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<title>6 ADVERSE REACTIONS </title>
<text>
<paragraph>The following adverse drug reactions are discussed in more detail in other sections of the labeling:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>Interstitial Lung Disease <content styleCode="italics">[see <linkHtml href="#ID_2d045521-95aa-4d4d-9692-ed8f004e43df">Warnings and Precautions (5.1)</linkHtml>]</content>
</item>
<item>
<caption>•</caption>Hepatotoxicity <content styleCode="italics">[see <linkHtml href="#ID_2d77f7d3-944b-4aea-9e6d-1a83f173b9b3">Warnings and Precautions (5.2)</linkHtml>]</content>
</item>
<item>
<caption>•</caption>Gastrointestinal Perforation <content styleCode="italics">[see <linkHtml href="#ID_a5ee96b2-ff22-43fc-85bc-138eb31489c5">Warnings and Precautions (5.3)</linkHtml>]</content>
</item>
<item>
<caption>•</caption>Severe or Persistent Diarrhea <content styleCode="italics">[see <linkHtml href="#ID_c6e16281-54c6-47eb-bbce-fba14bf70e40">Warnings and Precautions (5.4)</linkHtml>]</content>
</item>
<item>
<caption>•</caption>Ocular Disorders including Keratitis <content styleCode="italics">[see <linkHtml href="#ID_b08651dd-f6b1-4fdd-993c-c251d00ce1ff">Warnings and Precautions (5.5)</linkHtml>]</content>
</item>
<item>
<caption>•</caption>Bullous and Exfoliative Skin Disorders <content styleCode="italics">[see <linkHtml href="#ID_580caeb9-b38c-48a0-a048-92af625dad0b">Warning and Precautions (5.6)</linkHtml>]</content>
</item>
</list>
</text>
<effectiveTime value="20230228"/>
<excerpt>
<highlight>
<text>
<paragraph>The most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patients and greater than placebo were skin reactions and diarrhea. <linkHtml href="#ID_42b19f70-286e-4556-9e7d-5c35885add75">(6.1)</linkHtml>
</paragraph>
<paragraph>
<content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or </content>
<linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml>
</paragraph>
</text>
</highlight>
</excerpt>
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<section ID="ID_42b19f70-286e-4556-9e7d-5c35885add75">
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<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 safety of IRESSA is based on the data from 2462 patients with NSCLC who received IRESSA 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies.</paragraph>
<paragraph>Controlled Studies:</paragraph>
<paragraph>Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received IRESSA 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with IRESSA was 5.9 months. The study population characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%).</paragraph>
<paragraph>Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received IRESSA 250 mg daily and 562 patients received placebo. The median duration of treatment with IRESSA was 2.9 months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%).</paragraph>
<paragraph>Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received IRESSA 250 mg daily and 715 patients received docetaxel. The median duration of treatment with IRESSA was 2.4 months. The study population characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more prior therapies (16%).</paragraph>
<paragraph>The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in IRESSA-treated patients were skin reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in IRESSA-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). </paragraph>
<paragraph>Approximately 5% of IRESSA-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with IRESSA were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%).</paragraph>
<table ID="_RefID0EZHAE" width="100%">
<caption>Table 1 - Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥5% and an Increase of >2% of IRESSA-treated Patients in Study 3</caption>
<col width="33%"/>
<col width="15%"/>
<col width="19%"/>
<col width="15%"/>
<col width="19%"/>
<tbody>
<tr>
<td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Adverse Reaction</content>
</paragraph>
</td>
<td align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Percentage (%) of patients</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">IRESSA (N=1126)</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Placebo (N=562)</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 and 4</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 and 4</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin and subcutaneous tissue disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Skin reactions<footnote ID="_Ref523749595">Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>47%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>2%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>17%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.4%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nail disorders<footnote ID="_Ref413761388">Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>5%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<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="_Ref413761407">Includes Diarrhea, Feces soft, Frequent bowel movements</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>29%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>3%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>10%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Vomiting</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>14%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1.2%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>10%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.4%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Stomatitis<footnote ID="_Ref413761481">Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.3%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>4%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.2%</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 Botrule " valign="middle">
<paragraph>17%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>2.3%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>14%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>2.0%</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Eye disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Conjunctivitis/blepharitis/dry eye<footnote ID="_Ref413761540">Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>6%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>0%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>3.2%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>0%</paragraph>
</td>
</tr>
</tbody>
</table>
<table width="100%">
<caption>Table 2 - Treatment Emergent Laboratory Abnormalities Occurring More Frequently in IRESSA-Treated Patients in Study 3</caption>
<col width="39%"/>
<col width="14%"/>
<col width="17%"/>
<col width="14%"/>
<col width="17%"/>
<tbody>
<tr>
<td rowspan="2" 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">IRESSA</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 and 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold">%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade 3 and 4</content>
</paragraph>
<paragraph>
<content styleCode="bold">%</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Alanine aminotransferase increased<footnote ID="_Ref523749700">Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>38%<footnote ID="_Ref523749808">14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.4%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>23%<footnoteRef IDREF="_Ref523749808"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.4%<footnote ID="_Ref523749830">0.2% of placebo patients were CTC grade 3 at baseline</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Aspartate aminotransferase increased<footnoteRef IDREF="_Ref523749700"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>40%<footnote ID="_Ref523749839">15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.0%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>25%<footnoteRef IDREF="_Ref523749839"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.3%<footnote ID="_Ref523749860">0.4% of placebo patients were CTC grade 3 at baseline</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Proteinuria</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>35%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>4.7%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>31%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>3.3%</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>The following adverse reactions have been reported with IRESSA across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%), asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), elevations in blood creatinine (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%).</paragraph>
</text>
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<title>6.2 Postmarketing Experience </title>
<text>
<paragraph>The following adverse reactions have been identified during post-approval use of IRESSA. 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>
<paragraph>
<content styleCode="italics">Renal and urinary disorders</content>: cystitis, hemorrhagic cystitis</paragraph>
<paragraph>
<content styleCode="italics">Skin and subcutaneous tissue disorders</content>: cutaneous vasculitis</paragraph>
</text>
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