breastfeed during treatment and for weeks after your last dose of HERNEXEOS.. Take HERNEXEOS exactly as your healthcare provider tells you to take it.. Your healthcare provider may change your dose if needed. Do not change your dose or stop taking HERNEXEOS unless your healthcare provider tells you to.. Take HERNEXEOS time day, with or without food.. Swallow HERNEXEOS tablets whole with water. Do not split, crush, or chew tablets.. If you miss dose of HERNEXEOS, take it as soon as you remember within 12 hours. If you missed your dose by more than 12 hours, skip the missed dose and take your next dose at your next scheduled time.. If you vomit after taking dose of HERNEXEOS, do not take an extra dose. Take your next dose at your regularly scheduled time. If you take too much HERNEXEOS, call your healthcare provider or go to the nearest hospital emergency room right away.. liver problems. Liver problems are common with HERNEXEOS and can be severe and life-threatening. Your healthcare provider will do blood tests to check your liver function before you start taking HERNEXEOS and during your treatment. Tell your healthcare provider right away if you develop any signs and symptoms of liver problems, including:. yellowing of your skin or the white part of your eyes (jaundice). dark or brown (tea colored) urine. pain on the upper right side of your stomach area (abdomen). bleeding or bruising more easily than normal. feeling very tired. loss of appetite. nausea or vomiting. heart problems that may affect your hearts ability to pump blood. HERNEXEOS can cause severe heart problems. Your healthcare provider will do tests to check your heart function before you start taking HERNEXEOS and during treatment. Tell your healthcare provider right away if you have any new or worsening symptoms of heart problems, including:. feeling like your heart is pounding or racing. dizziness. tiredness. feeling lightheaded. shortness of breath. loss of consciousness. coughing. swelling of your legs, ankles or feet. lung problems. HERNEXEOS can cause lung problems that are severe or life-threatening. Tell your healthcare provider right away if you have any new or worsening symptoms of lung problems, including trouble breathing, shortness of breath, cough, or fever.. diarrhea. HERNEXEOS can cause severe diarrhea. Tell your healthcare provider right away if you have new or worsening diarrhea.. rash. liver problems. feeling tired. nausea. muscle and joint pain. upper respiratory tract infection. Store HERNEXEOS at room temperature between 68F to 77F (20C to 25C).. Store HERNEXEOS tablets in the original bottle.. Keep the HERNEXEOS bottle tightly closed.. The HERNEXEOS bottle contains two desiccants to help keep your tablets dry (protect from moisture). Do not remove the desiccants from the container after opening. Do not eat or swallow the desiccants.. HERNEXEOS comes in child-resistant bottle.. HERNEXEOS must be used within months of first opening the bottle. Throw away (discard) any unused tablets months after opening the bottle.. QR Code.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], HERNEXEOS can cause fetal harm when administered to pregnant woman. There are no available data on the use of HERNEXEOS in pregnant women to inform drug-associated risk. Oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures >= 19 times the human exposure based on AUC at the recommended dose [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study, pregnant rats received oral doses of 10, 30, or 60 mg/kg/day of zongertinib during the period of organogenesis (gestation day to 18). Zongertinib caused decreased fetal weights, delayed development of the urinary system, and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose). In an embryo-fetal development study in rabbits, there were no adverse embryo-fetal findings in pregnant animals administered oral doses of zongertinib up to 120 mg/kg/day (2.4 times the human exposure based on AUC at the recommended dose) during the period of organogenesis (gestation day to 19). literature-based assessment of the effects on reproduction demonstrated that mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction. 8.2 Lactation. Risk SummaryThere are no data on the presence of zongertinib or its metabolites 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 children, advise women not to breastfeed during treatment with HERNEXEOS and for weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on findings from animal studies and its mechanism of action, HERNEXEOS can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating HERNEXEOS.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with HERNEXEOS and for weeks after the last dose. Infertility. FemalesBased on findings from animal studies, HERNEXEOS may impair fertility in females. The effects in female animals were reversible [see Nonclinical Toxicology 13.1].. MalesBased on findings from animal studies, HERNEXEOS may impair fertility in males of reproductive potential. The effect on testes in animals was not reversible within 4-week recovery period [see Nonclinical Toxicology 13.1].. 8.4 Pediatric Use. The safety and effectiveness of HERNEXEOS have not been established in pediatric patients. 8.5 Geriatric Use. Of the 292 patients with non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS in clinical studies, 47% were 65 years of age and older and 13% were 75 years and older. No overall differences in safety or effectiveness of HERNEXEOS were observed between older and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration, every weeks during the first 12 weeks, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.1)Left Ventricular Dysfunction: Monitor LVEF at baseline prior to administration and at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.2)Interstitial Lung Disease/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4). Hepatotoxicity: Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration, every weeks during the first 12 weeks, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.1). Left Ventricular Dysfunction: Monitor LVEF at baseline prior to administration and at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.2). Interstitial Lung Disease/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4). 5.1 Hepatotoxicity. HERNEXEOS can cause severe and life-threatening hepatotoxicity, including drug induced liver injury. In the pooled safety population [see Adverse Reactions (6.1)], based on adverse reaction data, hepatotoxicity occurred in 27% of patients treated with HERNEXEOS. Grade drug induced liver injury occurred in 1.4% and Grade in 0.3% of patients treated with HERNEXEOS. Grade hepatic failure occurred in 0.3% of patients treated with HERNEXEOS.Based on laboratory data, 37% of patients treated with HERNEXEOS experienced increased alanine aminotransferase (ALT), including 4.9% Grade and 1% Grade 4. Increased aspartate aminotransferase (AST) occurred in 31% of patients treated with HERNEXEOS, including 3.8% Grade and 0.7% Grade 4. Increased bilirubin occurred in 20% of patients treated with HERNEXEOS, including 1% Grade and 0.3% Grade 4.HERNEXEOS was interrupted for an adverse reaction of hepatotoxicity in 8% of patients, the dose was reduced in 3.8% and permanently discontinued in 1%.Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration of HERNEXEOS, every weeks during the first 12 weeks, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on the severity of the adverse reaction [see Dosage and Administration (2.3)]. 5.2 Left Ventricular Dysfunction. HERNEXEOS can cause severe left ventricular dysfunction. Left ventricular ejection fractions (LVEF) decrease occurred with anti-HER2 therapies, including HERNEXEOS. Treatment with HERNEXEOS has not been studied in patients with history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.In the pooled safety population [see Adverse Reactions (6.1)], LVEF decrease occurred in 6% of patients treated with HERNEXEOS, including 1.7% Grade 3. Two patients with Grade LVEF decrease required permanent discontinuation of HERNEXEOS. The median time to onset of decreased LVEF was 12 weeks (range: 2.9 to 63 weeks).Before initiating HERNEXEOS, evaluate LVEF and monitor at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on the severity of the adverse reaction [see Dosage and Administration (2.3)]. 5.3 Interstitial Lung Disease/Pneumonitis. HERNEXEOS can cause severe and life-threatening interstitial lung disease (ILD)/pneumonitis.In the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2.1% of patients treated with HERNEXEOS. The median time to first onset of ILD/pneumonitis was 13 weeks (range: 1.4 to 65 weeks). One patient was able to resume therapy after resolution of pneumonitis. Two patients required permanent discontinuation and one patient died with unresolved pneumonitis 30 days after discontinuing HERNEXEOS.Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Interrupt, reduce the dose or permanently discontinue HERNEXEOS based on severity of confirmed ILD/pneumonitis [see Dosage and Administration (2.3)]. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, HERNEXEOS can cause fetal harm when administered to pregnant woman. In an animal reproduction study, oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures >= 19 times the human exposure based on AUC at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with HERNEXEOS and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].