TAGRISSO® (osimertinib) Prescribing Information

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TAGRISSO® (osimertinib)

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Full Prescribing Information: Contents*

Table Of Contents

SPL product data elements section
RECENT MAJOR CHANGES SECTION
RECENT MAJOR CHANGES SECTION
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
13 NONCLINICAL TOXICOLOGY
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
SPL PATIENT PACKAGE INSERT SECTION
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 40 mg
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 80 mg

SPL product data elements section

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codeSystem="2.16.840.1.113883.4.9"/> <name>FERRIC OXIDE RED</name> </ingredientSubstance> </ingredient> <ingredient classCode="IACT"> <ingredientSubstance> <code code="XM0M87F357" codeSystem="2.16.840.1.113883.4.9"/> <name>FERROSOFERRIC OXIDE</name> </ingredientSubstance> </ingredient> <ingredient classCode="IACT"> <ingredientSubstance> <code code="2165RE0K14" codeSystem="2.16.840.1.113883.4.9"/> <name>LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED</name> </ingredientSubstance> </ingredient> <asContent> <quantity> <numerator unit="1" value="30"/> <denominator value="1"/> </quantity> <containerPackagedProduct> <code code="0310-1350-30" codeSystem="2.16.840.1.113883.6.69"/> <formCode code="C43169" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="BOTTLE"/> </containerPackagedProduct> <subjectOf> <marketingAct> <code code="C53292" codeSystem="2.16.840.1.113883.3.26.1.1"/> <statusCode code="active"/> <effectiveTime> <low value="20151113"/> </effectiveTime> </marketingAct> 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RECENT MAJOR CHANGES SECTION

1 INDICATIONS AND USAGE

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_08dfbe8f-6f0a-4376-a21a-8476d2117723"> <id root="0c1fdd48-eaa1-45aa-9b4b-2e9566de290a"/> <code code="34067-9" codeSystem="2.16.840.1.113883.6.1" displayName="INDICATIONS & USAGE SECTION"/> <title>1 INDICATIONS AND USAGE </title> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <paragraph>TAGRISSO is a kinase inhibitor indicated for </paragraph> <list listType="unordered"> <item> <caption>•</caption>the first-line treatment of patients with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. (<linkHtml href="#ID_6f28ae64-9336-49c8-a792-caa6b256e420">1.1</linkHtml>, <linkHtml href="#ID_eec388bb-9c3f-4d7b-a29a-189e2bdf7d74">2.1</linkHtml>) </item> <item> <caption>•</caption>the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. (<linkHtml href="#ID_6d77f13e-3887-407c-b7b8-bd257fa64fda">1.2</linkHtml>, <linkHtml href="#ID_eec388bb-9c3f-4d7b-a29a-189e2bdf7d74">2.1</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_6f28ae64-9336-49c8-a792-caa6b256e420"> <id root="015412ef-6bfe-4b05-a06f-2205748de94d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.1 First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) </title> <text> <paragraph>TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test <content styleCode="italics">[see <linkHtml href="#ID_eec388bb-9c3f-4d7b-a29a-189e2bdf7d74">Dosage and Administration (2.1)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_6d77f13e-3887-407c-b7b8-bd257fa64fda"> <id root="c435b58d-9b2b-45ca-ac7c-25b6c23c56ec"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.2 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC </title> <text> <paragraph>TAGRISSO is indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy <content styleCode="italics">[see <linkHtml href="#ID_eec388bb-9c3f-4d7b-a29a-189e2bdf7d74">Dosage and Administration (2.1)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> </section>

2 DOSAGE AND ADMINISTRATION

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_379a5b9a-f84c-41f7-a94e-264789e70e5c"> <id root="91802389-a2ca-44a9-9c65-c1657d94b230"/> <code code="34068-7" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE & ADMINISTRATION SECTION"/> <title>2 DOSAGE AND ADMINISTRATION </title> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <paragraph>Recommended dosage: 80 mg orally once daily, with or without food. (<linkHtml href="#ID_fbefb3f9-2f73-49d4-b687-930cf4defcfd">2.2</linkHtml>)</paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_eec388bb-9c3f-4d7b-a29a-189e2bdf7d74"> <id root="27b59aed-33eb-401c-a3a5-e972db922b88"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2<content styleCode="xmChange">.</content>1 Patient Selection </title> <text> <paragraph>Select patients for the first-line treatment of metastatic EGFR-positive NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens <content styleCode="italics">[see <linkHtml href="#ID_f0b651d2-9f8d-410c-8974-732f8c284501">Clinical Studies (14)</linkHtml>]</content>. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible.</paragraph> <paragraph>Select patients for the treatment of metastatic EGFR T790M mutation-positive NSCLC with TAGRISSO following progression on or after EGFR TKI therapy based on the presence of an EGFR T790M mutation in tumor or plasma specimens <content styleCode="italics">[see <linkHtml href="#ID_f0b651d2-9f8d-410c-8974-732f8c284501">Clinical Studies (14)</linkHtml>]</content>. Testing for the presence of the T790M mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing.</paragraph> <paragraph>Information on FDA-approved tests for the detection of EGFR mutations is available at <linkHtml href="http://www.fda.gov/companiondiagnostics">http://www.fda.gov/companiondiagnostics</linkHtml>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_fbefb3f9-2f73-49d4-b687-930cf4defcfd"> <id root="e4c5973a-ff13-4805-a542-555347cf3136"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.2 Recommended Dosage Regimen </title> <text> <paragraph>The recommended dosage of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food.</paragraph> <paragraph>If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_2c7a21bf-bc06-44f7-b03b-6038e0e5a5bd"> <id root="36076978-3a82-4017-9bc3-7a2dd1a12d44"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.3 Administration to Patients Who Have Difficulty Swallowing Solids </title> <text> <paragraph>Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink.</paragraph> <paragraph>If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL).</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_46ab4337-434d-4819-837a-bd4df3b7a158"> <id root="2010fb50-ac79-4b49-baac-1dd7becea723"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.4 Dosage Modifications</title> <text> <paragraph> <content styleCode="underline">Adverse Reactions</content> </paragraph> <table width="100%"> <caption>Table 1. Recommended Dosage Modifications for TAGRISSO</caption> <col width="21%"/> <col width="28%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Target Organ</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Adverse Reaction</content> <footnote ID="_Ref25565655">Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).</footnote> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Dosage Modification</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Pulmonary [see <linkHtml href="#ID_f8532931-a9c4-45e1-8f6a-fc84a6160fb0">Warnings and Precautions (5.1)</linkHtml>]</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Interstitial lung disease (ILD)/Pneumonitis</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue TAGRISSO.</paragraph> </td> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Cardiac [see <linkHtml href="#ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0">Warnings and Precautions (5.2,</linkHtml> <linkHtml href="#ID_bded0629-2e69-46ec-903e-ca5e006409cb">5.3)</linkHtml>]</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>QTc<footnote ID="_Ref495313813">QTc = QT interval corrected for heart rate</footnote> interval greater than 500 msec on at least 2 separate ECGs<footnote ID="_Ref523912837">ECGs = Electrocardiogram</footnote> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>QTc interval prolongation with signs/symptoms of life-threatening arrhythmia</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue TAGRISSO.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Symptomatic congestive heart failure </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue TAGRISSO.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Cutaneous [see <linkHtml href="#ID_70573be5-c8b5-436a-a2d0-5948ef0d9e1c">Warnings and Precautions (5.5)</linkHtml>]</content> </content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="xmChange">Stevens-Johnson syndrome (SJS), Erythema Multiforme Major (EMM)</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="xmChange">Withhold TAGRISSO if suspected and permanently discontinue if confirmed.</content> </paragraph> </td> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Other [see <linkHtml href="#ID_a354128b-bf7f-4cb2-84a9-42b37bf92499">Adverse Reactions (6.1)</linkHtml>] </content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Adverse reaction of Grade 3 or greater severity</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold TAGRISSO for up to 3 weeks.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>If improvement to Grade 0-2 within 3 weeks</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Resume at 80 mg or 40 mg daily.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>If no improvement within 3 weeks</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Permanently discontinue TAGRISSO. </paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Drug Interactions</content> </paragraph> <paragraph> <content styleCode="italics">Strong CYP3A4 Inducers</content> <br/>If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer <content styleCode="italics">[see <linkHtml href="#ID_bd60f5a0-b83b-4343-99a6-0008f3171345">Drug Interactions (7)</linkHtml> and <linkHtml href="#ID_d962298c-f4c0-44b0-950d-762e8ff7141c">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> </section>

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_dda1cd8b-ad70-41f5-a1eb-0c75e416540c"> <id root="86ea42db-9a35-4f0b-97f2-8ea621cc5787"/> <code code="43685-7" codeSystem="2.16.840.1.113883.6.1" displayName="WARNINGS AND PRECAUTIONS SECTION"/> <title>5 WARNINGS AND PRECAUTIONS </title> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">Interstitial Lung Disease (ILD)/Pneumonitis</content>: Occurred in 3.9% of patients. Permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. (<linkHtml href="#_RefID_f8532931-a9c4-45e1-8f6a-fc84a6160">5.1</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">QTc Interval Prolongation</content>: Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold then restart at a reduced dose or permanently discontinue TAGRISSO. (<linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">2.4</linkHtml>, <linkHtml href="#ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0">5.2</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Cardiomyopathy</content>: Occurred in 2.6% of patients. Conduct cardiac monitoring, including left ventricular ejection fraction (LVEF) assessment in patients with cardiac risk factors. (<linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">2.4</linkHtml>, <linkHtml href="#ID_bded0629-2e69-46ec-903e-ca5e006409cb">5.3</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Keratitis</content>: Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist for evaluation. (<linkHtml href="#ID_fdc18710-41a6-4f57-bfa0-5e703721587f">5.4</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Erythema Multiforme and Stevens-Johnson Syndrome:</content> Withhold TAGRISSO if erythema multiforme major (EMM) or Stevens-Johnson syndrome (SJS) is suspected and permanently discontinue if confirmed. (<linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">2.4</linkHtml>, <linkHtml href="#ID_70573be5-c8b5-436a-a2d0-5948ef0d9e1c">5.5</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Embryo-Fetal Toxicity</content>: TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after final dose. Advise males to use effective contraception for 4 months, after the last dose of TAGRISSO. (<linkHtml href="#ID_fdc18710-41a6-4f57-bfa0-5e703721587f">5.6</linkHtml>, <linkHtml href="#_Ref">8.1</linkHtml>, <linkHtml href="#_RefID_34a54bb9-dadb-4461-b46a-5f5fbd428">8.3</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_f8532931-a9c4-45e1-8f6a-fc84a6160fb0"> <id root="9a6282a6-92ad-4d81-9a7a-12327a482104"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.1 Interstitial Lung Disease/Pneumonitis </title> <text> <paragraph>Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal.</paragraph> <paragraph>Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [<content styleCode="italics">see <linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">Dosage and Administration (2.4)</linkHtml> and <linkHtml href="#ID_ea817ba8-6404-4fb3-8163-8ff9653610b5">Adverse Reactions (6)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0"> <id root="f66f5023-fbed-452c-a181-45ae4694ca83"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.2 QTc Interval Prolongation </title> <text> <paragraph>Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec <content styleCode="italics">[see <linkHtml href="#ID_56a556f7-09e3-4a2a-930c-4e61e0ea4b2e">Clinical Pharmacology (12.2)</linkHtml>].</content> No QTc-related arrhythmias were reported.</paragraph> <paragraph>Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia <content styleCode="italics">[see <linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">Dosage and Administration (2.4)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_bded0629-2e69-46ec-903e-ca5e006409cb"> <id root="0fa4cf62-5570-4cc2-94c7-9852d485f8f5"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.3 Cardiomyopathy </title> <text> <paragraph>Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. </paragraph> <paragraph>A decline in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and to less than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. </paragraph> <paragraph>Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO <content styleCode="italics">[see <linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">Dosage and Administration (2.4)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_1f3e51e7-d489-4829-953c-74b52b510553"> <id root="19d448dd-e92c-4aaf-9ca9-7bf2cb759caf"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.4 Keratitis </title> <text> <paragraph>Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_70573be5-c8b5-436a-a2d0-5948ef0d9e1c"> <id root="681b732d-91aa-492b-8de2-405960f8f3c4"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title> <content styleCode="xmChange">5.5 Erythema Multiforme and Stevens-Johnson Syndrome</content> </title> <text> <paragraph> <content styleCode="xmChange">Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed</content>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_fdc18710-41a6-4f57-bfa0-5e703721587f"> <id root="3d8fa850-4c89-475a-ad27-ae15330799f2"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.6 Embryo-Fetal Toxicity </title> <text> <paragraph>Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose <content styleCode="italics">[see <linkHtml href="#ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde">Use in Specific Populations (8.1</linkHtml>, <linkHtml href="#ID_77cff57c-de1e-4ce5-8fec-cb821f6e4de3">8.3</linkHtml>)].</content> </paragraph> </text> <effectiveTime value="20200605"/> </section> </component> </section>

6 ADVERSE REACTIONS

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_ea817ba8-6404-4fb3-8163-8ff9653610b5"> <id root="915c870d-28ac-4187-9f9a-6396b1fea4d8"/> <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> <paragraph>Interstitial Lung Disease/Pneumonitis <content styleCode="italics">[see <linkHtml href="#_RefID_f8532931-a9c4-45e1-8f6a-fc84a6160">Warnings and Precautions (5.1)</linkHtml>]</content> </paragraph> <paragraph>QTc Interval Prolongation <content styleCode="italics">[see <linkHtml href="#ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0">Warnings and Precautions (5.2)</linkHtml>]</content> </paragraph> <paragraph>Cardiomyopathy <content styleCode="italics">[see <linkHtml href="#ID_bded0629-2e69-46ec-903e-ca5e006409cb">Warnings and Precautions (5.3)</linkHtml>]</content> </paragraph> <paragraph>Keratitis<content styleCode="italics"> [see <linkHtml href="#ID_1f3e51e7-d489-4829-953c-74b52b510553">Warnings and Precautions (5.4)</linkHtml>]</content> </paragraph> <paragraph>Erythema multiforme and Stevens-Johnson syndrome <content styleCode="italics">[see <linkHtml href="#_5.5_Erythema_Multiforme">Warnings and Precautions (5.5)</linkHtml>]</content> </paragraph> </text> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <paragraph>Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite. (<linkHtml href="#ID_a354128b-bf7f-4cb2-84a9-42b37bf92499">6.1</linkHtml>)</paragraph> <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 </content> <content styleCode="bold"> <linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml> </content> </paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_a354128b-bf7f-4cb2-84a9-42b37bf92499"> <id root="4d2f50cb-2825-40a6-9e6b-91def4dd8cb1"/> <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 1142 patients with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg once daily in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) <content styleCode="italics">[see <linkHtml href="#ID_dda1cd8b-ad70-41f5-a1eb-0c75e416540c">Warnings and Precautions (5)</linkHtml>].</content> </paragraph> <paragraph>The data described below reflect exposure to TAGRISSO (80 mg daily) in 558 patients with EGFR mutation-positive, metastatic NSCLC in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)]. 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">Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer </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>The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), and decreased appetite (20%). 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 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA. FLAURA was not designed to demonstrate a statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3. </paragraph> <table width="100%"> <caption>Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA<footnote ID="_Ref25566282">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="_Ref25566335">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</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>0.7</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>0.4</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="_Ref523916459">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.</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>6.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dry skin<footnote ID="_Ref523916468">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="_Ref523916476">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="_Ref523916486">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">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="_Ref523916499">The frequency of "Prolonged QT Interval" represents reported adverse events in the FLAURA study. Frequencies of QTc intervals of >500 ms or >60 ms are presented in Section 5.2.</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">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fatigue<footnote ID="_Ref523916511">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">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> <table width="100%"> <caption>Table 3. Laboratory Abnormalities Worsening from Baseline in ≥ 20% of Patients in FLAURA</caption> <col width="27%"/> <col width="18%"/> <col width="18%"/> <col width="19%"/> <col width="19%"/> <tbody> <tr> <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="_Ref523916624">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">Change from Baseline</content> </paragraph> <paragraph> <content styleCode="bold">All Grades (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Change from Baseline to</content> </paragraph> <paragraph> <content styleCode="bold">Grade 3 or Grade 4 (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Change from Baseline</content> </paragraph> <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">Change from Baseline to 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>5.6</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>3.0</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 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="_Ref523916596">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> <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> <content styleCode="underline">Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer </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>The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%). 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 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 4 and 5. </paragraph> <table width="100%"> <caption>Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3<footnote ID="_Ref25566854">NCI CTCAE v4.0.</footnote> </caption> <col width="49%"/> <col width="13%"/> <col width="0%"/> <col width="13%"/> <col width="12%"/> <col width="13%"/> <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="3" 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" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="bold">All Grades</content> <footnote ID="_Ref25566896">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="_Ref25566896"/> </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="_Ref25566896"/> </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="_Ref25566896"/> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="6" 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" colspan="2" 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" colspan="2" 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</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" colspan="2" 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" colspan="2" 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" colspan="2" 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="6" 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="_Ref523916743">Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneiform dermatitis.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5.9</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="_Ref523916755">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" colspan="2" 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="_Ref523916764">Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" colspan="2" 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="_Ref524009291">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" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="6" 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" colspan="2" 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="6" 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" colspan="2" 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="6" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Back pain</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</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>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.7</paragraph> </td> </tr> <tr> <td colspan="6" 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 Botrule Lrule Toprule " valign="top"> <paragraph>Fatigue<footnote ID="_Ref523916785">Includes fatigue, asthenia.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1.8</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>5.1</paragraph> </td> </tr> </tbody> </table> <table width="100%"> <caption>Table 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3</caption> <col width="37%"/> <col width="17%"/> <col width="15%"/> <col width="2%"/> <col width="15%"/> <col width="15%"/> <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="_Ref523916888">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="3" 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">Change from Baseline 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">Change from Baseline to Grade 3 or Grade 4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Change from Baseline</content> </paragraph> <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">Change from Baseline to Grade 3 or Grade 4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="6" 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" colspan="2" 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" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8.2</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>9.9</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" colspan="2" 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>7.4</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" colspan="2" 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="6" 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="_Ref523916888"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9.2</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="_Ref523916888"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" colspan="2" 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="_Ref523916915">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" colspan="2" 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="_Ref523916888"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9.0</paragraph> </td> <td align="center" colspan="2" 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="6" styleCode="Toprule " valign="top"> <paragraph>NA=not applicable</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_8ec8a3be-4951-4386-bbf1-2c34a14090d3"> <id root="1155d2d7-83c9-4ca3-8d7b-d045e46db0fb"/> <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> <paragraph> <content styleCode="italics">Cutaneous:</content> Stevens-Johnson syndrome, erythema multiforme</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> </section>

7 DRUG INTERACTIONS

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_bd60f5a0-b83b-4343-99a6-0008f3171345"> <id root="e6904f77-8c7f-4e6a-b080-d90966928f0b"/> <code code="34073-7" codeSystem="2.16.840.1.113883.6.1" displayName="DRUG INTERACTIONS SECTION"/> <title>7 DRUG INTERACTIONS </title> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <paragraph> <content styleCode="underline">Strong CYP3A Inducers</content>: Avoid if possible. If not possible, increase TAGRISSO to 160 mg daily in patients receiving a strong CYP3A4 inducer. (<linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">2.4</linkHtml>, <linkHtml href="#ID_e894fd25-c75c-4daa-bf59-f7ab238b0715">7.1</linkHtml>)</paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_e894fd25-c75c-4daa-bf59-f7ab238b0715"> <id root="67aa3265-bff1-487f-a7e6-e2d7815f34b0"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.1 Effect of Other Drugs on Osimertinib </title> <text> <paragraph> <content styleCode="underline">Strong CYP3A Inducers</content> </paragraph> <paragraph>Co-administering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone<content styleCode="italics"> [see <linkHtml href="#ID_bb4cbb63-0088-47e3-9581-3d5cba79ce03">Clinical Pharmacology (12.3)</linkHtml>]</content>. Decreased osimertinib exposure may lead to reduced efficacy. </paragraph> <paragraph>Avoid co-administering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when co-administering with a strong CYP3A4 inducer if concurrent use is unavoidable <content styleCode="italics">[see <linkHtml href="#ID_46ab4337-434d-4819-837a-bd4df3b7a158">Dosage and Administration (2.4)</linkHtml>]</content>. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_1537ee8d-c1a9-4a34-9339-7769e9cb1be2"> <id root="0fb1b06b-a7ce-40cb-84c9-f83c43b59ccc"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.2 Effect of Osimertinib on Other Drugs </title> <text> <paragraph>Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone <content styleCode="italics">[see <linkHtml href="#_12.3_Pharmacokinetics_1">Clinical Pharmacology (12.3)</linkHtml>]</content>. Increased BCRP or P-gp substrate exposure may increase the risk of exposure-related toxicity.</paragraph> <paragraph>Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_f0a00ab5-dba7-4a08-9447-e41f8afa29cd"> <id root="71ef6593-57c0-4ea2-b5b8-5684edb0b46d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.3 Drugs That Prolong the QTc Interval </title> <text> <paragraph>The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring <content styleCode="italics">[see <linkHtml href="#ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0">Warnings and Precautions (5.2)</linkHtml> and <linkHtml href="#ID_d962298c-f4c0-44b0-950d-762e8ff7141c">Clinical Pharmacology (12.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20180418"/> </section> </component> </section>

8 USE IN SPECIFIC POPULATIONS

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_0e71e254-94d9-4767-a291-540eaf822627"> <id root="217b9fba-babf-466a-9b58-ba92656c293f"/> <code code="43684-0" codeSystem="2.16.840.1.113883.6.1" displayName="USE IN SPECIFIC POPULATIONS SECTION"/> <title>8 USE IN SPECIFIC POPULATIONS </title> <effectiveTime value="20200605"/> <excerpt> <highlight> <text> <paragraph>Lactation: Do not breastfeed. (<linkHtml href="#_RefID_8aba6876-0e9e-439f-a3c3-7594f53d0">8.2</linkHtml>)</paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde"> <id root="1879e16d-5c46-4cfa-8632-4e921332a2aa"/> <code code="42228-7" codeSystem="2.16.840.1.113883.6.1" displayName="PREGNANCY SECTION"/> <title>8.1 Pregnancy </title> <text> <paragraph> <content styleCode="italics">Risk Summary</content> </paragraph> <paragraph>Based on data from animal studies and its mechanism of action <content styleCode="italics">[see <linkHtml href="#ID_56a556f7-09e3-4a2a-930c-4e61e0ea4b2e">Clinical Pharmacology (12.1)</linkHtml>]</content>, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose <content styleCode="italics">(see <linkHtml href="#_Data">Data</linkHtml>)</content>. Advise pregnant women of the potential risk to a fetus.</paragraph> <paragraph>In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. </paragraph> <paragraph> <content styleCode="italics">Data</content> </paragraph> <paragraph> <content styleCode="underline">Animal Data</content> </paragraph> <paragraph>When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_1b6864c8-f66c-49d6-a142-c763fedf8029"> <id root="a976588c-a226-4405-8159-35e4289934e6"/> <code code="77290-5" codeSystem="2.16.840.1.113883.6.1" displayName="LACTATION SECTION"/> <title>8.2 Lactation </title> <text> <paragraph> <content styleCode="underline">Risk Summary</content> </paragraph> <paragraph>There are no data on the presence of osimertinib or its active metabolites in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death <content styleCode="italics">[see <linkHtml href="#ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde">Use in Specific Populations (8.1)</linkHtml>]</content>. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_77cff57c-de1e-4ce5-8fec-cb821f6e4de3"> <id root="5eb7f9c1-f12d-472c-8695-231a4e7c16e3"/> <code code="77291-3" codeSystem="2.16.840.1.113883.6.1" displayName="FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION"/> <title>8.3 Females and Males of Reproductive Potential </title> <text> <paragraph> <content styleCode="underline">Pregnancy Testing</content> </paragraph> <paragraph>Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO.</paragraph> <paragraph> <content styleCode="underline">Contraception</content> </paragraph> <paragraph>TAGRISSO can cause fetal harm when administered to pregnant women <content styleCode="italics">[see <linkHtml href="#ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde">Use in Specific Populations (8.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="italics">Females</content> </paragraph> <paragraph>Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose <content styleCode="italics">[see <linkHtml href="#ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde">Use in Specific Populations (8.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="italics">Males</content> </paragraph> <paragraph>Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO <content styleCode="italics">[see <linkHtml href="#ID_54f37050-bdb5-465d-8750-ae06aa70e57c">Nonclinical Toxicology (13.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Infertility</content> </paragraph> <paragraph>Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible <content styleCode="italics">[see <linkHtml href="#ID_54f37050-bdb5-465d-8750-ae06aa70e57c">Nonclinical Toxicology (13.1)</linkHtml> <content styleCode="underline">]</content> </content> <content styleCode="underline">.</content> </paragraph> </text> <effectiveTime value="20200605"/> </section> </component> <component> <section ID="ID_895ea5e5-4dfb-40cf-84ba-551bcbffd314"> <id root="f9781cef-03d5-4b41-bac5-a052310c5ca1"/> <code code="34081-0" codeSystem="2.16.840.1.113883.6.1" displayName="PEDIATRIC USE SECTION"/> <title>8.4 Pediatric Use </title> <text> <paragraph>The safety and effectiveness of TAGRISSO in pediatric patients have not been established.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_93903694-b685-46ac-b801-ea31b6d9da09"> <id root="b2559e6f-75f9-48a9-bcdb-243e2ac46c3d"/> <code code="34082-8" codeSystem="2.16.840.1.113883.6.1" displayName="GERIATRIC USE SECTION"/> <title>8.5 Geriatric Use </title> <text> <paragraph>Forty-three percent (43%) of the 1142 patients in FLAURA (n=279), AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent dose modifications for adverse reactions (13.4% versus 7.6%) in patients 65 years or older as compared to those younger than 65 years.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_57520df2-4c4e-49a1-bb43-6b9d8619efd4"> <id root="4de34187-8009-4db6-9615-790ed7f1be4a"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.6 Renal Impairment </title> <text> <paragraph>No dose adjustment is recommended in patients with creatinine clearance (CLcr) 15 - 89 mL/min, as estimated by Cockcroft-Gault. There is no recommended dose of TAGRISSO for patients with end-stage renal disease (CLcr < 15 mL/min)<content styleCode="italics"> [see <linkHtml href="#_12.3_Pharmacokinetics_1">Clinical Pharmacology (12.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_ededbd31-6f59-483c-a475-75520a5b5589"> <id root="af750011-6dea-48a1-a770-4e84c497e8de"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.7 Hepatic Impairment </title> <text> <paragraph>No dose adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A and B or total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment (total bilirubin between 3 to 10 times ULN and any AST) <content styleCode="italics">[see <linkHtml href="#ID_d962298c-f4c0-44b0-950d-762e8ff7141c">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> </section>

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_48ed08d4-e5d8-4a78-88be-a9b8c582ea67"> <id root="ba0433d8-5f0a-422a-b081-bcba99511a26"/> <code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/> <title>12 CLINICAL PHARMACOLOGY </title> <effectiveTime value="20200605"/> <component> <section ID="ID_56a556f7-09e3-4a2a-930c-4e61e0ea4b2e"> <id root="51cbc379-2da3-437f-92ad-97b174a326eb"/> <code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/> <title>12.1 Mechanism of Action </title> <text> <paragraph>Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9-fold lower concentrations than wild-type. Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating at approximately 10% of the parent) with similar inhibitory profiles to osimertinib have been identified in the plasma after oral administration of osimertinib. AZ7550 showed a similar potency to osimertinib, while AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8-fold) and wild-type (approximately 15-fold) EGFR. <content styleCode="italics">In vitro</content>, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.</paragraph> <paragraph>In cultured cells and animal tumor implantation models, osimertinib exhibited anti-tumor activity against NSCLC lines harboring EGFR-mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-type EGFR amplifications. Osimertinib distributed to the brain in multiple animal species (monkey, rat, and mouse) with brain to plasma AUC ratios of approximately 2 following oral dosing. These data are consistent with observations of tumor regression and increased survival in osimertinib- versus control-treated animals in a pre-clinical mutant-EGFR intracranial mouse metastasis xenograft model (PC9; exon 19 deletion).</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_bb4cbb63-0088-47e3-9581-3d5cba79ce03"> <id root="59c12493-7533-4b2c-bad9-cfad341fed1a"/> <code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/> <title>12.2 Pharmacodynamics </title> <text> <paragraph>Based on an analysis of dose-exposure response relationships over the dose range of 20 mg (0.25 times the recommended dose) to 240 mg (3 times the recommended dose), no apparent relationship between osimertinib exposure and overall response rate, duration of response and progression-free survival was identified; however, there were limited data available at the 20 mg dose. Over the same dose range, increased exposure led to increased probability of adverse reactions, specifically rash, diarrhea and ILD.</paragraph> <paragraph> <content styleCode="underline">Cardiac Electrophysiology</content> </paragraph> <paragraph>The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily in AURA2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec). A pharmacokinetic/pharmacodynamic analysis in AURA2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of TAGRISSO 80 mg.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> <component> <section ID="ID_d962298c-f4c0-44b0-950d-762e8ff7141c"> <id root="1778f425-3cb0-4e9c-9f28-9c02f125471a"/> <code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/> <title>12.3 Pharmacokinetics </title> <text> <paragraph>The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (C<sub>max</sub>) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of TAGRISSO orally once daily resulted in approximately 3-fold accumulation with steady-state exposures achieved after 15 days of dosing. At steady state, the C<sub>max </sub>to C<sub>min</sub> (minimal concentration) ratio was 1.6-fold.</paragraph> <paragraph> <content styleCode="underline">Absorption</content> </paragraph> <paragraph>The median time to C<sub>max</sub> of osimertinib was 6 hours (range 3-24 hours).</paragraph> <paragraph>Following administration of a 20 mg TAGRISSO tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the C<sub>max</sub> and AUC of osimertinib were comparable to that under fasting conditions.</paragraph> <paragraph> <content styleCode="underline">Distribution</content> </paragraph> <paragraph>The mean volume of distribution at steady-state (V<sub>ss</sub>/F) of osimertinib was 918 L. Plasma protein binding of osimertinib was 95%.</paragraph> <paragraph> <content styleCode="underline">Elimination</content> </paragraph> <paragraph>Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.3 (L/h).</paragraph> <paragraph> <content styleCode="italics">Metabolism</content> </paragraph> <paragraph>The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation <content styleCode="italics">in vitro</content>. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after TAGRISSO oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state.</paragraph> <paragraph> <content styleCode="italics">Excretion</content> </paragraph> <paragraph>Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination.</paragraph> <paragraph> <content styleCode="underline">Specific Populations</content> </paragraph> <paragraph>No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, baseline albumin, line of therapy, smoking status, renal function (creatinine clearance (CLcr) ≥15 mL/min by Cockcroft-Gault), or hepatic impairment (Child-Pugh A and B, or total bilirubin ≤ ULN and AST > ULN or total bilirubin between 1 to 3 times ULN and any AST). The pharmacokinetics of osimertinib in patients with end-stage renal disease (CLcr < 15 mL/min) or severe hepatic impairment (total bilirubin 3 to 10 times ULN and any AST) are unknown <content styleCode="italics">[see <linkHtml href="#_8.6_Renal_Impairment">Use in Specific Populations (8.6)</linkHtml> and <linkHtml href="#_8.7_Hepatic_Impairment">(8.7)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Drug Interaction Studies</content> </paragraph> <paragraph> <content styleCode="italics">Effect of Other Drugs on TAGRISSO in Clinical Pharmacokinetic Studies Strong CYP3A Inducers:</content> The steady-state AUC of osimertinib was reduced by 78% in patients when co-administered with rifampin (600 mg daily for 21 days) <content styleCode="italics">[see <linkHtml href="#ID_e894fd25-c75c-4daa-bf59-f7ab238b0715">Drug Interactions (7.1)</linkHtml>].</content> </paragraph> <paragraph> <content styleCode="italics">Strong CYP3A Inhibitors:</content> Co-administering TAGRISSO with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and C<sub>max</sub> decreased by 20%).</paragraph> <paragraph> <content styleCode="italics">Gastric Acid Reducing Agents:</content> The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.</paragraph> <paragraph> <content styleCode="italics">Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic Studies</content> </paragraph> <paragraph> <content styleCode="italics">BCRP substrates:</content> Co-administering TAGRISSO with rosuvastatin (a BCRP substrate) increased rosuvastatin AUC by 35% and C<sub>max</sub> by 72% <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#ID_1537ee8d-c1a9-4a34-9339-7769e9cb1be2">Drug Interactions (7.2)</linkHtml> </content> <content styleCode="italics">]</content>.</paragraph> <paragraph> <content styleCode="italics">P-gp substrates</content>: Co-administering TAGRISSO with fexofenadine (a P-gp substrate) increased fexofenadine AUC and C<sub>max</sub> by 56% and 76% after a single dose and 27% and 25% at steady state, respectively.</paragraph> <paragraph> <content styleCode="italics">CYP3A4 substrates:</content> Co-administering TAGRISSO with simvastatin (a CYP3A4 substrate) had no clinically significant effect on the exposure of simvastatin. </paragraph> <paragraph> <content styleCode="italics">In Vitro Studies</content> </paragraph> <paragraph> <content styleCode="italics">CYP450 Metabolic Pathways:</content> Osimertinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1. Osimertinib induced CYP1A2 enzymes.</paragraph> <paragraph> <content styleCode="italics">Transporter Systems:</content> Osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2.</paragraph> </text> <effectiveTime value="20200605"/> </section> </component> </section>

13 NONCLINICAL TOXICOLOGY

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_c2b111c0-c350-439e-a7ab-608339753712"> <id root="92c0bc28-4e17-4a81-9b73-1655a1be96ce"/> <code code="43680-8" codeSystem="2.16.840.1.113883.6.1" displayName="NONCLINICAL TOXICOLOGY SECTION"/> <title>13 NONCLINICAL TOXICOLOGY </title> <effectiveTime value="20180418"/> <component> <section ID="ID_54f37050-bdb5-465d-8750-ae06aa70e57c"> <id root="b0d16e00-631b-4c4f-9b10-bd65e89520f9"/> <code code="34083-6" codeSystem="2.16.840.1.113883.6.1" displayName="CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION"/> <title>13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility </title> <text> <paragraph>Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in <content styleCode="italics">in vitro</content> and <content styleCode="italics">in vivo</content> assays.</paragraph> <paragraph>Based on studies in animals, male fertility may be impaired by treatment with TAGRISSO. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5 times the AUC observed at the recommended clinical dose of 80 mg once daily, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males.</paragraph> <paragraph>Based on studies in animals, female fertility may be impaired by treatment with TAGRISSO. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3 times the AUC observed at the recommended clinical dose of 80 mg once daily. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility. In a female fertility study in rats, administration of osimertinib from 2 weeks prior to mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately 1.5 times the C<sub>max</sub> at the recommended dose of 80 mg once daily) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility when females were mated 1 month after treatment discontinuation.</paragraph> </text> <effectiveTime value="20180418"/> </section> </component> </section>

14 CLINICAL STUDIES

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_f0b651d2-9f8d-410c-8974-732f8c284501"> <id root="ba257d5d-5470-48fa-8f55-2b4b96f06487"/> <code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/> <title>14 CLINICAL STUDIES </title> <effectiveTime value="20200605"/> <component> <section ID="ID_9f9dcf50-a337-46fd-b911-f9a46f6b1cef"> <id root="7d67eec8-7838-40f5-a657-0e8477df4bac"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.1 Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer</title> <text> <paragraph>The efficacy of TAGRISSO was demonstrated in a randomized, multicenter, double-blind, active-controlled trial (FLAURA [NCT02296125]) in patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, metastatic NSCLC, who had not received previous systemic treatment for metastatic disease. Patients were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletion or exon 21 L858R mutation in tumor prospectively identified by the cobas® EGFR Mutation Test in a central laboratory or by an investigational assay at a CLIA-certified or accredited laboratory. Patients with CNS metastases not requiring steroids and with stable neurologic status for at least two weeks after completion of definitive surgery or radiotherapy were eligible. Patients were assessed at the investigator’s discretion for CNS metastases if they had a history of, or suspected, CNS metastases at study entry.</paragraph> <paragraph>Patients were randomized (1:1) to receive TAGRISSO 80 mg orally once daily or to receive gefitinib 250 mg orally once daily or erlotinib 150 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R mutation) and ethnicity (Asian or non-Asian). Patients randomized to the control arm were offered TAGRISSO at the time of disease progression if tumor samples tested positive for the EGFR T790M mutation. The major efficacy outcome measure was progression-free survival (PFS), as assessed by investigator. Additional efficacy outcome measures included overall survival (OS) and overall response rate (ORR).</paragraph> <paragraph>A total of 556 patients were randomized to TAGRISSO (n=279) or to control (gefitinib n=183; erlotinib n=94). The median age was 64 years (range 26-93 years); 54% were < 65 years of age; 63% were female; 62% were Asian and 64% were never smokers. Baseline WHO performance status was 0 (41%) or 1 (59%); 5% had Stage IIIb and 95% had Stage IV; and 7% received prior systemic cytotoxic chemotherapy as neoadjuvant or adjuvant therapy. With regard to EGFR tumor testing, 63% were exon 19 deletion and 37% were exon 21 L858R; 5 patients (<1%) also had a concomitant de novo T790M mutation. EGFR mutation status was confirmed centrally using the cobas EGFR Mutation Test in 90% of patients. At the time of the final data cut-off, of those randomized to TAGRISSO and to investigator’s choice erlotinib or gefitinib arm, 133 (47.7%) and 180 (65.0%) patients had received at least one subsequent treatment, respectively. Out of the 180 patients randomized to erlotinib or gefitinib who received subsequent treatment, 85 (47.2%) patients received TAGRISSO as first subsequent therapy.</paragraph> <paragraph>FLAURA demonstrated a statistically significant improvement in PFS for patients randomized to TAGRISSO as compared to erlotinib or gefitinib (see Table 6 and Figure 1). The final analysis of overall survival demonstrated a statistically significant improvement in overall survival in patients randomized to TAGRISSO compared to erlotinib or gefitinib. (see Table 6 and Figure 2). </paragraph> <table width="100%"> <caption>Table 6. Efficacy Results in FLAURA according to Investigator Assessment</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Efficacy Parameter</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">TAGRISSO</content> <br/> <content styleCode="bold">(N=279)</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">EGFR TKI</content> <br/> <content styleCode="bold">(gefitinib or erlotinib)</content> <br/> <content styleCode="bold">(N=277)</content> </th> </tr> </thead> <tbody> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Progression-Free Survival (PFS)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>PFS events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>136 (49)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>206 (74)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Progressive disease (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>125 (45)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>192 (69)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Death<footnote ID="_Ref511209873">Without documented radiological disease progression</footnote> (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>11 (4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>14 (5)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Median PFS in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>18.9 (15.2, 21.4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10.2 (9.6, 11.1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Hazard Ratio (95% CI)<footnote ID="_Ref511210088">Stratified by ethnicity (Asian vs. non-Asian) and mutation status (Ex19del vs. L858R)</footnote> <footnote ID="_Ref511210127">Pike estimator</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0.46 (0.37, 0.57)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>p-value<footnoteRef IDREF="_Ref511210088"/> <footnote ID="_Ref511210474">Stratified log-rank test</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>P < 0.0001</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Overall Survival (OS)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Number of deaths (58% maturity)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>155 (56)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>166 (60)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Median OS in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38.6 (34.5, 41.8)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>31.8 (26.6, 36.0)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>HR (95.05% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.799 (0.641, 0.997)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>p-value</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>P=0.0462</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Overall Response Rate (ORR)</content> <footnote ID="_Ref511205582">Confirmed responses</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>ORR, % (95% CI)<footnoteRef IDREF="_Ref511210088"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>77 (71, 82)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>69 (63, 74)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Complete response, % </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Partial response, % </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>75%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>68%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Duration of Response (DoR)</content> <footnoteRef IDREF="_Ref511205582"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>Median in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>17.6 (13.8, 22.0)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>9.6 (8.3, 11.1)</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 1. Kaplan-Meier Curves of PFS by Investigator Assessment in FLAURA</content> </paragraph> <renderMultiMedia ID="id1607616415" referencedObject="B946DA92-3E9A-4201-B1B8-CBDAB49CDE3F"/> <paragraph>In a supportive analysis of PFS according to blinded independent central review, median PFS was 17.7 months in the TAGRISSO arm compared to 9.7 months in the EGFR TKI comparator arm (HR=0.45; 95% CI: 0.36, 0.57).</paragraph> <paragraph> <content styleCode="bold">Figure 2. Kaplan-Meier Curves of Overall Survival in FLAURA</content> </paragraph> <renderMultiMedia ID="id435866250" referencedObject="A9B4EBA1-8D4E-4D47-A73E-7E8174CB9673"/> <paragraph>Of 556 patients, 200 patients (36%) had baseline brain scans reviewed by BICR; this included 106 patients in the TAGRISSO arm and 94 patients in the investigator choice of EGFR TKI arm. Of these 200 patients, 41 had measurable CNS lesions per RECIST v1.1. Results of pre-specified exploratory analyses of CNS ORR and DoR by BICR in the subset of patients with measurable CNS lesions at baseline are summarized in Table 7.</paragraph> <table width="100%"> <caption>Table 7. CNS ORR and DOR by BICR in Patients with Measurable CNS Lesions at Baseline in FLAURA</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">TAGRISSO</content> </paragraph> <paragraph>N=22</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">EGFR TKI</content> </paragraph> <paragraph> <content styleCode="bold">(gefitinib or erlotinib)</content> </paragraph> <paragraph>N=19</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">CNS Tumor Response Assessment</content> <footnote ID="_Ref511206920">According to RECIST v1.1.</footnote> <footnote ID="_Ref511207000">Based on confirmed response.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>CNS ORR, % (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>77% (55, 92)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>63% (38, 84)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Complete response</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%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Duration of CNS Response</content> <content styleCode="italics"> <footnote ID="_Ref519598316">Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.</footnote> </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Number of responders</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>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Response Duration ≥6 months</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>50%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Response Duration ≥12 months</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>47%</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>33%</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20200605"/> <component> <observationMedia ID="B946DA92-3E9A-4201-B1B8-CBDAB49CDE3F"> <text>figure_1</text> <value mediaType="image/jpeg"> <reference value="figure_1.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="A9B4EBA1-8D4E-4D47-A73E-7E8174CB9673"> <text>figure_2</text> <value mediaType="image/jpeg"> <reference value="figure_2.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_08798906-48f7-4db0-9d50-7c9788765a3c"> <id root="96b00e22-00b2-4dd9-9cf6-22fabfc1284a"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.2 Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer </title> <text> <paragraph>The efficacy of TAGRISSO was demonstrated in a randomized, multicenter open-label, active-controlled trial in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI (AURA3). All patients were required to have EGFR T790M mutation-positive NSCLC identified by the cobas<sup>®</sup> EGFR Mutation Test performed in a central laboratory prior to randomization. </paragraph> <paragraph>A total of 419 patients were randomized 2:1 to receive TAGRISSO (n=279) or platinum-based doublet chemotherapy (n=140). Randomization was stratified by ethnicity (Asian vs. non-Asian). Patients in the TAGRISSO arm 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. Patients in the chemotherapy arm received pemetrexed 500 mg/m<sup>2</sup> with carboplatin AUC5 or pemetrexed 500mg/m<sup>2</sup> with cisplatin 75 mg/m<sup>2</sup> on Day 1 of every 21-day cycle for up to 6 cycles. Patients whose disease had not progressed after four cycles of platinum-based chemotherapy could have received pemetrexed maintenance therapy (pemetrexed 500 mg/m<sup>2</sup> on Day 1 of every 21-day cycle). </paragraph> <paragraph>The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by investigator assessment. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DoR), and overall survival (OS). Patients randomized to the chemotherapy arm who had radiological progression according to both investigator and blinded independent central review (BICR) were permitted to cross over to receive treatment with TAGRISSO.</paragraph> <paragraph>The baseline demographic and disease characteristics of the overall trial population were: median age 62 years (range: 20-90 years), ≥75 years old (15%), female (64%), White (32%), Asian (65%), never smoker (68%), WHO performance status 0 or 1 (100%). Fifty-four percent (54%) of patients had extra-thoracic visceral metastases, including 34% with central nervous system (CNS) metastases (including 11% with measurable CNS metastases) and 23% with liver metastases. Forty-two percent (42%) of patients had metastatic bone disease. </paragraph> <paragraph>In AURA3, there was a statistically significant improvement in PFS in the patients randomized to TAGRISSO compared to chemotherapy (See Table 8 and Figure 3). Overall survival data were not mature at the time of the PFS analysis.</paragraph> <table width="100%"> <caption>Table 8. Efficacy Results According to Investigator Assessment in AURA3</caption> <col width="43%"/> <col width="30%"/> <col width="27%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Efficacy Parameter</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">TAGRISSO</content> <br/> <content styleCode="bold">(N=279)</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Chemotherapy</content> <br/> <content styleCode="bold">(N=140)</content> </th> </tr> </thead> <tbody> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>140 (50)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>110 (79)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Progressive disease</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>129 (46)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>104 (74)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Death<footnote ID="_Ref511212224">Without documented radiological disease progression</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>11 (4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>6 (4)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Median PFS in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10.1 (8.3, 12.3)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>4.4 (4.2, 5.6)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Hazard Ratio (95% CI)<footnote ID="_Ref511212268">Stratified by ethnicity (Asian vs. non-Asian)</footnote> <footnote ID="_Ref511212310">Pike estimator</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0.30 (0.23,0.41)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>P-value<footnoteRef IDREF="_Ref511212268"/> <footnote ID="_Ref511212430">Stratified log-rank test</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph><0.001</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Overall Response Rate<footnote ID="_Ref511212449">Confirmed</footnote> </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Overall Response Rate</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>65%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>29%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>(95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>(59%, 70%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>(21%, 37%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Complete response</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>1%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>1%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Partial response</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>63%</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>27%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>P-value<footnoteRef IDREF="_Ref511212268"/> <footnote ID="_Ref511212489">Logistic regression analysis</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph><0.001</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Duration of Response (DoR)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>Median Duration of Response in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>11.0 (8.6, 12.6)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>4.2 (3.0, 5.9)</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 3. Kaplan-Meier Curves of PFS by Investigator Assessment in AURA3</content> </paragraph> <renderMultiMedia ID="id944659024" referencedObject="B9DAFD35-B7DF-42B0-A682-2D28D82103D7"/> <paragraph>In a supportive analysis of PFS according to blinded independent central review, median PFS was 11 months in the TAGRISSO arm compared to 4.2 months in the chemotherapy arm (HR 0.28; 95% CI: 0.20, 0.38).</paragraph> <paragraph>Of 419 patients, 205 (49%) had baseline brain scans reviewed by BICR; this included 134 (48%) patients in the TAGRISSO arm and 71 (51%) patients in the chemotherapy arm. Assessment of CNS efficacy by RECIST v1.1 was performed in the subgroup of 46/419 (11%) patients identified by BICR to have measurable CNS lesions on a baseline brain scan. Results are summarized in Table 9.</paragraph> <table width="100%"> <caption>Table 9. CNS ORR and DoR by BICR in Patients with Measurable CNS Lesions at Baseline in AURA3</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">TAGRISSO</content> </paragraph> <paragraph> <content styleCode="bold">N=30</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> <paragraph> <content styleCode="bold">N=16</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">CNS Tumor Response Assessment</content> <footnote ID="_Ref511212544">According to RECIST v1.1.</footnote> <footnote ID="_Ref511212555">Based on confirmed response.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>CNS ORR, % (95% CI) </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>57% (37, 75)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25% (7, 52)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Complete response</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="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Duration of CNS Response</content> <footnoteRef IDREF="_Ref511212555"/> <footnote ID="_Ref511212713">Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Number of responders</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Response Duration ≥ 6 months</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> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Response Duration ≥ 9 months</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20200605"/> <component> <observationMedia ID="B9DAFD35-B7DF-42B0-A682-2D28D82103D7"> <text>figure_3</text> <value mediaType="image/jpeg"> <reference value="figure_3.jpg"/> </value> </observationMedia> </component> </section> </component> </section>

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_a5b8084c-320c-40f4-b222-7c0d1e1d950f"> <id root="1d6262db-cd56-40db-a420-f257a34be12c"/> <code code="34076-0" codeSystem="2.16.840.1.113883.6.1" displayName="INFORMATION FOR PATIENTS SECTION"/> <title>17 PATIENT COUNSELING INFORMATION </title> <text> <paragraph>Advise the patient to read the FDA-approved patient labeling (Patient Information).</paragraph> <paragraph> <content styleCode="underline">Interstitial Lung Disease/Pneumonitis</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Inform patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms <content styleCode="italics">[see <linkHtml href="#_RefID_f8532931-a9c4-45e1-8f6a-fc84a6160">Warnings and Precautions (5.1)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">QTc Interval Prolongation</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications <content styleCode="italics">[see <linkHtml href="#ID_528664c5-d8d8-4f0d-a55f-14a94db9f9f0">Warnings and Precautions (5.2)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Cardiomyopathy</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Inform patients that TAGRISSO can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider <content styleCode="italics">[see <linkHtml href="#ID_bded0629-2e69-46ec-903e-ca5e006409cb">Warnings and Precautions (5.3)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Keratitis</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Advise patients to contact their healthcare provider immediately if they develop eye symptoms (eye inflammation, lacrimation, light sensitivity, eye pain, red eye or changes in vision) <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#ID_1f3e51e7-d489-4829-953c-74b52b510553">Warnings and Precautions (5.4)</linkHtml> </content> <content styleCode="italics">]</content>.</item> </list> <paragraph> <content styleCode="underline">Erythema multiforme and Stevens-Johnson syndrome</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Inform patients of signs and symptoms that may be indicative of EM or SJS. Advise patients to contact their healthcare provider immediately if they develop target lesions or severe blistering or peeling of skin <content styleCode="italics">[see <linkHtml href="#ID_70573be5-c8b5-436a-a2d0-5948ef0d9e1c">Warnings and Precautions (5.5)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Embryo-Fetal Toxicity</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking TAGRISSO <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#ID_fdc18710-41a6-4f57-bfa0-5e703721587f">Warnings and Precautions (5.6)</linkHtml> </content> <content styleCode="italics"> and <linkHtml href="#ID_b30a969b-cf1b-43dc-b121-ba43d2cfffde">Use in Specific Populations (8.1)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Females and Males of Reproductive Potential</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose <content styleCode="italics">[see <linkHtml href="#_RefID_34a54bb9-dadb-4461-b46a-5f5fbd428">Use in Specific Populations (8.3)</linkHtml>]</content>.</item> <item> <caption>•</caption>Advise males to use effective contraception during treatment and for 4 months after the final dose of TAGRISSO <content styleCode="italics">[see <linkHtml href="#_RefID_34a54bb9-dadb-4461-b46a-5f5fbd428">Use in Specific Populations (8.3)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Lactation</content> </paragraph> <paragraph>Advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose <content styleCode="italics">[see <linkHtml href="#_RefID_8aba6876-0e9e-439f-a3c3-7594f53d0">Use in Specific Populations (8.2)</linkHtml>]</content>.</paragraph> <paragraph>Distributed by:<br/>AstraZeneca Pharmaceuticals LP<br/>Wilmington, DE 19850</paragraph> <paragraph>TAGRISSO is a registered trademark of the AstraZeneca group of companies.</paragraph> <paragraph> <sup>©</sup>AstraZeneca 2020</paragraph> </text> <effectiveTime value="20200605"/> </section>

SPL PATIENT PACKAGE INSERT SECTION

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_a9c790bd-044e-4917-a1a6-90ccd1ad7672"> <id root="a87fd266-bd18-45d6-846f-c1aeba20ed56"/> <code code="42230-3" codeSystem="2.16.840.1.113883.6.1" displayName="SPL PATIENT PACKAGE INSERT SECTION"/> <text> <table width="100%"> <col width="52%"/> <col width="48%"/> <tbody> <tr> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Patient Information</content> <br/> <content styleCode="bold">TAGRISSO<sup>®</sup> (</content>tuh-GRISS-oh<content styleCode="bold">)</content> <br/> <content styleCode="bold">(osimertinib)</content> <br/> <content styleCode="bold">tablets</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What is the most important information I should know about TAGRISSO?</content> </paragraph> <paragraph> <content styleCode="bold">TAGRISSO may cause serious side effects, including:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">lung problems.</content> TAGRISSO may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your doctor right away if you have any new or worsening lung symptoms, including trouble breathing, shortness of breath, cough, or fever.</item> <item> <caption>•</caption> <content styleCode="bold">heart problems, including heart failure.</content> TAGRISSO may cause heart problems that may lead to death. Your doctor should check your heart function before you start taking TAGRISSO and during treatment as needed. Tell your doctor right away if you have any of the following signs and symptoms of a heart problem: feeling like your heart is pounding or racing, shortness of breath, swelling of your ankles and feet, feeling lightheaded.</item> <item> <caption>•</caption> <content styleCode="bold">eye problems.</content> TAGRISSO may cause eye problems. Tell your doctor right away if you have symptoms of eye problems which may include watery eyes, sensitivity to light, eye pain, eye redness, or vision changes. Your doctor may send you to see an eye specialist (ophthalmologist) if you get eye problems with TAGRISSO.</item> <item> <caption>•</caption> <content styleCode="bold">skin problems.</content> TAGRISSO may cause skin problems. Tell your doctor right away if you develop target lesions (skin reactions that look like rings), severe blistering or peeling of the skin.</item> </list> <paragraph>See <content styleCode="bold">“What are the possible side effects of TAGRISSO?”</content> for more information about side effects.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What is TAGRISSO?</content> </paragraph> <paragraph>TAGRISSO is a prescription medicine used to treat non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic):</paragraph> <list listType="unordered"> <item> <caption>•</caption>as your first treatment if your tumor has a certain abnormal epidermal growth factor receptor (EGFR) gene(s)</item> <item> <caption> </caption>or</item> <item> <caption>•</caption>if you have a certain type of EGFR gene and had previous treatment with an EGFR tyrosine kinase inhibitor (TKI) medicine that did not work or is no longer working.</item> </list> <paragraph>Your doctor will perform a test to make sure that TAGRISSO is right for you.</paragraph> <paragraph>It is not known if TAGRISSO is safe and effective in children.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Before taking TAGRISSO, tell your doctor about all of your medical conditions, including if you:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>have lung or breathing problems.</item> <item> <caption>•</caption>have heart problems, including a condition called long QTc syndrome.</item> <item> <caption>•</caption>have problems with your electrolytes, such as sodium, potassium, calcium or magnesium.</item> <item> <caption>•</caption>have a history of eye problems.</item> <item> <caption>•</caption>are pregnant or plan to become pregnant. TAGRISSO can harm your unborn baby. Tell your doctor right away if you become pregnant during treatment with TAGRISSO or think you may be pregnant.<list listType="unordered"> <item> <caption>o</caption> <content styleCode="bold">Females</content> who are able to become pregnant should use effective birth control during treatment with TAGRISSO and for 6 weeks after the final dose of TAGRISSO.</item> <item> <caption>o</caption> <content styleCode="bold">Males</content> who have female partners that are able to become pregnant should use effective birth control during treatment with TAGRISSO and for 4 months after the final dose of TAGRISSO.</item> </list> </item> <item> <caption>•</caption>are breastfeeding or plan to breastfeed. It is not known if TAGRISSO passes into your breast milk. Do not breastfeed during treatment with TAGRISSO and for 2 weeks after your final dose of TAGRISSO. Talk to your doctor about the best way to feed your baby during this time.</item> </list> <paragraph>Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Especially tell your doctor if you take a heart or blood pressure medicine.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I take TAGRISSO?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Take TAGRISSO exactly as your doctor tells you to take it.</item> <item> <caption>•</caption>Your doctor may change your dose, temporarily stop, or permanently stop treatment with TAGRISSO if you have side effects.</item> <item> <caption>•</caption>Take TAGRISSO 1 time each day.</item> <item> <caption>•</caption>You can take TAGRISSO with or without food.</item> <item> <caption>•</caption>If you miss a dose of TAGRISSO, do not make up for the missed dose. Take your next dose at your regular time.</item> <item> <caption>•</caption> <content styleCode="bold">If you cannot swallow TAGRISSO tablets whole:</content> <list listType="unordered"> <item> <caption>o</caption>place your dose of TAGRISSO in a container that contains 60 mL (2 ounces) of water. Do not use carbonated water or any other liquids.</item> <item> <caption>o</caption>stir the TAGRISSO tablet and water until the TAGRISSO tablet is in small pieces (the tablet will not completely dissolve). Do not crush, heat, or use ultrasound to prepare the mixture.</item> <item> <caption>o</caption>drink the TAGRISSO and water mixture right away.</item> <item> <caption>o</caption>add 120 mL to 240 mL (4 to 8 ounces) of water into the container and drink to make sure that you take your full dose of TAGRISSO.</item> </list> </item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">What are the possible side effects of TAGRISSO?</content> </paragraph> <paragraph> <content styleCode="bold">TAGRISSO may cause serious side effects, including:</content> </paragraph> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>•</caption>See <content styleCode="bold">“What is the most important information I should know about TAGRISSO?”</content> </item> <item> <caption>•</caption>Severe blistering or peeling of skin – seek medical attention right away if you develop these symptoms.</item> <item> <caption>•</caption>Target lesions, which are skin reactions that look like rings – seek medical attention right away if you develop these symptoms.</item> </list> </item> </list> <paragraph> <content styleCode="bold">The most common side effects of TAGRISSO are:</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>diarrhea</item> <item> <caption>•</caption>rash</item> <item> <caption>•</caption>dry skin</item> <item> <caption>•</caption>changes in your nails, including: redness, tenderness, pain, inflammation, brittleness, separation from nailbed, and shedding of nails</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>mouth sores</item> <item> <caption>•</caption>tiredness</item> <item> <caption>•</caption>decreased appetite</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Tell your doctor if you have any side effect that bothers you or that does not go away.</paragraph> <paragraph>These are not all the possible side effects of TAGRISSO. For more information, ask your doctor or pharmacist.</paragraph> <paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I store TAGRISSO?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Store TAGRISSO at room temperature between 68°F to 77°F (20°C to 25°C).</item> <item> <caption>•</caption>Safely throw away medicine that is out of date or that you no longer need.</item> <item> <caption>•</caption> <content styleCode="bold">Keep TAGRISSO and all medicines out of the reach of children.</content> </item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General information about the safe and effective use of TAGRISSO.</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TAGRISSO for a condition for which it was not prescribed. Do not give TAGRISSO to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about TAGRISSO that is written for a healthcare professional.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> <content styleCode="bold">What are the ingredients in TAGRISSO?</content> </paragraph> <paragraph> <content styleCode="bold">Active ingredient:</content> osimertinib</paragraph> <paragraph> <content styleCode="bold">Inactive ingredients:</content> mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl fumarate. Tablet coating contains: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide yellow, ferric oxide red and ferric oxide black.</paragraph> <paragraph>For more information, go to <linkHtml href="http://www.Tagrisso.com">www.Tagrisso.com</linkHtml> or call 1-800-236-9933.</paragraph> <paragraph>Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850</paragraph> <paragraph> <sup>©</sup>AstraZeneca 2020</paragraph> </td> </tr> </tbody> </table> <list listType="ordered"> <item> <caption> </caption>This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 05/2020</item> </list> </text> <effectiveTime value="20200605"/> </section>

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