<?xml version="1.0" encoding="UTF-8"?><section ID="ID_6f78173b-4a20-45ff-8e7f-a3dbaac9b0bb">
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<code code="34084-4" codeSystem="2.16.840.1.113883.6.1" displayName="ADVERSE REACTIONS SECTION"/>
<title>6 ADVERSE REACTIONS </title>
<text>
<paragraph>The following adverse reactions are discussed in greater detail in other sections of the labeling:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>Interstitial Lung Disease/Pneumonitis <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>QTc Interval Prolongation <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Cardiomyopathy <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Keratitis<content styleCode="italics"> [see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Cutaneous Vasculitis <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Aplastic Anemia <content styleCode="italics">[see </content>
<content styleCode="bold">Error! Hyperlink reference not valid.</content>
<content styleCode="italics">]</content>
</item>
</list>
</text>
<effectiveTime value="20240925"/>
<excerpt>
<highlight>
<text>
<paragraph>Most common (≥20%) adverse reactions, including laboratory abnormalities, were:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue. (<linkHtml href="#_RefID_a1f3b98a-9199-4daf-b1ff-4513e5802">6.1</linkHtml>)</item>
<item>
<caption>•</caption>TAGRISSO monotherapy following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough and COVID-19. (<linkHtml href="#_RefID_a1f3b98a-9199-4daf-b1ff-4513e5802">6.1</linkHtml>)</item>
<item>
<caption>•</caption>TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine. (<linkHtml href="#_RefID_a1f3b98a-9199-4daf-b1ff-4513e5802">6.1</linkHtml>)</item>
</list>
<paragraph>
<content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or <linkHtml href="https://www.tagrisso.com/">www.TAGRISSO.com</linkHtml> or FDA at 1-800-FDA-1088 or <linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml>
</content>
</paragraph>
</text>
</highlight>
</excerpt>
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>6.1 Clinical Trials Experience </title>
<text>
<paragraph>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.</paragraph>
<paragraph>The data in the WARNINGS AND PRECAUTIONS section reflect exposure to TAGRISSO in 1813 patients with EGFR mutation-positive NSCLC who received TAGRISSO monotherapy at the recommended dose of 80 mg orally once daily until disease progression or unacceptable toxicity in four randomized, controlled trials [ADAURA (n=337), FLAURA (n=338), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)] <content styleCode="italics">[see <linkHtml href="#_RefID_130cb4b4-6b61-4bd0-9fc4-0d9449d1e">Clinical Studies (14)</linkHtml>]</content>, two single arm trials [AURA Extension (n=201) {NCT01802632} and AURA2 (n=210)]{NCT02094261}, and one dose-finding study, AURA1 (n=173). Among 1813 patients who received TAGRISSO monotherapy, 82% were exposed for 6 months or longer and 67% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions in ≥20% of 1813 patients who received TAGRISSO monotherapy were diarrhea (47%), rash (46%), musculoskeletal pain (38%), nail toxicity (34%), dry skin (32%), stomatitis (24%), and fatigue (21%). The most common laboratory abnormalities in ≥20% of 1813 patients who received TAGRISSO monotherapy were leukopenia (65%), lymphopenia (64%), thrombocytopenia (53%), anemia (52%), and neutropenia (36%). In addition to the 1813 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to TAGRISSO monotherapy (80 mg orally once daily until disease progression or unacceptable toxicity) following definitive platinum-based chemoradiation therapy (n=143) in the LAURA study.</paragraph>
<paragraph>The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, 143 patients with EGFR mutation-positive locally advanced, unresectable (stage III) NSCLC, and 833 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in five randomized, controlled trials [ADAURA (n=337), LAURA (n=143), FLAURA (n=279), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)]. The data also reflect exposure to TAGRISSO at the recommended dose of 80 mg daily given in combination with pemetrexed and platinum-based chemotherapy in 276 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in one randomized controlled trial [FLAURA2 (n=276)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies.</paragraph>
<paragraph>
<content styleCode="underline">Adjuvant Treatment of EGFR Mutation-Positive NSCLC - Monotherapy</content>
</paragraph>
<paragraph>The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.</paragraph>
<paragraph>Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%).</paragraph>
<paragraph>Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.</paragraph>
<table ID="_RefID0EZGBG" width="100%">
<caption>Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA<footnote ID="_Ref178942629">NCI CTCAE v4.0.</footnote>
</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="14%"/>
<thead>
<tr>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Adverse Reaction</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=337)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">PLACEBO</content>
<br/>
<content styleCode="bold">(N=343)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or higher</content>
<footnote ID="_Ref178864506">All events were grade 3.</footnote>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or higher</content>
<footnoteRef IDREF="_Ref178864506"/>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diarrhea<footnote ID="_Ref178864540">Includes diarrhea, colitis, enterocolitis, enteritis.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>47</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref178864588">Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Abdominal Pain<footnote ID="_Ref178864607">Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref178864626">Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nail toxicity<footnote ID="_Ref178864645">Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dry skin<footnote ID="_Ref178864664">Includes dry skin, skin fissures, xerosis, eczema, xeroderma.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pruritus<footnote ID="_Ref178864682">Includes pruritus, pruritus generalized, eyelid pruritus.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Cough<footnote ID="_Ref178864703">Includes cough, productive cough, upper-airway cough syndrome.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Musculoskeletal Pain<footnote ID="_Ref178864725">Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Infection and Infestation Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nasopharyngitis</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Upper respiratory tract infection</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Urinary Tract Infection<footnote ID="_Ref178864760">Includes cystitis, urinary tract infection, and urinary tract infection bacterial.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">General Disorders and Administration Site Conditions</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Fatigue<footnote ID="_Ref178864782">Includes asthenia, fatigue.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Metabolism and Nutrition Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Decreased appetite</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Nervous System Disorders</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Dizziness<footnote ID="_Ref178865034">Includes dizziness, vertigo, and vertigo positional.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), skin hyperpigmentation (1.8%), urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiforme (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.</paragraph>
<table ID="_RefID0EXYBG" width="100%">
<caption>Table 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref59203742">NCI CTCAE v4.0</footnote>
<footnote ID="_Ref59203775">Based on the number of patients with available follow-up laboratory data.</footnote>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=337)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">PLACEBO</content>
<br/>
<content styleCode="bold">(N=343)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or Grade 4 (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or Grade 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematology</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Leukopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>54</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Thrombocytopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>47</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Lymphopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Anemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Neutropenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Chemistry </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hyperglycemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hypermagnesemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Hyponatremia</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>1.8</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Laboratory abnormalities in ADAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (10%).</paragraph>
<paragraph>
<content styleCode="underline">Locally Advanced, Unresectable (Stage III) EGFR Mutation Positive NSCLC </content>
</paragraph>
<paragraph>The safety of TAGRISSO was evaluated in LAURA, a double blind, randomized (2:1), placebo controlled study conducted in 216 patients with EGFR exon 19 deletions or exon 21 L858R mutation positive, locally advanced, unresectable (stage III) NSCLC, who had not progressed during or following definitive platinum based chemoradiation therapy. Among patients who received TAGRISSO, 81% were exposed for 6 months or longer and 74% were exposed for one year or longer.</paragraph>
<paragraph>Serious adverse reactions were reported in 38% of patients treated with TAGRISSO. The most common serious adverse reactions (≥1%) included ILD/pneumonitis (13%), pneumonia (6%) and gastroenteritis (1.4%). Fatal adverse reactions occurred in 1.4% of patients who received TAGRISSO due to pneumonia (0.7%) and ILD/pneumonitis (0.7%).</paragraph>
<paragraph>Permanent discontinuation of TAGRISSO due to an adverse reaction occurred in 13% of patients. The adverse reactions resulting in permanent discontinuation of TAGRISSO in > 1 patient were ILD/pneumonitis (7%) and pneumonia (1.4%). </paragraph>
<paragraph>Dosage interruptions of TAGRISSO due to an adverse reaction occurred in 56% of patients. The adverse reactions requiring dosage interruption in ≥2% of patients were ILD/pneumonitis (35%), pneumonia (6%), COVID-19 (4.2%), neutropenia (2.1%), and QTc interval prolongation (2.1%).</paragraph>
<paragraph>Dose reductions of TAGRISSO due to an adverse reaction occurred in 8% of patients. </paragraph>
<paragraph>The most common adverse reactions, including laboratory abnormalities worsening from baseline, were lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19.</paragraph>
<paragraph>Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in LAURA.</paragraph>
<table ID="_RefID0ERCAI" width="100%">
<caption>Table 6. Adverse Reactions in ≥10% of Patients Receiving TAGRISSO in LAURA<footnote ID="_Ref178865479">NCI CTCAE v5.0</footnote>
</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="15%"/>
<thead>
<tr>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Adverse Reaction</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=143)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">(N=73)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Any Grade (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or 4(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Any Grade (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>ILD/pneumonitis<footnote ID="_Ref178865748">Includes radiation pneumonitis, radiation lung fibrosis, pneumonitis, interstitial lung disease (ILD), pulmonary fibrosis.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>56</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>38</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Cough<footnote ID="_Ref178865772">Includes cough, productive cough.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref178865822">Includes rash, maculo-papular rash, pustular rash, pruritic rash, folliculitis, papule, dermatitis, acneiform dermatitis, atopic dermatitis, eczema, asteatotic eczema, acne, urticaria.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nail toxicity<footnote ID="_Ref178865863">Includes nail bed disorder, nail disorder, nail discoloration, nail infection, onychoclasis, paronychia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dry skin<footnote ID="_Ref178865985">Includes dry skin, skin fissures, senile xerosis, xeroderma.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pruritus</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diarrhea<footnote ID="_Ref178866019">Includes diarrhea, enteritis.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref178866037">Includes stomatitis, aphthous ulceration, mouth ulceration.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Musculoskeletal pain<footnote ID="_Ref178866062">Includes musculoskeletal chest pain, myalgia, arthritis, arthralgia, back pain, bone pain, musculoskeletal pain, neck pain, pain in extremity, spinal osteoarthritis.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Infection and Infestation Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>COVID-19<footnote ID="_Ref178866151">Includes COVID-19 and COVID-19 pneumonia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pneumonia<footnote ID="_Ref178866167">Includes pneumonia, aspiration pneumonia, viral pneumonia, Pneumocystis jiroveci pneumonia, Haemophilus pneumonia, lower respiratory tract infection.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Metabolism and Nutrition Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Decreased appetite</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in LAURA in <10% of patients receiving TAGRISSO were dyspnea (8%), urinary tract infection (8%), alopecia (1.4%), urticaria (1.4%), epistaxis (0.7%), keratitis (0.7%), and QTc interval prolongation (0.7%). QTc interval prolongation represents the incidence of patients who had a QTc prolongation >500 msec.</paragraph>
<table ID="_RefID0EXQAI" width="100%">
<caption>Table 7. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in LAURA</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref178866594">NCI CTCAE v5.0</footnote>
<footnote ID="_Ref178866613">Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO arm: 142 and placebo arm: 72).</footnote>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=143)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">(N=73)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades </content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematology</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Lymphopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>70</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Leukopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>66</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Thrombocytopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>51</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Neutropenia</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>42</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>2.1</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>A clinically relevant laboratory abnormality in LAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (19%).</paragraph>
<paragraph>
<content styleCode="underline">Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer - Monotherapy</content>
</paragraph>
<paragraph>The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active‑controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months.</paragraph>
<paragraph>Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%).</paragraph>
<paragraph>Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.</paragraph>
<table ID="_RefID0ECXAI" width="100%">
<caption>Table 8. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA<footnote ID="_Ref178929742">NCI CTCAE v4.0</footnote>
</caption>
<col width="30%"/>
<col width="20%"/>
<col width="18%"/>
<col width="14%"/>
<col width="18%"/>
<tbody>
<tr>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Adverse Reaction</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">TAGRISSO</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=279)</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">EGFR TKI comparator</content>
</paragraph>
<paragraph>
<content styleCode="bold">(gefitinib or erlotinib)</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=277)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Any Grade </content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 or higher (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Any Grade (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 or higher (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diarrhea<footnote ID="_Ref178930444">One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>58</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>57</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref178930462">Includes stomatitis and mouth ulceration.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nausea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Constipation</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Vomiting</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref178930518">Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>58</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>78</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dry skin<footnote ID="_Ref178930534">Includes dry skin, skin fissures, xerosis, eczema, xeroderma.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nail toxicity<footnote ID="_Ref178930551">Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>35</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>33</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pruritus<footnote ID="_Ref178930589">Includes pruritus, pruritus generalized, eyelid pruritus.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">General Disorders and Administration Site Conditions</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Fatigue<footnote ID="_Ref178930765">Includes fatigue, asthenia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pyrexia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Metabolism and Nutrition Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Decreased appetite</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Cough</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dyspnea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Neurologic Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Headache</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Cardiac Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Prolonged QT Interval<footnote ID="_Ref178930931">Includes prolonged QT interval reported as adverse reaction.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Infection and Infestation Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Upper Respiratory Tract Infection</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia syndrome (1.4%), QTc interval prolongation (1.1%), keratitis (0.4%), and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.</paragraph>
<table ID="_RefID0EZJBI" width="100%">
<caption>Table 9. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA</caption>
<col width="25%"/>
<col width="25%"/>
<col width="16%"/>
<col width="17%"/>
<col width="17%"/>
<tbody>
<tr styleCode="Toprule">
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref523916562">NCI CTCAE v4.0</footnote>
<footnote ID="_Ref178931228">Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI comparator range: 256 - 268).</footnote>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">TAGRISSO</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=279)</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">EGFR TKI comparator</content>
</paragraph>
<paragraph>
<content styleCode="bold">(gefitinib or erlotinib)</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=277)</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 or </content>
</paragraph>
<paragraph>
<content styleCode="bold">Grade 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3</content>
</paragraph>
<paragraph>
<content styleCode="bold">or Grade 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematology</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Lymphopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>63</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Anemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>59</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>47</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Thrombocytopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>51</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Neutropenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>41</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Chemistry</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hyperglycemia<footnote ID="_Ref178931251">Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191).</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hypermagnesemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hyponatremia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Increased AST</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>43</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Increased ALT</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>52</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hypokalemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Hyperbilirubinemia</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>1.1</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>A clinically relevant laboratory abnormality in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%).</paragraph>
<paragraph>Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy</paragraph>
<paragraph>The safety of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was evaluated in FLAURA2, a multicenter international open-label, randomized (1:1), active-controlled trial conducted in 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was 22.3 months and the median duration of exposure to TAGRISSO monotherapy was 19.3 months.</paragraph>
<paragraph>Serious adverse reactions were reported in 38% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; the most frequently reported serious adverse reactions (≥2%) in the combination arm were anemia (3.3%), COVID-19 (2.5%), pneumonia (2.5%), febrile neutropenia (2.2%), thrombocytopenia (2.2%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 7% of patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy including pulmonary embolism (1.1%), pneumonia (1.1%) and cardiomyopathy (1.1%).</paragraph>
<paragraph>Dosage interruptions of TAGRISSO, when given with pemetrexed and platinum-based chemotherapy, due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia (4.7%), neutropenia (4.3%), diarrhea (3.6%), febrile neutropenia (3.3%) and thrombocytopenia (2.9%).</paragraph>
<paragraph>Permanent discontinuation of TAGRISSO when given in combination with pemetrexed and platinum-based chemotherapy due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of TAGRISSO in ≥1% of patients included ILD/pneumonitis (2.9%), pneumonia (1.4%), and decreased ejection fraction (1.1%).</paragraph>
<paragraph>Adverse reactions leading to dose reduction of TAGRISSO occurred in 10% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy. The most frequently reported adverse reactions leading to dose reduction of TAGRISSO in the combination arm in ≥1% of patients were diarrhea (1.1%) and rash (1.1%).</paragraph>
<paragraph>Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2.</paragraph>
<table ID="_RefID0EOWBI" width="100%">
<caption>Table 10. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2<footnote ID="_Ref158984528">NCI CTCAE v5.0</footnote>
</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Adverse Reaction</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=275)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Any Grade (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or higher</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Any Grade (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or higher</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref178931857">Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>49</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nail toxicity<footnote ID="_Ref178931881">Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dry skin<footnote ID="_Ref178931896">Includes dry skin, skin fissures, xerosis, eczema, xeroderma.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pruritus<footnote ID="_Ref178931934">Includes pruritus, eyelid pruritus.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diarrhea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>43</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>41</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref178931949">Includes stomatitis and mouth ulceration.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.4</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in FLAURA2 in <10% of patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy were alopecia (9%), epistaxis (7%), palmar-plantar erythrodysesthesia syndrome (5%), interstitial lung disease (3.3%), skin hyperpigmentation (2.5%), QTc interval prolongation (1.8%), erythema multiforme (1.4%), urticaria (1.4%), and keratitis (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.</paragraph>
<table ID="_RefID0EO5BI" width="100%">
<caption>Table 11. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2<footnote ID="_Ref158987615">NCI CTCAE v5.0</footnote>
<footnote ID="_Ref178932111">Findings based on test results presented as CTCAE grade shifts.</footnote>
</caption>
<col width="28%"/>
<col width="28%"/>
<col width="15%"/>
<col width="15%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref178932140">Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO with pemetrexed and platinum-based chemotherapy arm: 275 and TAGRISSO monotherapy arm: 275).</footnote>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TAGRISSO</content>
<br/>
<content styleCode="bold">(N=275)</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or Grade 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">All Grades</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Grade 3 or Grade 4</content>
<br/>
<content styleCode="bold">(%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematology</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Leukopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>88</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>53</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Thrombocytopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>85</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Neutropenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>85</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Lymphopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>78</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>55</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Chemistry</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>Blood creatinine increased</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy</content>
</paragraph>
<paragraph>The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).</paragraph>
<paragraph>Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).</paragraph>
<paragraph>Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).</paragraph>
<paragraph>Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.</paragraph>
<table ID="_RefID0EXFCI" width="100%">
<caption>Table 12. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3<footnote ID="_Ref25566854">NCI CTCAE v4.0.</footnote>
</caption>
<col width="34%"/>
<col width="33%"/>
<col width="10%"/>
<col width="12%"/>
<col width="11%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Adverse Reaction</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">TAGRISSO</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=279)</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Chemotherapy</content>
</paragraph>
<paragraph>
<content styleCode="bold">(Pemetrexed/Cisplatin or</content>
</paragraph>
<paragraph>
<content styleCode="bold">Pemetrexed/Carboplatin)</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=136)</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">All Grades</content>
<footnote ID="_Ref178932813">No grade 4 events were reported.</footnote>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Grade 3/4</content>
<footnoteRef IDREF="_Ref178932813"/>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">All Grades</content>
<footnoteRef IDREF="_Ref178932813"/>
<content styleCode="bold"> (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Grade 3/4</content>
<footnoteRef IDREF="_Ref178932813"/>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Diarrhea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>41</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Nausea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>49</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref178932860">Includes stomatitis and mouth ulceration.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Constipation</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>35</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Vomiting</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref178932874">Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>34</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dry skin<footnote ID="_Ref178932888">Includes dry skin, eczema, skin fissures, xerosis.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Nail toxicity<footnote ID="_Ref178932902">Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Pruritus<footnote ID="_Ref178932914">Includes pruritus, pruritus generalized, eyelid pruritus.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">General Disorders and Administration Site Conditions</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Fatigue<footnote ID="_Ref178932923">Includes fatigue, asthenia.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5.1</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Metabolism and Nutrition Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Decreased appetite</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.9</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Cough</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Back pain</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.7</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiforme (0.7%), and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.</paragraph>
<table ID="_RefID0EFVCI" width="100%">
<caption>Table 13. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3</caption>
<col width="31%"/>
<col width="30%"/>
<col width="14%"/>
<col width="13%"/>
<col width="13%"/>
<tbody>
<tr>
<td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref523916862">NCI CTCAE v4.0</footnote>
<footnote ID="_Ref178934212">Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131).</footnote>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">TAGRISSO</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=279)</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=131)</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 or Grade 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 or Grade 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematology</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Anemia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>43</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>79</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Lymphopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>63</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>61</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Thrombocytopenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>46</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>48</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Neutropenia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>49</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12 </paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Chemistry</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Hypermagnesemia<footnoteRef IDREF="_Ref178934212"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Hyponatremia<footnoteRef IDREF="_Ref178934212"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Hyperglycemia<footnote ID="_Ref178934303">Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm).</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>NA</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>NA</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Hypokalemia<footnoteRef IDREF="_Ref178934212"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.5</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Botrule Toprule " valign="top">
<paragraph>NA=Not Applicable</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).</paragraph>
<paragraph>
<content styleCode="underline">Other Clinical Trials Experience</content>
</paragraph>
<paragraph>The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.</paragraph>
</text>
<effectiveTime value="20240925"/>
</section>
</component>
<component>
<section ID="ID_6ed59b10-a908-4a9e-b233-263fed4b5a1b">
<id root="213f579d-1a79-4172-854b-c408ca8d2ab2"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>6.2 Postmarketing Experience </title>
<text>
<paragraph>The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</paragraph>
<list listType="unordered">
<item>
<caption> </caption>
<list listType="unordered">
<item>
<caption>o</caption>
<content ID="_RefID_6ed59b10-a908-4a9e-b233-263fed4b5">
<content styleCode="italics">Skin and subcutaneous tissue:</content> Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans</content>
</item>
<item>
<caption>o</caption>
<content styleCode="italics">Blood and lymphatic system disorders:</content> Aplastic anemia</item>
</list>
</item>
</list>
</text>
<effectiveTime value="20240925"/>
</section>
</component>
</section>