FDA label 654f8e2c-0b86-4320-b392-81f42fa8cadd

5 WARNINGS AND PRECAUTIONS Diarrhea : At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment, and to increase their fluid and electrolyte intake. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity. ( 5.1 ) Hepatotoxicity : Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration of HYRNUO, every 2 weeks during the first month, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity. ( 5.2 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Discontinue HYRNUO upon confirmation of ILD/pneumonitis. ( 5.3 ) Ocular Toxicity : Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Interrupt, reduce the dose or permanently discontinue HYRNUO based on severity. ( 5.4 ) Pancreatic Enzyme Elevation : Monitor amylase and lipase regularly during treatment. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity. ( 5.5 ) Embryo-fetal toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Diarrhea HYRNUO can cause severe diarrhea that can lead to dehydration and electrolyte imbalances. In the pooled safety population [see Adverse Reactions (6.1) ] , diarrhea was reported in 86% of patients who received HYRNUO including Grade 3 in 15%. The median time to first onset of any grade diarrhea was four days. Dosage interruptions occurred in 15% of patients, and dose reductions occurred in 12% of patients. At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide [refer to full Prescribing Information] ), and to increase their fluid and electrolyte intake. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity [see Dosage and Administration (2.3) ] . 5.2 Hepatotoxicity HYRNUO can cause severe hepatotoxicity characterized by elevations of liver function tests. In the pooled safety population [see Adverse Reactions (6.1) ], based on adverse reaction data, hepatotoxicity occurred in 24% of patients treated with HYRNUO including 3% Grade 3. Based on laboratory data, 35% of patients treated with HYRNUO experienced increased alanine aminotransferase (ALT), including 2.3% Grade 3. Increased aspartate aminotransferase (AST) occurred in 35% of patients treated with HYRNUO, including 2.3% Grade 3. Increased bilirubin occurred in 12% of patients treated with HYRNUO. The median time to first onset of AST or ALT elevation was 1.4 (range 0.2 to 14.5) months. HYRNUO was interrupted for an adverse reaction of hepatotoxicity in 4.1% of patients, the dose was reduced in 4.1% and permanently discontinued in 0.4%. Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to the first administration of HYRNUO, every 2 weeks for the first month, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on the severity of the adverse reaction [see Dosage and Administration (2.3) ] . 5.3 Interstitial Lung Disease/Pneumonitis HYRNUO can cause severe interstitial lung disease (ILD)/pneumonitis. In the pooled safety population [see Adverse Reactions (6.1) ], ILD/pneumonitis occurred in two patients (0.7%) treated with HYRNUO, including 0.4% Grade 3. One patient required interruption of HYRNUO. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Discontinue HYRNUO upon confirmation of ILD/pneumonitis [see Dosage and Administration (2.3) ] . 5.4 Ocular Toxicity HYRNUO can cause ocular toxicity. In the pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 14% of patients treated with HYRNUO, including 11% Grade 1, 2.6% Grade 2 and 0.4% Grade 3 (one case of corneal epithelial microcysts with temporary unilateral blindness). Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Interrupt, reduce the dose or permanently discontinue HYRNUO based on severity [see Dosage and Administration (2.3) ]. 5.5 Pancreatic Enzyme Elevation HYRNUO can cause elevations of amylase and lipase levels . In the pooled safety population [see Adverse Reactions (6.1) ] , based on laboratory data, increased amylase occurred in 32% of patients treated with HYRNUO, including 3.2% Grade 3 or 4. Increased lipase elevation occurred in 40% of patients treated with HYRNUO, including 10% Grade 3 or 4. Two patients (0.7%) required interruption of HYRNUO due to increased lipase and 3 (1.1%) required interruption of HYRNUO due to increased amylase. The median time to onset of increased amylase/lipase was 1.4 months (range 0.2 to 17 months). Monitor amylase and lipase regularly during treatment with HYRNUO. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity [see Dosage and Administration (2.3) ]. 5.6 Embryo-fetal toxicity Based on findings from animal studies and its mechanism of action, HYRNUO can cause fetal harm when administered to a pregnant woman. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Diarrhea [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.3) ] Ocular Toxicity [see Warnings and Precautions (5.4) ] Pancreatic Enzyme Elevation [see Warnings and Precautions (5.5) ] Most common adverse reactions (>20%) : diarrhea, rash, paronychia, stomatitis, and nausea. Most common Grade 3 or 4 laboratory abnormalities (≥2%) : decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population in the WARNINGS AND PRECAUTIONS reflects exposure to HYRNUO at 20 mg orally twice daily in 268 patients with locally advanced or metastatic NSCLC harboring HER2 and/or other mutations from the SOHO-01 study [see Clinical Studies (14) ] . Among 268 patients who received HYRNUO, 35% were exposed for greater than 6 months and 12% were exposed for greater than 1 year. In this pooled safety population, the most common (>20%) adverse reactions were diarrhea, rash, stomatitis, and paronychia. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST. The safety of HYRNUO at 20 mg orally twice daily was evaluated in 136 patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations who had received prior systemic therapy in the SOHO-01 study [see Clinical Studies (14) ] . Among 136 patients who received HYRNUO, 46% were exposed greater than 6 months and 15% were exposed for greater than 1 year. The median age of patients who received HYRNUO was 62 years (range: 29 to 91); 63% female; 65% Asian, 27% White, 3.7% Black or African American; and 2.2% were of Hispanic or Latino ethnicity. The most common adverse reactions (>20%) in patients who received HYRNUO were diarrhea, rash, paronychia, stomatitis, and nausea. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were potassium decreased, lipase increased, lymphocyte count decreased, sodium decreased, amylase increased, aspartate aminotransferase (AST) increased, and alanine aminotransferase (ALT) increased. Serious adverse reactions occurred in 31% of patients who received HYRNUO. Serious adverse reactions in ≥2% of patients were diarrhea (6%), pneumonia (3.7%), dyspnea (2.2%), and pleural effusion (2.2%). Permanent discontinuation of HYRNUO due to an adverse reaction occurred in 3.7% of patients. Adverse reactions which resulted in permanent discontinuation were corneal epithelial microcysts, hepatic function abnormal, electrocardiogram QT prolonged, pain in extremity and dyspnea (0.7%, 1 patient each). Dosage interruptions of HYRNUO due to an adverse reaction occurred in 46% of patients. Adverse reactions which resulted in dosage interruptions in >3% of patients were diarrhea, hypokalemia, nausea, decreased appetite, and pneumonia. Dose reductions of HYRNUO due to adverse reactions occurred in 28% of patients. Adverse reactions which resulted in dose reductions in >2% of patients were diarrhea, rash, and hypokalemia. Table 4 summarizes the adverse reactions in SOHO-01 (Groups D and E). Table 4: Adverse Reactions (≥10%) in Patients with NSCLC with HER2 Activating Mutations Who Received HYRNUO in SOHO-01 (Groups D and E) Adverse Reaction Graded per NCI CTCAE version 5. HYRNUO N = 136 All Grades (%) Grade 3 or 4 All were Grade 3, except for dyspnea (0.7%, Grade 4). (%) Gastrointestinal disorders Diarrhea Includes diarrhea, enterocolitis. 87 18 Stomatitis Includes cheilitis, mouth ulceration, mucosal inflammation, stomatitis. 29 1.5 Nausea 21 1.5 Vomiting 15 2.2 Abdominal pain Includes abdominal pain, abdominal pain upper. 10 0 Skin and subcutaneous tissue disorders Rash Includes dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash maculopapular, rash pruritic, rash pustular, skin exfoliation. 66 1.5 Paronychia Includes ingrowing nail, nail disorder, onychoclasis, onycholysis, onychomadesis, paronychia. 33 0 Dry skin Includes dry skin, xeroderma. 20 0 Pruritus 14 1.5 Metabolism and nutrition disorders Decreased appetite 18 2.9 Investigations Weight decreased 19 0.7 General disorders and administration site conditions Fatigue Includes asthenia, fatigue. 13 0.7 Eye disorders Ocular toxicity Includes blindness unilateral, cataract, conjunctivitis, conjunctivitis allergic, corneal epithelial microcysts, dry eye, eye discharge, eye pain, lacrimation increased, ocular hyperemia, ocular hypertension, ocular toxicity, vision blurred, visual acuity reduced, visual impairment, xerophthalmia. 16 0.7 Respiratory disorders Dyspnea Includes dyspnea, dyspnea exertional. 10 1.5 Clinically relevant adverse reactions in <10% of patients who received HYRNUO included edema (8%), cardiac arrhythmia (6%; includes arrhythmia, atrioventricular block complete, electrocardiogram QT prolonged, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia) and alopecia (3.7%). Table 5 summarizes the laboratory abnormalities observed in SOHO-01 (Groups D and E). Table 5: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with NSCLC with HER2 Activating Mutations in SOHO-01 (Groups D and E) Laboratory Abnormality HYRNUO N=136 The denominator used to calculate the rate varied from 103 to 135 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Graded per NCI CTCAE version 5 using only numeric values. Grade 3 or 4 All were Grade 3, except for calcium decreased (0.7%, Grade 4) and amylase increased (1.5%; Grade 4) (%) Hematology Hemoglobin decreased 47 1.5 Lymphocyte count decreased 32 6 White blood cell decreased 21 0.7 Chemistry Lipase increased 48 12 Potassium decreased 45 13 Aspartate aminotransferase increased 41 3 Magnesium decreased 40 0 Alanine aminotransferase increased 37 3 Glucose increased Graded per NCI CTCAE version 4.03 using only numeric values. 36 0.7 Albumin decreased 32 1.5 Amylase increased 31 3.8 Calcium decreased 28 1.5 Creatinine increased 27 0 Sodium decreased 26 4.4 Alkaline phosphatase increased 24 0 Triglycerides increased 22 0 Laboratory abnormalities in <20% of patients who received HYRNUO include blood bilirubin increased (14%; all were Grades 1 and 2).

<table width="80%"><caption>Table 4: Adverse Reactions (&#x2265;10%) in Patients with NSCLC with HER2 Activating Mutations Who Received HYRNUO in SOHO-01 (Groups D and E)</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule" rowspan="2">Adverse Reaction<footnote>Graded per NCI CTCAE version 5.</footnote></th><th styleCode="Rrule" colspan="2">HYRNUO N = 136</th></tr><tr styleCode="botrule"><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4<footnote>All were Grade 3, except for dyspnea (0.7%, Grade 4).</footnote> (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal disorders </content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Diarrhea<footnote>Includes diarrhea, enterocolitis.</footnote></td><td styleCode="Rrule">87</td><td styleCode="Rrule">18</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Stomatitis<footnote>Includes cheilitis, mouth ulceration, mucosal inflammation, stomatitis.</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">2.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote>Includes abdominal pain, abdominal pain upper.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Rash<footnote>Includes dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash maculopapular, rash pruritic, rash pustular, skin exfoliation.</footnote></td><td styleCode="Rrule">66</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Paronychia<footnote>Includes ingrowing nail, nail disorder, onychoclasis, onycholysis, onychomadesis, paronychia.</footnote></td><td styleCode="Rrule">33</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Dry skin<footnote>Includes dry skin, xeroderma.</footnote></td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Pruritus</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">18</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Weight decreased</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Includes asthenia, fatigue.</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Eye disorders</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Ocular toxicity<footnote>Includes blindness unilateral, cataract, conjunctivitis, conjunctivitis allergic, corneal epithelial microcysts, dry eye, eye discharge, eye pain, lacrimation increased, ocular hyperemia, ocular hypertension, ocular toxicity, vision blurred, visual acuity reduced, visual impairment, xerophthalmia.</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Dyspnea<footnote>Includes dyspnea, dyspnea exertional.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">1.5</td></tr></tbody></table>

<table width="80%"><caption>Table 5: Select Laboratory Abnormalities (&#x2265;20%) That Worsened from Baseline in Patients with NSCLC with HER2 Activating Mutations in SOHO-01 (Groups D and E)</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2">HYRNUO N=136<footnote>The denominator used to calculate the rate varied from 103 to 135 based on the number of patients with a baseline value and at least one post-treatment value.</footnote></th></tr><tr styleCode="botrule"><th styleCode="Rrule" align="center">All Grades (%)<footnote>Graded per NCI CTCAE version 5 using only numeric values.</footnote></th><th styleCode="Rrule">Grade 3 or 4<footnote>All were Grade 3, except for calcium decreased (0.7%, Grade 4) and amylase increased (1.5%; Grade 4)</footnote> (%)</th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Hemoglobin decreased</td><td styleCode="Rrule">47</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Lymphocyte count decreased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">6</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> White blood cell decreased</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Lipase increased</td><td styleCode="Rrule">48</td><td styleCode="Rrule">12</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Potassium decreased</td><td styleCode="Rrule">45</td><td styleCode="Rrule">13</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Aspartate aminotransferase increased</td><td styleCode="Rrule">41</td><td styleCode="Rrule">3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Magnesium decreased</td><td styleCode="Rrule">40</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Alanine aminotransferase increased</td><td styleCode="Rrule">37</td><td styleCode="Rrule">3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Glucose increased<footnote>Graded per NCI CTCAE version 4.03 using only numeric values.</footnote></td><td styleCode="Rrule">36</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Albumin decreased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Amylase increased</td><td styleCode="Rrule">31</td><td styleCode="Rrule">3.8</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Calcium decreased</td><td styleCode="Rrule">28</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Creatinine increased</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Sodium decreased</td><td styleCode="Rrule">26</td><td styleCode="Rrule">4.4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule"> Alkaline phosphatase increased</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"> Triglycerides increased</td><td styleCode="Rrule">22</td><td styleCode="Rrule">0</td></tr></tbody></table>