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Prescribing Information
KOSELUGO®

KOSELUGO (selumetinib)

selumetinib

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Highlights of Prescribing Information

<?xml version="1.0" encoding="UTF-8"?><title>These highlights do not include all the information needed to use KOSELUGO safely and effectively. See full prescribing information for KOSELUGO.<br/>KOSELUGO<sup>®</sup> (selumetinib) capsules, for oral use<br/>KOSELUGO<sup>®</sup> (selumetinib) oral granules<br/>Initial U.S. Approval: 2020</title>

SPL product data elements 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
10 OVERDOSAGE
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
Instructions for Use
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 10mg
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 25mg
Package/Label Display Panel 5 mg
Package/Label Display Panel 7.5 mg

SPL product data elements section

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root="2.16.840.1.113883.3.150"/> <code code="C73594" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="NDA"/> <author> <territorialAuthority> <territory> <code code="USA" codeSystem="2.16.840.1.113883.5.28"/> </territory> </territorialAuthority> </author> </approval> </subjectOf> <subjectOf> <marketingAct> <code code="C53292" codeSystem="2.16.840.1.113883.3.26.1.1"/> <statusCode code="active"/> <effectiveTime> <low value="20250910"/> </effectiveTime> </marketingAct> </subjectOf> <consumedIn> <substanceAdministration> <routeCode code="C38288" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="ORAL"/> </substanceAdministration> </consumedIn> </manufacturedProduct> </subject> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_3E24CF99-EA1B-426E-A40B-92CA72ED2E29"> <id root="d5dd5321-2115-491a-b5a8-880324c1ad19"/> <code code="43683-2" codeSystem="2.16.840.1.113883.6.1" displayName="RECENT MAJOR CHANGES SECTION"/> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <paragraph/> <paragraph>Indications and Usage (<linkHtml href="#ID_6f516e09-3d40-492f-ad77-03cf8ee4d29d">1</linkHtml>) 11/2025</paragraph> <paragraph>Dosage and Administration (<linkHtml href="#ID_4397ea83-b8d5-4ffe-89ff-952afbe88d59">2.1</linkHtml>) 11/2025</paragraph> <paragraph>Warnings and Precautions (<linkHtml href="#ID_06cbec9d-94d0-4927-a175-a70517ad947f">5.1</linkHtml>, <linkHtml href="#ID_2e1f4415-e88b-4331-905d-83ed52fa1697">5.2</linkHtml>, <linkHtml href="#ID_bfcc51c5-7572-4441-a947-e1686a877dc0">5.3</linkHtml>, <linkHtml href="#ID_af06e137-7226-443e-9e23-464cd07923be">5.4</linkHtml>, <linkHtml href="#ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8">5.5</linkHtml>, <linkHtml href="#ID_1caa6ee7-5302-49c7-bedd-1bd70ce9868e">5.7</linkHtml>) 11/2025</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_6f516e09-3d40-492f-ad77-03cf8ee4d29d"> <id root="99095396-a0ef-4201-b420-6f51b62e545f"/> <code code="34067-9" codeSystem="2.16.840.1.113883.6.1" displayName="INDICATIONS & USAGE SECTION"/> <title>1 INDICATIONS AND USAGE </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO is indicated for the treatment of adult and pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) <content styleCode="italics">[see <linkHtml href="#ID_62324d57-876a-4952-ab00-e1a532195186">Dosage and Administration (2)</linkHtml>].</content> </content> </paragraph> </text> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <paragraph>KOSELUGO is a kinase inhibitor indicated for the treatment of adult and pediatric patients 1 year of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). (<linkHtml href="#ID_6f516e09-3d40-492f-ad77-03cf8ee4d29d">1</linkHtml>)</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_62324d57-876a-4952-ab00-e1a532195186"> <id root="a0d5b665-d79a-4a55-80d0-0666d2e35b49"/> <code code="34068-7" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE & ADMINISTRATION SECTION"/> <title>2 DOSAGE AND ADMINISTRATION </title> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">KOSELUGO capsules:</content> The recommended dosage is 25 mg/m<sup>2</sup>, swallowed whole, taken orally twice daily with or without food <content styleCode="italics">(see Table 1)</content>. <linkHtml href="#ID_4397ea83-b8d5-4ffe-89ff-952afbe88d59">(2.1</linkHtml>, <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.2</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">KOSELUGO oral granules:</content> The recommended dosage is equivalent to 25 mg/m<sup>2</sup>, sprinkled onto or mixed with soft food and taken orally twice daily <content styleCode="italics">(see Table 2).</content> (<linkHtml href="#ID_4397ea83-b8d5-4ffe-89ff-952afbe88d59">2.1</linkHtml>, <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.2</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Moderate hepatic impairment (Child-Pugh B):</content> The recommended dosage is 20 mg/m<sup>2</sup> orally twice daily <content styleCode="italics">(see Tables 6 and 7)</content>. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.2</linkHtml>, <linkHtml href="#ID_975d0775-d76d-4ef1-87a7-e022d5590bc9">2.4</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Severe hepatic impairment (Child-Pugh C):</content> The recommended dosage has not been established. (<linkHtml href="#ID_975d0775-d76d-4ef1-87a7-e022d5590bc9">2.4</linkHtml>, <linkHtml href="#ID_7f8b32f8-4409-487c-815c-97221abdb689">8.6</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Strong or Moderate CYP3A4 Inhibitors or Fluconazole:</content> If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO <content styleCode="italics">(see Tables 8 and 9)</content>. (<linkHtml href="#ID_975d0775-d76d-4ef1-87a7-e022d5590bc9">2.5</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_4397ea83-b8d5-4ffe-89ff-952afbe88d59"> <id root="4ce86f6f-342e-4dae-99e7-c7c435defea7"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.1 Recommended Dosage </title> <text> <paragraph> <content styleCode="xmChange">The recommended dosage of KOSELUGO capsules (<content styleCode="italics">see Table 1</content>) and KOSELUGO oral granules (<content styleCode="italics">see Table 2</content>) for adult and pediatric patients 1 year of age and older, based on body surface area, is 25 mg/m<sup>2</sup> orally twice daily, until disease progression or unacceptable toxicity <content styleCode="italics">[see <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">Dosage and Administration (2.2)].</linkHtml> </content> </content> </paragraph> <table styleCode="Noautorules" width="100%"> <caption>Table 1 Recommended Dosage: KOSELUGO Capsules</caption> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Body Surface Area</content> <footnote ID="_Ref37257193">The <content styleCode="xmChange">recommended dosage of KOSELUGO capsules for patients with a BSA less than 0.55 m<sup>2</sup> has not been established.</content> </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">KOSELUGO Capsules</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.55 – 0.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20 mg in the morning and 10 mg in the evening</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>40 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>50 mg twice daily</paragraph> </td> </tr> </tbody> </table> <table styleCode="Noautorules" width="100%"> <caption>Table 2 Recommended Dosage: KOSELUGO Oral Granules</caption> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Body Surface Area</content> <footnote ID="_Ref207887589">The <content styleCode="xmChange">recommended dosage of KOSELUGO oral granules for patients with a BSA less than 0.40 m<sup>2</sup> has not been established.</content> </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">KOSELUGO Oral Granules</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.40 – 0.59 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12.5 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.60 – 0.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>40 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45 mg twice daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>50 mg twice daily</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_12a15f24-d5a2-4d3f-ba9a-4608249ae1f9"> <id root="a8d100e9-c87c-4145-9d54-b23f76b1fb03"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.2 Administration </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO is available in two dosage forms: KOSELUGO capsules and KOSELUGO oral granules. Prescribe KOSELUGO oral granules for patients who have difficulty swallowing whole capsules.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">KOSELUGO Capsules</content> </content> </paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="xmChange">Administer KOSELUGO capsules to patients who can swallow a whole capsule.</content> </item> <item> <caption>•</caption> <content styleCode="xmChange">Swallow KOSELUGO capsules whole. Do not open, chew or crush KOSELUGO capsules.</content> </item> <item> <caption>•</caption> <content styleCode="xmChange">KOSELUGO capsules may be administered with or without food.</content> </item> </list> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">KOSELUGO Oral Granules</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">Administer KOSELUGO oral granules to patients who have difficulty swallowing a whole capsule.</content> </paragraph> <paragraph> <content styleCode="xmChange">Sprinkle KOSELUGO oral granules on or mix with a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry and consume within 30 minutes of preparation. If not consumed within 30 minutes of preparation, discard and prepare a new dose. If a dose has been partially consumed within 30 minutes of preparation, discard the remainder of the dose and do not prepare a new dose, aim to complete dosing within 30 minutes next time.</content> </paragraph> <paragraph> <content styleCode="xmChange">The KOSELUGO oral granules should be free-flowing. Do NOT use if the oral granules are clumped or stuck inside the capsule shell. Instruct the patient or caregiver to contact their pharmacy if this happens.</content> </paragraph> <paragraph> <content styleCode="xmChange">Discard the empty capsule shells after use.</content> </paragraph> <paragraph> <content styleCode="xmChange">Do NOT swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules.</content> </paragraph> <paragraph> <content styleCode="xmChange">Do NOT chew or crush the KOSELUGO oral granules. Do NOT add oral granules to liquids.</content> </paragraph> <paragraph> <content styleCode="xmChange">Do NOT mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Missed Dose</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">If a dose of KOSELUGO capsules or KOSELUGO oral granules is missed, make up that dose unless the next dose is due within 6 hours.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Vomiting</content> </content> </paragraph> <paragraph>If vomiting occurs after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_4e3ffdee-7038-48d1-b5ba-572109f19121"> <id root="abe2bde6-f408-4e69-ba32-007ea69a2e6a"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.3 Dosage Modifications for Adverse Reactions </title> <text> <paragraph> <content styleCode="xmChange">The recommended dose reductions for adverse reactions for KOSELUGO capsules and KOSELUGO oral granules are provided in Tables 3 and 4, respectively.</content> </paragraph> <table width="100%"> <caption>Table 3 Recommended Dose Reductions for KOSELUGO Capsules for Adverse Reactions</caption> <col width="28%"/> <col width="18%"/> <col width="19%"/> <col width="18%"/> <col width="17%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">Body Surface Area</th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">First Dose Reduction<br/>(mg/dose)</th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">Second Dose Reduction<br/>(mg/dose)</th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">Morning</th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">Evening</th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">Morning</th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">Evening</th> </tr> </thead> <tbody> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>0.55 – 0.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10 mg once daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Permanently discontinue KOSELUGO capsules in patients unable to tolerate two dose reductions.</paragraph> </td> </tr> </tbody> </table> <table width="100%"> <caption>Table 4 Recommended Dose Reductions for KOSELUGO Oral Granules for Adverse Reactions</caption> <col width="28%"/> <col width="18%"/> <col width="19%"/> <col width="18%"/> <col width="17%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body Surface Area</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">First Dose Reduction</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Second Dose Reduction</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> </tr> </thead> <tbody> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.40 – 0.59 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>7.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>7.5</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.60 – 0.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>12.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>12.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>12.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>12.5</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>22.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>22.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"> <paragraph>15</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Permanently discontinue KOSELUGO oral granules in patients unable to tolerate two dose reductions.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="xmChange">The recommended dosage modifications of KOSELUGO capsules and KOSELUGO oral granules for adverse reactions are provided in Table 5.</content> </paragraph> <table cellpadding="0pt" width="100%"> <caption>Table 5 Recommended Dosage Modifications for Adverse Reactions</caption> <col width="36%"/> <col width="64%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Severity of Adverse Reaction</content> </th> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <content styleCode="bold">Recommended Dosage Modifications for KOSELUGO capsules and KOSELUGO oral granules</content> </th> </tr> </thead> <tbody> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Left Ventricular Dysfunction [see <linkHtml href="#ID_06cbec9d-94d0-4927-a175-a70517ad947f">Warnings and Precautions (5.1)</linkHtml>]</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold until resolution. Resume at reduced dose.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Symptomatic decreased LVEF</item> <item> <caption>•</caption>Grade 3 or 4 decreased LVEF</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Ocular Toxicity [see <linkHtml href="#ID_2e1f4415-e88b-4331-905d-83ed52fa1697">Warnings and Precautions (5.2)</linkHtml>]</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Retinal Pigment Epithelial Detachment (RPED) </item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold until resolution. Resume at reduced dose.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Retinal vein occlusion (RVO) </item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Gastrointestinal Toxicity [see <linkHtml href="#ID_bfcc51c5-7572-4441-a947-e1686a877dc0">Warnings and Precautions (5.3)</linkHtml>]</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 3 Diarrhea</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold until improved to Grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days. </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 4 Diarrhea</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 3 or 4 Colitis</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Skin Toxicity [see <linkHtml href="#ID_af06e137-7226-443e-9e23-464cd07923be">Warnings and Precautions (5.4)</linkHtml>]</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 3 or 4</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold until improvement. Resume at reduced dose.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Increased Creatine Phosphokinase (CPK) [see <linkHtml href="#ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8">Warnings and Precautions (5.5)</linkHtml>]</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 4 Increased CPK</item> <item> <caption>•</caption>Any Increased CPK and myalgia</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Rhabdomyolysis</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Permanently discontinue.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Other Adverse Reactions [see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)]</linkHtml> </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Intolerable Grade 2 </item> <item> <caption>•</caption>Grade 3</item> </list> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Grade 4</item> </list> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation.</paragraph> </td> </tr> </tbody> </table> <paragraph>* Per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_152da0e5-0437-441e-a8b1-80a654492d59"> <id root="cf701d26-3bfb-41a0-98e1-8406f4dc917b"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.4 Recommended Dosage in Patients with Hepatic Impairment </title> <text> <paragraph> <content styleCode="italics">Severe Hepatic Impairment</content> </paragraph> <paragraph>The recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#ID_7f8b32f8-4409-487c-815c-97221abdb689">Use in Specific Populations (8.6)</linkHtml> </content> <content styleCode="italics">]</content>.</paragraph> <paragraph> <content styleCode="italics">Moderate Hepatic Impairment</content> </paragraph> <paragraph>The recommended dosage of KOSELUGO capsules <content styleCode="italics">(see Table 6)</content> and KOSELUGO oral granules <content styleCode="italics">(see Table 7)</content> for pediatric patients 1 year of age or older with moderate hepatic impairment (Child-Pugh B) is based on body surface area; 20 mg/m<sup>2</sup> orally twice daily, until disease progression or unacceptable toxicity <content styleCode="italics">[see <linkHtml href="#ID_12a15f24-d5a2-4d3f-ba9a-4608249ae1f9">Dosage and Administration (2.2)</linkHtml>].</content> </paragraph> <table width="100%"> <caption>Table 6 Recommended Dosage of KOSELUGO Capsules for Moderate Hepatic Impairment</caption> <col width="37%"/> <col width="31%"/> <col width="31%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body Surface Area </content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Moderate Hepatic Impairment </content> <br/> <content styleCode="bold">(Child-Pugh B)</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> </tr> </thead> <tbody> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>0.55 – 0.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>40</paragraph> </td> </tr> </tbody> </table> <table width="100%"> <caption>Table 7 Recommended Dosage of KOSELUGO Oral Granules for Moderate Hepatic Impairment</caption> <col width="37%"/> <col width="31%"/> <col width="31%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body Surface Area</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Moderate Hepatic Impairment</content> <br/> <content styleCode="bold">(Child‑Pugh B)</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.40 – 0.59 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.60 – 0.69 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12.5</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>35</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>40</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>40</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_975d0775-d76d-4ef1-87a7-e022d5590bc9"> <id root="e38fb7e6-3ca4-4fc0-8103-35121690d325"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.5 Dosage Modifications for Drug Interactions </title> <text> <paragraph> <content styleCode="xmChange"> <content styleCode="underline">Strong or Moderate CYP3A4 Inhibitors or Fluconazole</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the KOSELUGO dosage as recommended in Table 8 (KOSELUGO capsules) and Table 9 (KOSELUGO oral granules). After discontinuation of the strong or moderate CYP3A4 inhibitor or fluconazole for 3-elimination half-lives, resume the KOSELUGO dose that was taken prior to initiating the inhibitor or fluconazole [see <linkHtml href="#ID_4beb058e-fa95-47b6-853d-e96704d8eea2">Drug Interactions (7.1)</linkHtml>]</content> <content styleCode="italics">.</content> </paragraph> <table width="100%"> <caption>Table 8 Recommended Dosage of KOSELUGO Capsules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole</caption> <col width="25%"/> <col width="18%"/> <col width="20%"/> <col width="18%"/> <col width="18%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body Surface Area</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">If the current dosage is 25 mg/m<sup>2</sup> twice daily, reduce to 20 mg/m<sup>2</sup> twice daily</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">If the current dosage is 20 mg/m<sup>2</sup> twice daily, reduce to 15 mg/m<sup>2</sup> twice daily</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> </tr> </thead> <tbody> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>0.55 – 0.69 m<sup>2</sup> </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>10</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10 mg once daily</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </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>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </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>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>10</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </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>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </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>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </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>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </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>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>30</paragraph> </td> </tr> </tbody> </table> <table width="100%"> <caption>Table 9 Recommended Dosage of KOSELUGO Oral Granules for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole</caption> <col width="25%"/> <col width="18%"/> <col width="20%"/> <col width="18%"/> <col width="18%"/> <thead> <tr> <th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Body Surface Area</content> </th> <th align="left" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">If the current dosage is 25 mg/m<sup>2</sup> twice daily, reduce to 20 mg/m<sup>2</sup> twice daily</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> <th align="left" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">If the current dosage is 20 mg/m<sup>2</sup> twice daily, reduce to 15 mg/m<sup>2</sup> twice daily</content> <br/> <content styleCode="bold">(mg/dose)</content> </th> </tr> <tr> <th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top">Morning</th> <th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top">Evening</th> <th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Morning</content> </th> <th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Evening</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.40 – 0.59 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7.5</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.60 – 0.69 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12.5</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12.5</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.70 – 0.89 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.90 – 1.09 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.10 – 1.29 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.30 – 1.49 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>20</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.50 – 1.69 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.70 – 1.89 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>30</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>≥ 1.90 m<sup>2</sup> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>40</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>40</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>30</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>30</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_aeaaa2db-9356-4b7d-885d-4a45559ec129"> <id root="0dc8955f-ad94-4f1e-9879-fa121c96dfa6"/> <code code="43678-2" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE FORMS & STRENGTHS SECTION"/> <title>3 DOSAGE FORMS AND STRENGTHS </title> <text> <paragraph>Capsules:</paragraph> <list listType="unordered"> <item> <caption>•</caption>10 mg selumetinib: white to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.</item> <item> <caption>•</caption>25 mg selumetinib: blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink.</item> </list> <paragraph>Oral Granules:</paragraph> <list listType="unordered"> <item> <caption>•</caption>5 mg selumetinib: off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening.</item> <item> <caption>•</caption>7.5 mg selumetinib: off-white to light-yellow free-flowing oral granules contained within capsules. The capsules have a pink cap and white body. The cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening.</item> </list> </text> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <paragraph>Capsules: 10 mg and 25 mg of selumetinib. (<linkHtml href="#ID_aeaaa2db-9356-4b7d-885d-4a45559ec129">3</linkHtml>)</paragraph> <paragraph>Oral Granules: 5 mg and 7.5 mg of selumetinib. (<linkHtml href="#ID_aeaaa2db-9356-4b7d-885d-4a45559ec129">3</linkHtml>)</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_0f3373bc-3e12-45b6-bc46-8f4e18a88e4b"> <id root="0f3373bc-3e12-45b6-bc46-8f4e18a88e4b"/> <code code="34070-3" codeSystem="2.16.840.1.113883.6.1" displayName="CONTRAINDICATIONS SECTION"/> <title>4 CONTRAINDICATIONS </title> <text> <paragraph>None.</paragraph> </text> <effectiveTime value="20200410"/> <excerpt> <highlight> <text> <paragraph>None. (<linkHtml href="#ID_0f3373bc-3e12-45b6-bc46-8f4e18a88e4b">4</linkHtml>)</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_501152bd-d55d-44b7-a2ae-679b31a5d6d9"> <id root="7e9d104a-cb84-4c36-b131-df2f65fc928a"/> <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="20251119"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">Left Ventricular Dysfunction</content>: Assess ejection fraction prior to initiating treatment, every 3 months during the first year, then every 6 months thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.3</linkHtml>, <linkHtml href="#ID_06cbec9d-94d0-4927-a175-a70517ad947f">5.1</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Ocular Toxicity</content>: Conduct ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment and for new or worsening visual changes. Permanently discontinue KOSELUGO for retinal vein occlusion (RVO). Withhold KOSELUGO for retinal pigment epithelial detachment (RPED), monitor with optical coherence tomography assessments until resolution, and resume at reduced dose. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.3</linkHtml>, <linkHtml href="#ID_2e1f4415-e88b-4331-905d-83ed52fa1697">5.2</linkHtml>) </item> <item> <caption>•</caption> <content styleCode="underline">Gastrointestinal Toxicity</content>: Advise patients to start an anti-diarrheal agent immediately after the first episode of loose stool and to increase fluid intake. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.3</linkHtml>, <linkHtml href="#ID_bfcc51c5-7572-4441-a947-e1686a877dc0">5.3</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Skin Toxicity</content>: Monitor for severe skin rashes. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.3</linkHtml>, <linkHtml href="#ID_af06e137-7226-443e-9e23-464cd07923be">5.4</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Increased Creatine Phosphokinase (CPK)</content>: Increased CPK and rhabdomyolysis can occur. Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate for rhabdomyolysis or other causes. Withhold, reduce the dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">2.3</linkHtml>, <linkHtml href="#ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8">5.5</linkHtml>) </item> <item> <caption>•</caption> <content styleCode="underline">Increased Vitamin E Levels and Increased Risk of Bleeding</content> <content styleCode="underline">(KOSELUGO Capsules)</content>: KOSELUGO capsules contain vitamin E and daily intake of vitamin E that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients co-administered vitamin-K antagonists or anti-platelet agents. KOSELUGO oral granules do not contain vitamin E. (<linkHtml href="#ID_2604d125-0030-474c-a1ef-62ab18340a0b">5.6</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Embryo-Fetal Toxicity:</content> Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception (<linkHtml href="#ID_1caa6ee7-5302-49c7-bedd-1bd70ce9868e">5.7</linkHtml>, <linkHtml href="#ID_2392b2e1-45c1-4044-9977-fa848e0a5453">8.1</linkHtml>, <linkHtml href="#ID_d892a823-ad59-46db-8735-957bbd3684be">8.3</linkHtml>).</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_06cbec9d-94d0-4927-a175-a70517ad947f"> <id root="21bbd318-61d8-4ea3-a09a-38203b5aa9f0"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.1 Left Ventricular Dysfunction </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO can cause cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% below baseline. KOSELUGO has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 55% prior to treatment.</content> </paragraph> <paragraph> <content styleCode="xmChange">Pediatric patients</content> </paragraph> <paragraph> <content styleCode="xmChange">In the NF1 PN pediatric safety pool (N = 134) [see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml>], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on reported adverse reactions, occurred in 17% of evaluable patients. Decreased LVEF of ≥ 20% occurred in 0.7% of patients and resulted in dose interruption and dose reduction. Decreased LVEF resolved in 75% of these patients. The median time to first occurrence of LVEF decrease was approximately 12 months (median duration approximately 3 months).</content> </paragraph> <paragraph> <content styleCode="xmChange">Adult Patients</content> </paragraph> <paragraph> <content styleCode="xmChange">In the KOMET adult NF1 PN study (N = 71) [see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml>], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40% to 50%; 10 to 19% drop from baseline)], based on echocardiogram results, occurred in 14% of evaluable patients. Decreased LVEF resulted in dose interruption in 1.4% of patients. The median time to first occurrence of LVEF decrease was approximately 4 months (median duration approximately 4 months).</content> </paragraph> <paragraph>Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction [see Dosage and Administration (2.3)]. In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks until resolution. Upon resolution of decreased LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_2e1f4415-e88b-4331-905d-83ed52fa1697"> <id root="895321ab-408f-493e-aa33-1ceb0a955ffe"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.2 Ocular Toxicity </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO can cause ocular toxicity, including retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), and blurred vision.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Pediatric Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the NF1 PN pediatric safety pool (N = 134) <content styleCode="italics">[see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> </content>], blurred vision, photophobia, cataracts, ocular hypertension, and retinal tear occurred in 13% of pediatric patients receiving KOSELUGO. Blurred vision resulted in dose interruption in 1.5% of patients. Ocular toxicity resolved in 76% of these patients. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Adult Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the KOMET adult NF1 PN study (N = 71) <content styleCode="italics">[see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> </content>], blurred vision and vitreous floaters occurred in 6% of patients receiving KOSELUGO. Serious ocular toxicities including RVO and RPED, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.</content> </paragraph> <paragraph>Conduct comprehensive ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue KOSELUGO in patients with RVO. Withhold KOSELUGO in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of the adverse reaction <content styleCode="italics">[see <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">Dosage and Administration (2.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_bfcc51c5-7572-4441-a947-e1686a877dc0"> <id root="19879eb9-8de7-478c-8c02-16bc348aef87"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.3 Gastrointestinal Toxicity </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO can cause gastrointestinal toxicities, including diarrhea and colitis.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Pediatric Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the NF1 PN pediatric safety pool (N = 134) <content styleCode="italics">[see </content> </content> <content styleCode="italics"> <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> <content styleCode="xmChange">]</content> </content> <content styleCode="xmChange">, diarrhea occurred in 59% of patients who received KOSELUGO, including Grade 3 in 10% of patients. Diarrhea resulting in permanent discontinuation occurred in 0.7% of patients. Diarrhea resulting in dose interruption occurred in 10% of patients. The median time to first onset of diarrhea was approximately 2 months and the median duration was 5 days. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Adult Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the KOMET adult NF1 PN study (N = 71) <content styleCode="italics">[see </content> </content> <content styleCode="italics"> <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> <content styleCode="xmChange">]</content> </content> <content styleCode="xmChange">, diarrhea occurred in 42% patients who received KOSELUGO. Diarrhea resulting in dose interruption occurred in 1.4% of patients. The median time to first onset of diarrhea was approximately 1 month and the median duration was 7 days. Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.</content> </paragraph> <paragraph>Advise patients to start an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction <content styleCode="italics">[see <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">Dosage and Administration (2.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_af06e137-7226-443e-9e23-464cd07923be"> <id root="5ede30eb-7f0c-44be-83e8-422288dd0324"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.4 Skin Toxicity </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO can cause severe rashes, including dermatitis acneiform.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Pediatric Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the NF1 PN pediatric safety pool (N = 134) <content styleCode="italics">[see </content> </content> <content styleCode="italics"> <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> <content styleCode="xmChange">]</content> </content> <content styleCode="xmChange">, rash occurred in 68% of patients who received KOSELUGO. The most frequent rashes included dermatitis acneiform (47%) and maculopapular rash (31%). Pruritus (30%), alopecia (26%), and eczema (24%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 5% of patients. Rash resulted in dose interruption in 8% of patients and dose reduction in 3.7% of patients.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Adult Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the KOMET adult NF1 PN study (N = 71) <content styleCode="italics">[see </content> </content> <content styleCode="italics"> <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml> <content styleCode="xmChange">],</content> </content> <content styleCode="xmChange"> rash occurred in 85% of patients who received KOSELUGO. The most frequent rash included dermatitis acneiform (66%). Alopecia (18%) and pruritus (10%) occurred in patients who received KOSELUGO. Grade 3 rash occurred in 4.2% of patients. Rash resulted in dose interruption in 2.8% of patients, dose reduction in 2.8% of patients, and permanent discontinuation in 2.8% of patients. </content> </paragraph> <paragraph> <content styleCode="xmChange">Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.</content> </paragraph> <paragraph>Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction <content styleCode="italics">[see <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">Dosage and Administration (2.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8"> <id root="cd0b055f-9e17-4a2b-844a-43ad67bdfb97"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.5 Increased Creatine Phosphokinase </title> <text> <paragraph> <content styleCode="xmChange">KOSELUGO can cause increased creatine phosphokinase (CPK), myalgia, and rhabdomyolysis.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Pediatric Patients</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the NF1 PN pediatric safety pool (N = 134) <content styleCode="italics">[see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1)</linkHtml>]</content>, increased creatine phosphokinase (CPK), based on laboratory data, occurred in 73% of patients who received KOSELUGO, including Grade 3 or 4 in 8% of patients. Increased CPK resulted in dose interruption and dose reduction in 4% of patients. Increased CPK concurrent with myalgia occurred in 5% of patients, including one patient who permanently discontinued KOSELUGO for myalgia.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="italics">Adults</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">In the KOMET adult NF1 PN study (N = 71) <content styleCode="italics">[see <linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">Adverse Reactions (6.1</linkHtml>)]</content>, increased creatine phosphokinase (CPK), based on laboratory data, occurred in 70% of patients who received KOSELUGO, including Grade 3 or 4 in 7% of patients. Increased CPK resulted in dose interruption and dose reduction in 4.2% and 2.8% of patients, respectively. Increased CPK concurrent with myalgia occurred in 1.4% of patients. Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent.</content> </paragraph> <paragraph>Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction <content styleCode="italics">[see <linkHtml href="#ID_4e3ffdee-7038-48d1-b5ba-572109f19121">Dosage and Administration (2.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_2604d125-0030-474c-a1ef-62ab18340a0b"> <id root="feda27f9-1098-4ca1-b3a1-4125f533d619"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.6 Increased Levels of Vitamin E and Increased Risk of Bleeding (KOSELUGO Capsules) </title> <text> <paragraph>KOSELUGO capsules can cause increased levels of vitamin E and increased risk of bleeding.</paragraph> <paragraph>KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while KOSELUGO 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO and supplement) will exceed the recommended or safe limits.</paragraph> <paragraph>An increased risk of bleeding in patients may occur in patients who are co-administered vitamin K antagonists or anti-platelet antagonists with KOSELUGO capsules. Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin K antagonist. Perform anticoagulant assessments, including INR or prothrombin time, more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.</paragraph> <paragraph>KOSELUGO oral granules do not contain vitamin E <content styleCode="italics">[see <linkHtml href="#ID_4beb058e-fa95-47b6-853d-e96704d8eea2">Drug Interactions (7.1)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_1caa6ee7-5302-49c7-bedd-1bd70ce9868e"> <id root="debc67bc-4184-4f36-9ecd-a1e189fa567c"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.7 Embryo-Fetal Toxicity </title> <text> <paragraph> <content styleCode="xmChange">Based on findings from clinical trials, animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO.</content> </paragraph> <paragraph>In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo fetal survival at approximate exposures > 5 times the human exposure at the clinical dose of 25 mg/m<sup>2</sup> twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose <content styleCode="italics">[see <linkHtml href="#_8.1_Pregnancy">Use in Specific Populations (8.1</linkHtml>, <linkHtml href="#ID_d892a823-ad59-46db-8735-957bbd3684be">8.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_a934cf99-aeac-426c-b053-ce00b4468a59"> <id root="c3c70bb7-4fff-437c-af79-0747c96f9340"/> <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 clinically significant adverse reactions are described elsewhere in the labeling:</paragraph> <list listType="unordered"> <item> <caption>•</caption>Left Ventricular Dysfunction <content styleCode="italics">[see <linkHtml href="#ID_06cbec9d-94d0-4927-a175-a70517ad947f">Warnings and Precautions (5.1)</linkHtml>]</content> </item> <item> <caption>•</caption>Ocular Toxicity <content styleCode="italics">[see <linkHtml href="#ID_2e1f4415-e88b-4331-905d-83ed52fa1697">Warnings and Precautions (5.2)</linkHtml>] </content> </item> <item> <caption>•</caption>Gastrointestinal Toxicity <content styleCode="italics">[see <linkHtml href="#ID_bfcc51c5-7572-4441-a947-e1686a877dc0">Warnings and Precautions (5.3)</linkHtml>]</content> </item> <item> <caption>•</caption>Skin Toxicity <content styleCode="italics">[see <linkHtml href="#ID_af06e137-7226-443e-9e23-464cd07923be">Warnings and Precautions (5.4)</linkHtml>]</content> </item> <item> <caption>•</caption>Increased Creatine Phosphokinase <content styleCode="italics">[see <linkHtml href="#ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8">Warnings and Precautions (5.5)</linkHtml>]</content> </item> </list> </text> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <paragraph>Most common adverse reactions in pediatric patients (≥ 40%) are: vomiting, diarrhea, increased creatine phosphokinase, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia. (<linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">6.1</linkHtml>)</paragraph> <paragraph>Most common adverse reactions in adult patients (≥ 40%) are rash (all), dermatitis acneiform, and diarrhea. (<linkHtml href="#ID_89bb490d-30cc-42b5-a21c-7849630aefbf">6.1</linkHtml>)</paragraph> <paragraph> <content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact </content> <content styleCode="bold">AstraZeneca 1-800-236-9933</content> <content styleCode="bold"> or FDA at 1-800-FDA-1088 or <linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml> </content> </paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_89bb490d-30cc-42b5-a21c-7849630aefbf"> <id root="7a672b89-669c-469c-9771-c6c6a379fe8f"/> <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 NF1 PN pediatric safety pool described in the WARNINGS AND PRECAUTIONS reflects exposure to KOSELUGO at the recommended dosage in 134 pediatric patients in SPRINKLE (N = 36) (NCT05309668), SPRINT Phase I (N = 24) (NCT01362803), SPRINT Phase II Stratum 1 (N = 50) <content styleCode="italics">[see <linkHtml href="#ID_8723f141-8067-4b4e-be12-c6121cc3c927">Clinical Studies (14.1)</linkHtml>]</content>, and Phase I Food Effect Study (N = 24) (NCT05101148). Among pediatric patients, the duration of KOSELUGO exposure was 12 months or longer (80%), more than 2 years (44%), or more than 3 years (37%). The most common adverse reactions in pediatric patients (≥ 40%) are vomiting, diarrhea, increased creatine phosphokinase, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia.</paragraph> <paragraph>In the KOMET adult NF1 PN study, 71 adult patients received KOSELUGO at the recommended dosage <content styleCode="italics">[see <linkHtml href="#ID_8723f141-8067-4b4e-be12-c6121cc3c927">Clinical Studies (14.1)</linkHtml>]</content>. Among adult patients, the duration of KOSELUGO exposure in the randomized period was 6 months or longer (92%), and 11 months or longer (66%). The most common adverse reactions in adult patients (≥ 40%) are rash (all), dermatitis acneiform, and diarrhea.</paragraph> <paragraph> <content styleCode="underline">Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)</content> </paragraph> <paragraph> <content styleCode="italics">Pediatrics 2-18 years of Age (SPRINT Phase II Stratum 1)</content> </paragraph> <paragraph>The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1 <content styleCode="italics">[see <linkHtml href="#ID_8723f141-8067-4b4e-be12-c6121cc3c927">Clinical Studies (14.1)</linkHtml>]</content>. Eligible patients were 2-18 years of age with neurofibromatosis type 1 (NF1) who had inoperable plexiform neurofibromas (PN) that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure ≥ the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m<sup>2</sup> orally twice daily (N = 50). Among these patients, 88% were exposed for 12 months or longer and 66% were exposed for greater than 2 years.</paragraph> <paragraph>Serious adverse reactions occurred in 24% of patients who received KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea.</paragraph> <paragraph>Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.</paragraph> <paragraph>Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain.</paragraph> <paragraph>The most common adverse reactions (≥ 40%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.</paragraph> <paragraph>Table 10 presents the adverse reactions in SPRINT Phase II Stratum 1.</paragraph> <table width="100%"> <caption>Table 10 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1</caption> <col width="42%"/> <col width="29%"/> <col width="29%"/> <tbody> <tr> <td align="justify" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">KOSELUGO </content> </paragraph> <paragraph> <content styleCode="bold">(N = 50)</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="bold">All Grades</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grade ≥ 3 </content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> <sup>*</sup> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal </content> </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>82</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abdominal pain<footnote ID="_Ref37310624">Abdominal pain includes abdominal pain; abdominal pain upper</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>76</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>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>70</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>16</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>66</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Stomatitis<footnote ID="_Ref37311017">Stomatitis includes stomatitis; mouth ulceration</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>50</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>34</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">Skin and Subcutaneous Tissue </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Rash (all)<footnote ID="_Ref37311033">Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>80</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dry skin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>60</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>Rash acneiform<footnote ID="_Ref37311051">Rash (acneiform) includes dermatitis acneiform</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>50</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>Paronychia<footnote ID="_Ref37311066">Paronychia includes paronychia; nail infection</footnote> </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>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Pruritus</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>46</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>Dermatitis<footnote ID="_Ref37311126">Dermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hair changes<footnote ID="_Ref37311141">Hair changes include alopecia; hair color change</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Musculoskeletal pain<footnote ID="_Ref37311154">Musculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain</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>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fatigue<footnote ID="_Ref37311167">Fatigue includes fatigue; malaise</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>56</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</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>56</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>Edema<footnote ID="_Ref37311176">Edema includes peripheral swelling; edema; localized edema</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Nervous System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>48</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Respiratory, Thoracic and Mediastinal </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Epistaxis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28</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="middle"> <paragraph> <content styleCode="bold">Renal and Urinary System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hematuria</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>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Proteinuria</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Metabolism and Nutrition </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>22</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="middle"> <paragraph> <content styleCode="bold">Cardiac System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decreased ejection fraction </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Sinus tachycardia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Skin infection<footnote ID="_Ref37311189">Skin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="3" valign="top"> <paragraph> <sup>* </sup>All events were Grade 3.</paragraph> </td> </tr> </tbody> </table> <paragraph>Clinically relevant adverse reactions that occurred < 20% of patients include:</paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="italics">Eye:</content> visual impairment.</item> <item> <caption>•</caption> <content styleCode="italics">Gastrointestinal Disorders:</content> dry mouth.</item> <item> <caption>•</caption> <content styleCode="italics">General Disorders:</content> facial edema, including periorbital edema and face edema.</item> <item> <caption>•</caption> <content styleCode="italics">Metabolism and Nutrition:</content> increased weigh.t</item> <item> <caption>•</caption> <content styleCode="italics">Renal and Urinary System:</content> acute kidney injury.</item> <item> <caption>•</caption> <content styleCode="italics">Respiratory, Thoracic & Mediastinal:</content> dyspnea, including exertional dyspnea and dyspnea at rest.</item> <item> <caption>•</caption> <content styleCode="italics">Vascular:</content> hypertension.</item> </list> <paragraph>Table 11 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.</paragraph> <table width="100%"> <caption>Table 11 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1</caption> <col width="43%"/> <col width="26%"/> <col width="32%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Laboratory Abnormality</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">KOSELUGO </content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="bold">All Grades (%)</content> <footnote ID="_Ref37311846">The denominator used to calculate the rate varied from 39 to 49 based on the number of patients with a baseline value and at least one post-treatment value.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grade ≥ 3 (%)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Chemistry</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased creatine phosphokinase (CPK)</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>7<footnote ID="_Ref37311938">Includes one Grade 4 increased CPK and one Grade 4 increased potassium.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Decreased albumin</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</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased aspartate aminotransferase (AST)</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>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased alanine aminotransferase (ALT)</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased lipase</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased potassium</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Decreased potassium</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>2<sup>§</sup> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased alkaline phosphatase</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 styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased amylase</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 styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increased sodium</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 styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Decreased sodium</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</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hematology</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Decreased hemoglobin</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Decreased neutrophils</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>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> Decreased lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>2</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="italics">Adults ≥ 18 years of Age (KOMET)</content> </paragraph> <paragraph>The safety of KOSELUGO was evaluated in KOMET <content styleCode="italics">[see</content> <content styleCode="italics"> <linkHtml href="#_KOMET_NF1-PN_Patients">Clinical Studies (14.1)</linkHtml>]</content>. Eligible patients were 18 years of age or older with NF1 who had symptomatic, inoperable PN. Patients were excluded for abnormal LVEF, uncontrolled hypertension, any current or past history of RVO or RPED/CSR, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Among the patients (N = 137) who have received KOSELUGO, the median duration of KOSELUGO treatment was 11 months with a range of 10 days to 31 months.</paragraph> <paragraph>Serious adverse reactions occurred in 14% of patients who received KOSELUGO. Serious adverse reactions occurring in more than one patient included cellulitis (2.8%).</paragraph> <paragraph>Permanent discontinuation due to an adverse reaction occurred in 13% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included dermatitis acneiform, cellulitis, nausea, wound, neurofibrosarcoma, neurofibrosarcoma recurrent, psychiatric decompensation, ulcerative keratitis, and nail disorder.</paragraph> <paragraph>Dosage interruptions and dose reductions due to adverse reactions occurred in 27% and 14% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage reduction in 2 or more patients were paronychia, increased CPK, increased ALT, increased AST, rash, and alopecia. Adverse reactions requiring a dosage interruption in 2 or more patients were increased CPK, rash, headache, abdominal pain, nausea, and COVID‑19.</paragraph> <paragraph>The most common adverse reactions (≥ 40%) were rash (all), rash (acneiform), and diarrhea.</paragraph> <paragraph>Table 12 presents the adverse reactions in the KOMET study. The 12 cycle (48 weeks) randomization period for KOSELUGO versus placebo was followed by a single arm treatment period where all patients received KOSELUGO (placebo patients crossed over to KOSELUGO at end of the randomized period). No new adverse reactions were identified during the open-label period.</paragraph> <table cellpadding="0pt" width="100%"> <caption>Table 12 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO Compared with Placebo in KOMET</caption> <col width="34%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <col width="17%"/> <thead> <tr> <th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <content styleCode="bold">Adverse Reactions</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Randomized to</content> <br/> <content styleCode="bold">KOSELUGO</content> <sup>*</sup> <br/> <content styleCode="bold">(N = 71)</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Randomized to</content> <br/> <content styleCode="bold">Placebo</content> <sup>*</sup> <br/> <content styleCode="bold">(N = 74)</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All Grades</content> <br/> <content styleCode="bold">(%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades ≥ 3</content> <br/> <content styleCode="bold">(%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All Grades</content> <br/> <content styleCode="bold">(%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades ≥ 3</content> <br/> <content styleCode="bold">(%)</content> </th> </tr> </thead> <tbody> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Skin and Subcutaneous Tissue</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Rash (all)<footnote ID="_Ref215309538">Rash (all): acne, dermatitis, dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash follicular, rash maculo-papular, rash pruritic, rash pustular, urticaria, rash macular, and rash papular.</footnote> </item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>85</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Rash acneiform<footnote ID="_Ref215309829">Rash acneiform: acne and dermatitis acneiform</footnote> </item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>66</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Musculoskeletal and Connective Tissue</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Musculoskeletal pain<footnote ID="_Ref215309845">Musculoskeletal pain: arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity.</footnote> </item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Gastrointestinal</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Diarrhea</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Vomiting</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Nausea</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <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</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">General</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Edema<footnote ID="_Ref215309861">Edema: localized edema, edema, edema peripheral, and peripheral swelling.</footnote> </item> </list> </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</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>Fatigue<footnote ID="_Ref215309973">Fatigue: asthenia and fatigue.</footnote> </item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Toprule " valign="top"> <paragraph>* ADRs of patients during the 12 Cycle (48 weeks) randomization period.</paragraph> </td> </tr> </tbody> </table> <paragraph>Clinically relevant adverse reactions in < 20% of patients who received KOSELUGO versus placebo based on reported adverse reactions included hair changes (18% vs 11%), paronychia (13% vs 4%), pyrexia (7% vs 4%), stomatitis (18% vs 5%), and skin infection (6% vs 1%), respectively. Decreased ejection fraction in patients who received KOSELUGO versus placebo based on reported echocardiogram results occurred in 14% and 11% of patients, respectively.</paragraph> <paragraph>Table 13 presents the laboratory abnormalities in the KOMET study.</paragraph> <table cellpadding="0pt" width="100.12%"> <caption>Table 13 Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients Who Received KOSELUGO with a Difference Between Arms of > 10% Compared to Placebo in KOMET</caption> <col width="34%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <col width="16%"/> <tbody> <tr> <td rowspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Laboratory Abnormalities</content> </item> </list> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Randomized to</content> </paragraph> <paragraph> <content styleCode="bold">KOSELUGO</content> <sup>*</sup> </paragraph> <paragraph> <content styleCode="bold">(N = 71)</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Randomized to</content> </paragraph> <paragraph> <content styleCode="bold">Placebo</content> <sup>*</sup> </paragraph> <paragraph> <content styleCode="bold">(N = 74)</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">All Grades </content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades ≥</content> <content styleCode="bold">3</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">All Grades </content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades ≥</content> <content styleCode="bold">3</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Chemistry</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Increase creatine phosphokinase</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>70</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</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 Toprule Botrule " valign="top"> <paragraph>Increased aspartate aminotransferase (AST)</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>2.9</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</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Increased alanine aminotransferase (ALT)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Decreased albumin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Increased alkaline phosphatase</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>1.4</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 styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Increased amylase</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>1.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Decreased magnesium</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</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Hematology</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Decreased hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Toprule " valign="top"> <paragraph> <sup>*</sup> Lab abnormalities of patients during the 12 Cycle (48 weeks) randomization period.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="italics">Pediatrics > 1 year of Age on KOSELUGO Granules (SPRINKLE)</content> </paragraph> <paragraph>The safety of KOSELUGO oral granules was evaluated in SPRINKLE (NCT05309668), a dose-finding and activity estimating, single-arm, multicenter study in 36 pediatric patients ages 1 year to less than 7 years with a clinical diagnosis of NF1- related symptomatic, inoperable PN. The study evaluated the pharmacokinetics (PK), safety, efficacy, and tolerability of KOSELUGO oral granules. Study patients were to receive KOSELUGO oral granules for 25 cycles at a dose equivalent to 25 mg/m<sup>2</sup> BSA twice daily until disease progression or unacceptable toxicity. The median age was approximately 4 years (range: 1 to 7 years), 61% were male, 61% were White, 14% were Asian and 3% were Black or African American.</paragraph> <paragraph>In the SPRINKLE study, the median duration of KOSELUGO oral granules treatment in pediatric patients with neurofibromatosis type 1 (NF1) plexiform neurofibromas (PN) was 11 months (range: 3-25 months). Serious adverse reactions occurred in 6% of patients who received KOSELUGO oral granules. Serious adverse reactions occurred in 1 patient each and included pyrexia, gastroenteritis and upper respiratory infection. A total of 31% of patients had an adverse reaction leading to a dosage interruption. Adverse reactions requiring a dosage interruption in ≥ 5% of patients were pyrexia, vomiting, diarrhea, upper respiratory infection, gastroenteritis and eczema. The most common adverse reactions (≥ 40%) were pyrexia, dry skin, and paronychia.</paragraph> <paragraph>The observed safety profile of KOSELUGO oral granules in the SPRINKLE study was consistent with the known safety profile of KOSELUGO capsules.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_7dc7fd57-a71d-4094-9d24-be82ee7e39af"> <id root="a6da5492-4fe9-4e25-82e1-ffb3643c274f"/> <code code="34073-7" codeSystem="2.16.840.1.113883.6.1" displayName="DRUG INTERACTIONS SECTION"/> <title>7 DRUG INTERACTIONS </title> <effectiveTime value="20251119"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">Strong or Moderate CYP3A4 Inhibitors or Fluconazole</content>: Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration cannot be avoided, reduce the dose of KOSELUGO. (<linkHtml href="#ID_975d0775-d76d-4ef1-87a7-e022d5590bc9">2.5</linkHtml>, <linkHtml href="#ID_4beb058e-fa95-47b6-853d-e96704d8eea2">7.1</linkHtml>)</item> <item> <caption>•</caption> <content styleCode="underline">Strong or Moderate CYP3A4 Inducers</content>: Avoid concomitant use of strong and moderate CYP3A4 inducers. (<linkHtml href="#ID_4beb058e-fa95-47b6-853d-e96704d8eea2">7.1</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_4beb058e-fa95-47b6-853d-e96704d8eea2"> <id root="edf51bff-f073-4587-9b2b-b2066df963fb"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.1 Effect of Other Drugs on KOSELUGO </title> <text> <table cellpadding="0pt" width="100%"> <col width="16%"/> <col width="84%"/> <tbody> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph>Strong or Moderate CYP3A4 Inhibitors or Fluconazole</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Management</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Avoid concomitant use of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce KOSELUGO dosage <content styleCode="italics">[see <linkHtml href="#_2.4__Recommended">Dosage and Administration (2.4)</linkHtml>].</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations <content styleCode="italics">[see <linkHtml href="#ID_153e93c4-cf08-4d6f-a476-026d1a51ae68">Clinical Pharmacology (12.3)</linkHtml>]</content>, which may increase the risk of adverse reactions.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Strong or Moderate CYP3A4 Inducers</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Management</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Avoid concomitant use of strong or moderate CYP3A4 inducers with KOSELUGO.</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations <content styleCode="italics">[see <linkHtml href="#_12.3__Pharmacokinetics">Clinical Pharmacology (12.3)</linkHtml>]</content>, which may reduce KOSELUGO efficacy.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Vitamin E</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Management</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO capsules and supplement) will exceed the recommended or safe limits.</item> <item> <caption>•</caption>Monitor for bleeding in patients administered a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules. Increase INR monitoring, as appropriate, in patients taking a vitamin‑K antagonist<content styleCode="italics"> [see <linkHtml href="#_5.3x_Vitamin_E">Warnings and Precautions (5.3)</linkHtml>]</content>.</item> </list> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>KOSELUGO capsules contain vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin‑K antagonist or an anti‑platelet agent with KOSELUGO capsules.</item> </list> </td> </tr> </tbody> </table> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_001731d0-1100-4a05-babc-937a77ce4261"> <id root="7ef0860d-5a10-4e98-a2b7-3d0f565e1cc3"/> <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="20251119"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Lactation: Advise not to breastfeed. <linkHtml href="#ID_ed665125-565b-4456-962e-eee9d6a759dc">(8.2)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_2392b2e1-45c1-4044-9977-fa848e0a5453"> <id root="98de3cd8-9b38-47ff-9e4d-35ec300d1127"/> <code code="42228-7" codeSystem="2.16.840.1.113883.6.1" displayName="PREGNANCY SECTION"/> <title>8.1 Pregnancy </title> <text> <paragraph> <content styleCode="underline">Risk Summary</content> </paragraph> <paragraph>Based on findings from animal studies and its mechanism of action <content styleCode="italics">[see <linkHtml href="#ID_06f4e51a-f87f-48d1-abd2-b015e5897eb4">Clinical Pharmacology (12.1)</linkHtml>]</content>, KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m<sup>2</sup> twice daily (<content styleCode="italics">see Data</content>). Advise pregnant women of the potential risk to the 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="underline">Data</content> </paragraph> <paragraph> <content styleCode="italics">Human Data</content> </paragraph> <paragraph>In KOMET, a first trimester spontaneous abortion was reported in a patient receiving KOSELUGO.</paragraph> <paragraph> <content styleCode="italics">Animal Data</content> </paragraph> <paragraph>In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m<sup>2</sup> twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate, but did not induce significant maternal toxicity. </paragraph> <paragraph>Administration of selumetinib to pregnant mice from gestation Day 6 through lactation Day 20 resulted in reduced pup body weights and fewer pups met the pupil constriction criterion on day 21 post-partum. The incidence of malformations (e.g., prematurely open eye(s) and cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [C<sub>max</sub>] of ~0.6 times the human C<sub>max</sub> at the clinical dose of 25 mg/m<sup>2</sup> twice daily).</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_ed665125-565b-4456-962e-eee9d6a759dc"> <id root="716bdf81-df7d-4329-9b54-3034e0c1f6bf"/> <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 selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. Selumetinib and its active metabolite were present in the milk of lactating mice (<content styleCode="italics">see Data</content>). Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose. </paragraph> <paragraph> <content styleCode="underline">Data</content> </paragraph> <paragraph> <content styleCode="italics">Animal Data</content> </paragraph> <paragraph>Selumetinib and its active metabolite were present in milk from mice dosed with selumetinib throughout gestation and lactation, with a mean plasma/milk ratio of 1.5 in lactating dams dosed at 5 mg/kg twice daily. Administration of selumetinib to dams during gestation and early lactation was associated with adverse events in pups, including reduced growth rates and incidence of malformations <content styleCode="italics">[see <linkHtml href="#ID_2392b2e1-45c1-4044-9977-fa848e0a5453">Use in Specific Populations (8.1)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20250910"/> </section> </component> <component> <section ID="ID_d892a823-ad59-46db-8735-957bbd3684be"> <id root="26870e51-9730-480a-9eec-d366fe40759b"/> <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>KOSELUGO can cause fetal harm when administered to a pregnant woman <content styleCode="italics">[see <linkHtml href="#ID_2392b2e1-45c1-4044-9977-fa848e0a5453">Use in Specific Populations (8.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Pregnancy Testing</content> </paragraph> <paragraph>Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO <content styleCode="italics">[see <linkHtml href="#ID_2392b2e1-45c1-4044-9977-fa848e0a5453">Use in Specific Populations (8.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Contraception</content> </paragraph> <paragraph> <content styleCode="italics">Females</content> </paragraph> <paragraph>Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. </paragraph> <paragraph> <content styleCode="italics">Males</content> </paragraph> <paragraph>Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.</paragraph> </text> <effectiveTime value="20250910"/> </section> </component> <component> <section ID="ID_b81ba9cc-82f0-488e-9a75-17d7fa4e8260"> <id root="2d2524b8-170c-481f-ba46-509bdea811e1"/> <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 have been established in pediatric patients 1 year of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling. The safety and effectiveness of KOSELUGO have not been established in pediatric patients younger than 1 year of age.</paragraph> <paragraph> <content styleCode="underline">Animal Toxicity Data</content> </paragraph> <paragraph>In 3-month general toxicology studies, male rats receiving selumetinib at doses ≥ 10 mg/kg daily (~60-times the human exposure based on AUC at the clinical dose of 25 mg/m<sup>2</sup> twice daily) showed growth plate dysplasia. </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_c2df850d-1c1f-4cfc-b6f5-d6512f0eae7c"> <id root="c44b34fd-d5b1-4554-bf2a-f0326021b00a"/> <code code="34082-8" codeSystem="2.16.840.1.113883.6.1" displayName="GERIATRIC USE SECTION"/> <title>8.5 Geriatric Use </title> <text> <paragraph>Clinical studies of KOSELUGO did not include a sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_7f8b32f8-4409-487c-815c-97221abdb689"> <id root="c5e1ab6e-e9b0-4596-8453-983eb2e8ea02"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.6 Hepatic Impairment </title> <text> <paragraph>Selumetinib exposures increased in patients with moderate or severe hepatic impairment <content styleCode="italics">[see <linkHtml href="#ID_153e93c4-cf08-4d6f-a476-026d1a51ae68">Clinical Pharmacology (12.3)</linkHtml>]</content>. Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established <content styleCode="italics">[see <linkHtml href="#ID_152da0e5-0437-441e-a8b1-80a654492d59">Dosage and Administration (2.4)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_509b87f9-9ef8-4c70-aa0e-b416ea64e26c"> <id root="3d827d39-d1fc-4311-be5d-304cd83338a5"/> <code code="34088-5" codeSystem="2.16.840.1.113883.6.1" displayName="OVERDOSAGE SECTION"/> <title>10 OVERDOSAGE </title> <text> <paragraph>Dialysis is not effective as KOSELUGO is highly protein bound and is extensively metabolized.</paragraph> </text> <effectiveTime value="20251119"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_f210f16e-0521-478e-a1c0-1af4469e3b2e"> <id root="e3ef2922-4683-4f92-a77e-910817bb3747"/> <code code="34089-3" codeSystem="2.16.840.1.113883.6.1" displayName="DESCRIPTION SECTION"/> <title>11 DESCRIPTION </title> <text> <paragraph>KOSELUGO contains selumetinib sulfate, a kinase inhibitor. The chemical name is 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1<content styleCode="italics">H</content>-benzimidazol-3-ium hydrogen sulfate. The molecular formula for selumetinib sulfate is C<sub>17</sub>H<sub>17</sub>BrClFN<sub>4</sub>O<sub>7</sub>S and the relative molecular mass is 555.76 g/mol. Selumetinib sulfate has the following structural formula:</paragraph> <renderMultiMedia ID="id1688010714" referencedObject="ID_8e9461c8-92f8-47ef-b6b4-491381c09975"/> <paragraph>Selumetinib sulfate is a white to yellow monomorphic crystalline powder that exhibits a pH dependent solubility. Selumetinib sulfate is freely soluble at pH < 1.5, sparingly soluble in the pH range at 1.5 to 3 and slightly soluble at pH > 3. Selumetinib sulfate has two ionizable functions with pKa values of 2.8 and 8.4.</paragraph> <paragraph>KOSELUGO (selumetinib) 10 mg capsules for oral use, contain 10 mg selumetinib (equivalent to 12.1 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.</paragraph> <paragraph>KOSELUGO (selumetinib) 25 mg capsules for oral use, contain 25 mg selumetinib (equivalent to 30.25 mg selumetinib sulfate) and the excipient, vitamin E polyethylene glycol succinate. The capsule shell contains carnauba wax and/or cornstarch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide. The capsule is imprinted with black ink that contains carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac.</paragraph> <paragraph>KOSELUGO (selumetinib) 5 mg oral granules contain 5 mg selumetinib (equivalent to 6.05 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide yellow, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.</paragraph> <paragraph>KOSELUGO (selumetinib) 7.5 mg oral granules contain 7.5 mg selumetinib (equivalent to 9.08 mg selumetinib sulfate). The uncoated cores contain selumetinib sulfate, glyceryl dibehenate, and stearoyl polyoxylglycerides. The granule coating contains acetone, hypromellose acetate succinate, and stearic acid. The capsule shell contains ferric oxide red, hypromellose, and titanium dioxide. The capsule shell is imprinted with black ink that contains butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.</paragraph> </text> <effectiveTime value="20250910"/> <component> <observationMedia ID="ID_8e9461c8-92f8-47ef-b6b4-491381c09975"> <text>structure</text> <value mediaType="image/jpeg"> <reference value="chemicalstructure_selumetinib.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_0ad75699-8a84-4b05-b0a8-8781918c5652"> <id root="375350a1-3885-4c6b-b504-3d734de3f93a"/> <code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/> <title>12 CLINICAL PHARMACOLOGY </title> <effectiveTime value="20251119"/> <component> <section ID="ID_06f4e51a-f87f-48d1-abd2-b015e5897eb4"> <id root="aa15aa0e-fb5e-4f3c-ad8d-86c5f0d8686e"/> <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>Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers.</paragraph> <paragraph>In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.</paragraph> </text> <effectiveTime value="20250910"/> </section> </component> <component> <section ID="ID_22b059e7-0ba9-44c1-9418-84481efa428d"> <id root="faae4d30-0fa0-46d8-8828-d1be80de6c4d"/> <code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/> <title>12.2 Pharmacodynamics </title> <text> <paragraph>The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized.</paragraph> <paragraph> <content styleCode="underline">Cardiac Electrophysiology</content> </paragraph> <paragraph>At a dose 1.5-times the maximum recommended dose, clinically significant QTc interval prolongation was not observed.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_153e93c4-cf08-4d6f-a476-026d1a51ae68"> <id root="4ae3e20d-66b7-4595-8471-19e7513e9aae"/> <code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/> <title>12.3 Pharmacokinetics </title> <text> <paragraph>Selumetinib pharmacokinetics were observed at steady state in adult and pediatric patients with NF1 and are presented as mean (CV%) unless otherwise indicated.</paragraph> <paragraph>The maximum plasma concentration (C<sub>max</sub>) is 792 (49) ng/mL and systemic exposure (AUC) is 2141 (55) ng•h/mL following KOSELUGO 25 mg/m<sup>2</sup> twice daily. Selumetinib AUC and C<sub>max</sub> increases in a dose proportional manner over a dose range from 20 mg/m<sup>2</sup> to 30 mg/m<sup>2</sup> (0.8 to 1.2 times the recommended dose).</paragraph> <paragraph>Selumetinib accumulation range is 1.2-1.5 fold following administration of KOSELUGO at 25 mg/m<sup>2</sup>.</paragraph> <paragraph>At the recommended dosage of 25 mg/m<sup>2</sup> of KOSELUGO oral granules (sprinkled on smooth yogurt, smooth fruit sauce, smooth fruit puree, or smooth fruit jam) twice daily in pediatric patients (> 1 year old to < 7 years old), the AUC<sub>0-24h </sub>following the first dose of KOSELUGO oral granules was within the range of that in patients administered KOSELUGO capsules.</paragraph> <paragraph>No clinically relevant differences in the pharmacokinetics of selumetinib were observed following administration of a single-dose of either the granule or capsule dosage forms of KOSELUGO at equivalent dosages, under fasted and fed conditions, in healthy adults.</paragraph> <paragraph> <content styleCode="underline">Absorption</content> </paragraph> <paragraph>Selumetinib absolute oral bioavailability is 62%. Selumetinib median (min, max) time to maximum plasma concentrations (Tmax) is 1.5 (0.22, 6.0) hours.</paragraph> <paragraph> <content styleCode="italics">Effect of Food</content> </paragraph> <paragraph>No clinically significant differences in selumetinib pharmacokinetics were observed following administration of low fat (400-500 calories) or high-fat (800-1000 calories) meal.</paragraph> <paragraph> <content styleCode="underline">Distribution</content> </paragraph> <paragraph>Selumetinib apparent volume of distribution across a dose range of 20 mg/m<sup>2</sup> to 30 mg/m<sup>2</sup> (0.8 to 1.2 times the recommended dosage) ranges from 40 L-3710 L (66).</paragraph> <paragraph>The plasma protein binding is 98.4% (primarily albumin).</paragraph> <paragraph> <content styleCode="underline">Elimination</content> </paragraph> <paragraph>Selumetinib elimination half-life is 9 (28) hours with an apparent (oral) clearance of 16 (44) L/hr/m<sup>2</sup>.</paragraph> <paragraph> <content styleCode="italics">Metabolism</content> </paragraph> <paragraph>Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib can be attributed to CYP metabolism and about 29% to direct glucuronidation by UGT enzymes.</paragraph> <paragraph>The active metabolite, N desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and it is metabolized through the same routes as selumetinib.</paragraph> <paragraph>N-desmethyl selumetinib represents < 10% of selumetinib levels in human plasma, but is approximately 3- to 5- times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.</paragraph> <paragraph> <content styleCode="italics">Excretion</content> </paragraph> <paragraph>After a single oral dose of radiolabeled selumetinib 75 mg (1.5-times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent).</paragraph> <paragraph> <content styleCode="underline">Specific Populations</content> </paragraph> <paragraph>No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on age (1-79 years) race [White (56%), Asian (22%), Black (19%)].</paragraph> <paragraph> <content styleCode="italics">Pediatric Patients</content> </paragraph> <paragraph>No clinically significant differences in the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed between the pediatric (aged 1 to < 17 years) and adult patients.</paragraph> <paragraph> <content styleCode="italics">Patients with Renal Impairment</content> </paragraph> <paragraph>No clinically significant differences in selumetinib exposures were observed in patients with end stage renal disease (CLcr < 15 mL/min) who required dialysis. CLcr was estimated using the Cockroft-Gault formula.</paragraph> <paragraph> <content styleCode="italics">Patients with Hepatic Impairment</content> </paragraph> <paragraph>Dose normalized total AUC increased by 1.6-fold in patients with moderate hepatic impairment (Child-Pugh B) and in patients with severe hepatic impairment (Child-Pugh class C). Selumetinib unbound AUC increased by 1.4-fold in patients with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in patients with severe hepatic impairment (Child-Pugh C).</paragraph> <paragraph> <content styleCode="underline">Drug Interaction Studies</content> </paragraph> <paragraph> <content styleCode="italics">Clinical Studies and Model-Informed Approaches</content> </paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Strong or Moderate CYP3A4 Inhibitors:</content> </content> Selumetinib AUC increased by 1.5-fold and C<sub>max</sub> by 1.2-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor). Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 1.4-fold and C<sub>max</sub> by 1.2-fold.</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Fluconazole:</content> </content> Selumetinib AUC increased by 1.5 fold and C<sub>max</sub> by 1.3 fold following concomitant administration of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor).</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Strong or Moderate CYP3A4 Inducers:</content> </content> Selumetinib AUC decreased by 51% and C<sub>max</sub> by 26% following concomitant administration of rifampicin (strong CYP3A4 inducer). Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and C<sub>max</sub> by 22%.</paragraph> <paragraph> <content styleCode="italics">In Vitro</content> Studies</paragraph> <paragraph> <content styleCode="italics">CYP Enzymes:</content> Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6.</paragraph> <paragraph> <content styleCode="italics">Transporter Systems:</content> Selumetinib does not inhibit BCRP, P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K.</paragraph> <paragraph>Selumetinib is a substrate of BCRP and P-gp.</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_7097d005-11bf-48ab-964c-d687e38048ca"> <id root="9bd26f27-cad2-4479-800f-830957dab066"/> <code code="43680-8" codeSystem="2.16.840.1.113883.6.1" displayName="NONCLINICAL TOXICOLOGY SECTION"/> <title>13 NONCLINICAL TOXICOLOGY </title> <effectiveTime value="20251119"/> <component> <section ID="ID_c52a677c-5fa8-4586-8770-f34befbdd8bf"> <id root="92f157c1-840d-410d-ba5c-1f399596b23f"/> <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> <content styleCode="underline">Carcinogenicity</content> </paragraph> <paragraph>Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m<sup>2</sup>.</paragraph> <paragraph> <content styleCode="underline">Mutagenicity</content> </paragraph> <paragraph>Selumetinib was not mutagenic or clastogenic <content styleCode="italics">in vitro</content>. Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C<sub>max</sub> at the clinical dose of 25 mg/m<sup>2</sup>).</paragraph> <paragraph> <content styleCode="underline">Impairment of Fertility</content> </paragraph> <paragraph>In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m<sup>2</sup> twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5-times the human exposure based on AUC at the clinical dose of 25 mg/m<sup>2</sup> twice daily).</paragraph> </text> <effectiveTime value="20251119"/> </section> </component> <component> <section ID="ID_fa3e1509-f633-4890-b4d6-c81d7fe59775"> <id root="6838d6fd-1bfd-4ef7-ad11-1f5c3b890db1"/> <code code="34091-9" codeSystem="2.16.840.1.113883.6.1" displayName="ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION"/> <title>13.2 Animal Toxicology and/or Pharmacology </title> <text> <paragraph>In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m<sup>2</sup> twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.</paragraph> </text> <effectiveTime value="20250910"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_62e96065-f2d8-4be7-8137-363731f9474f"> <id root="0fd46a7f-8b8d-4872-b302-c7c65dab80d7"/> <code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/> <title>14 CLINICAL STUDIES </title> <effectiveTime value="20251119"/> <component> <section ID="ID_8723f141-8067-4b4e-be12-c6121cc3c927"> <id root="7f8029f6-0961-4220-b62f-4374af2c7aea"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.1 Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN) </title> <text> <paragraph> <content styleCode="italics"> <content styleCode="underline">Pediatrics 2 18 years of Age (SPRINT Phase II Stratum 1) </content> </content> </paragraph> <paragraph>The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an-open label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to the target PN. Morbidities that were present in > 20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received KOSELUGO 25 mg/m<sup>2</sup> orally twice daily until disease progression or unacceptable toxicity.</paragraph> <paragraph>The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). The target PN, defined as the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumor response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles. An additional efficacy outcome measure was duration of response (DoR).</paragraph> <paragraph>A total of 50 pediatric patients received KOSELUGO. The median age was 10.2 years (range 3.5 to 17.4 years); 60% were male; and 84% were White, 8% were Black and 2% were Asian.</paragraph> <paragraph>Efficacy results are provided in Table 14. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).</paragraph> <table width="100%"> <caption>Table 14 Efficacy Results from SPRINT Phase II Stratum 1</caption> <col width="48%"/> <col width="52%"/> <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">SPRINT </content> <br/> <content styleCode="bold">N = 50</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Response Rate </content> <footnote ID="_Ref37317779">Responses required confirmation at least 3 months after the criteria for first response were met.</footnote> <footnote ID="_Ref157421785">The ORR assessment (data cut-off date [DCO]: June 2018) was conducted by a single National Cancer Institute reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites.</footnote> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Overall Response Rate, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33 (66%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> 95% CI</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>(51, 79)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Complete Response<footnote ID="_Ref37317799">Complete response: disappearance of the target lesion; Partial response: decrease in target PN volume by ≥ 20% compared to baseline.</footnote> </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> Confirmed Partial Response, n (%)<footnoteRef IDREF="_Ref37317799"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33 (66%)</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Duration of Response</content> <footnote ID="_Ref157367432">DCO: March 2021.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Median (95% CI) months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>NR (41.2 – NE)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> DoR ≥ 24 months, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26 (79%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> DoR ≥ 36 months, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21 (64%)</paragraph> </td> </tr> <tr> <td colspan="2" valign="top"> <paragraph>CI – confidence interval, DoR – duration of response, NE – not evaluable, NR – not reached. </paragraph> </td> </tr> </tbody> </table> <paragraph>An independent centralized review of tumor response per REiNS criteria (data cut-off June 2018) resulted in an ORR of 44% (95% CI: 30, 59).</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Adults ≥ 18 years of Age (KOMET) </content> </content> </paragraph> <paragraph>The efficacy of KOSELUGO in adult patients was evaluated in KOMET, a randomized, multicenter, double-blind, placebo-controlled trial (NCT04924608). Eligible patients were required to be 18 years of age or older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibroma (PN). Inoperable plexiform neurofibroma (PN) is defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.</paragraph> <paragraph>A total of 145 patients were randomized (1:1) to KOSELUGO 25 mg/m<sup>2</sup> (BSA) or placebo twice daily for 12 cycles (28-day cycles). After the end of Cycle 12, or earlier if disease progression was confirmed by the Independent Central Review (ICR), patients initially randomized to placebo crossed over to receive KOSELUGO in the open-label treatment phase. Treatment was discontinued if a patient was no longer deriving clinical benefit, experienced unacceptable toxicity, patient decision, PN progression, or at the discretion of the investigator.</paragraph> <paragraph>One target and when applicable one non-target PN was assessed by using volumetric MRI analysis and REiNS criteria.</paragraph> <paragraph>The major efficacy outcome measure was overall response rate (ORR) by the end of Cycle 16, as determined by ICR per REiNS criteria. Duration of response was an additional efficacy outcome measure.</paragraph> <paragraph>The study demographics were 52% male, 56% White, 31% Asian, 6% Black or African American, 10% Hispanic or Latino ethnicity, and the median age was 29 years (range: 18 to 60 years). PN-related morbidities that were present in > 20% of patients included pain, motor dysfunction, and disfigurement. </paragraph> <paragraph>The trial demonstrated statistically significant ORR in patients randomized to KOSELUGO compared to placebo by the end of Cycle 16. The median time to response was 3.7 months (range: 3.6 months to 11.2 months).</paragraph> <paragraph>Efficacy results are shown in Table 15.</paragraph> <table width="100%"> <caption>Table 15 Efficacy Results from KOMET</caption> <col width="44%"/> <col width="27%"/> <col width="29%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Efficacy Parameters</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">KOSELUGO</content> </paragraph> <paragraph> <content styleCode="bold">(N = 71)</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">(N = 74)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Overall Response Rate by the end of Cycle 16 (ORR)<footnote ID="_Ref215315311">Patients with confirmed complete response or partial response by independent central review (ICR) per REiNS criteria. Response confirmation was by a consecutive scan within 3 to 6 months after the first response as determined by ICR per REiNS criteria.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>ORR % (95% CI)<sup/> <footnote ID="_Ref215315336">All.Partial responders.</footnote> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20 (11, 31)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5 (2, 13)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>p value<sup/> <footnote ID="_Ref215315367">2-sided p-value calculated using Fisher’s exact method.</footnote> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.011</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Duration of Response<sup/> <footnote ID="_Ref215315383">Calculated using Kaplan-Meier method.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Median (95% CI) months</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>NR (11.5, NE)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>ND</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>≥ 6 months, n (%)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12 (86%)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>ND</paragraph> </td> </tr> <tr> <td colspan="3" valign="top"> <paragraph>CI – confidence interval, ND – Not determined for placebo arm, NE – not estimable, NR - not reached.</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20251119"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_b2c1ebf6-07b7-406a-ab5c-2bf4d301d710"> <id root="e5d37f2e-6b69-4bcc-92d6-9839987a6ffb"/> <code code="34069-5" codeSystem="2.16.840.1.113883.6.1" displayName="HOW SUPPLIED SECTION"/> <title>16 HOW SUPPLIED/STORAGE AND HANDLING </title> <text> <paragraph> <content styleCode="underline">How Supplied</content> </paragraph> <paragraph> <content styleCode="italics">Selumetinib Capsules</content> </paragraph> <table width="100%"> <col width="20%"/> <col width="38%"/> <col width="21%"/> <col width="21%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Strength</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Description</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Capsules per Bottle</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">NDC Number</content> </paragraph> </td> </tr> <tr> <td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>10 mg</paragraph> </td> <td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>White to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0310-0610-60</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0310-0610-28</paragraph> </td> </tr> <tr> <td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>25 mg</paragraph> </td> <td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>Blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0310-0625-60</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>0310-0625-28</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="italics">Selumetinib Oral Granules</content> </paragraph> <table width="100%"> <col width="20%"/> <col width="38%"/> <col width="21%"/> <col width="21%"/> <thead> <tr> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <content styleCode="bold">Strength</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <content styleCode="bold">Description</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Capsules per Bottle</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <content styleCode="bold">NDC Number</content> </th> </tr> </thead> <tbody> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>5 mg</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>Off‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a yellow cap and white body. The cap is printed with “sel 5” in black ink, and body is printed with a sprinkle capsule image indicating opening.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0310‑0635‑60</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>7.5 mg</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>Off‑white to light‑yellow free‑flowing oral granules contained within capsules. The capsules have a pink cap and white body where the cap is printed with “sel 7.5” in black ink, and body is printed with a sprinkle capsule image indicating opening.</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph>0310‑0640‑60</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Storage</content> </paragraph> <paragraph> <content styleCode="italics">KOSELUGO Capsules</content> </paragraph> <paragraph>Store KOSELUGO capsules at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening.</paragraph> <paragraph> <content styleCode="italics">KOSELUGO Oral Granules</content> </paragraph> <paragraph>Store and transport KOSELUGO oral granules refrigerated at 2°C to 8°C (36°F to 46°F). After receipt, patients may store at room temperature 20°C to 25°C (68°F to 77°F). Do NOT exceed 30°C (86°F). KOSELUGO oral granules may clump together or stick to the capsule shell if exposed to high temperatures, which may lead to underdose. Dispense and store in the original bottle to protect from light and moisture. Do not remove desiccant. Keep the bottle tightly closed after first opening.</paragraph> </text> <effectiveTime value="20250910"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_28978d39-9a3e-4d4e-bfab-1c057a2e30b4"> <id root="e5286ca6-0104-43cd-8d30-61d3e4c1e944"/> <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 and Instructions for Use).</paragraph> <paragraph> <content styleCode="underline">Left Ventricular Dysfunction</content> </paragraph> <paragraph>Advise patients and caregivers that KOSELUGO can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider <content styleCode="italics">[see <linkHtml href="#ID_06cbec9d-94d0-4927-a175-a70517ad947f">Warnings and Precautions (5.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Ocular Toxicity</content> </paragraph> <paragraph>Advise patients and caregivers that KOSELUGO can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision <content styleCode="italics">[see <linkHtml href="#ID_2e1f4415-e88b-4331-905d-83ed52fa1697">Warnings and Precautions (5.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Gastrointestinal Toxicity</content> </paragraph> <paragraph>Advise patients and caregivers that KOSELUGO can cause diarrhea, nausea, vomiting, stomatitis and to contact their healthcare provider at the first sign of gastrointestinal toxicity <content styleCode="italics">[see <linkHtml href="#ID_bfcc51c5-7572-4441-a947-e1686a877dc0">Warnings and Precautions (5.3)</linkHtml>]</content>. </paragraph> <paragraph> <content styleCode="underline">Skin Toxicity</content> </paragraph> <paragraph>Advise patients and caregivers that KOSELUGO can cause serious skin toxicities and to contact their healthcare provider for severe skin changes <content styleCode="italics">[see <linkHtml href="#ID_af06e137-7226-443e-9e23-464cd07923be">Warnings and Precautions (5.4)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Increased Creatine Phosphokinase </content> </paragraph> <paragraph>Advise patients and caregivers that KOSELUGO can cause increased CPK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider <content styleCode="italics">[see <linkHtml href="#ID_66dea946-c2c9-4a5d-96e0-3978c533c6f8">Warnings and Precautions (5.5)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Increased Vitamin E Levels and Increased Risk of Bleeding (KOSELUGO Capsules)</content> </paragraph> <paragraph>Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist or an anti-platelet agent <content styleCode="italics">[see <linkHtml href="#ID_2604d125-0030-474c-a1ef-62ab18340a0b">Warnings and Precautions (5.6)</linkHtml>]</content>.</paragraph> <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 of reproductive potential to inform their healthcare provider of a known or suspected pregnancy <content styleCode="italics">[see <linkHtml href="#ID_1caa6ee7-5302-49c7-bedd-1bd70ce9868e">Warnings and Precautions (5.7)</linkHtml>, <linkHtml href="#ID_2392b2e1-45c1-4044-9977-fa848e0a5453">Use in Specific Populations (8.1)</linkHtml>].</content> </item> <item> <caption>•</caption>Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose <content styleCode="italics">[see <linkHtml href="#ID_d892a823-ad59-46db-8735-957bbd3684be">Use in Specific Populations (8.3)</linkHtml>]</content>.</item> <item> <caption>•</caption>Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose <content styleCode="italics">[see <linkHtml href="#ID_d892a823-ad59-46db-8735-957bbd3684be">Use in Specific Populations (8.3)</linkHtml>, <linkHtml href="#ID_c52a677c-5fa8-4586-8770-f34befbdd8bf">Nonclinical Toxicology (13.1)</linkHtml>]</content>.</item> </list> <paragraph> <content styleCode="underline">Lactation</content> </paragraph> <paragraph>Advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose <content styleCode="italics">[see <linkHtml href="#ID_ed665125-565b-4456-962e-eee9d6a759dc">Use in Specific Populations (8.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Drug Interactions</content> </paragraph> <paragraph>Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice, and Seville orange while taking KOSELUGO <content styleCode="italics">[see <linkHtml href="#ID_7dc7fd57-a71d-4094-9d24-be82ee7e39af">Drug Interactions (7)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Dosing and Administration</content> </paragraph> <paragraph>Inform patients and caregivers on how to take KOSELUGO and what to do for missed or vomited doses <content styleCode="italics">[see <linkHtml href="#ID_4397ea83-b8d5-4ffe-89ff-952afbe88d59">Dosage and Administration (2.1)</linkHtml>]</content>.</paragraph> <paragraph>Distributed by: </paragraph> <paragraph>AstraZeneca Pharmaceuticals LP </paragraph> <paragraph>Wilmington, DE 19850 </paragraph> <paragraph>© AstraZeneca 2025</paragraph> </text> <effectiveTime value="20251119"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_18df6168-0666-4cbf-8d59-fd346bc84402"> <id root="8200c198-e44b-42ca-85b1-9c34834b65c6"/> <code code="42230-3" codeSystem="2.16.840.1.113883.6.1" displayName="SPL PATIENT PACKAGE INSERT SECTION"/> <text> <table width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="top"> <paragraph> <br/> <content styleCode="bold">Patient Information</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">KOSELUGO<sup>®</sup> (ko-SEL-u-go)</content> </paragraph> <paragraph> <content styleCode="bold">(selumetinib)</content> </paragraph> <paragraph> <content styleCode="bold">capsules, for oral use</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">KOSELUGO<sup>®</sup> (ko-SEL-u-go)</content> </paragraph> <paragraph> <content styleCode="bold">(selumetinib)</content> </paragraph> <paragraph> <content styleCode="bold">oral granules</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What is KOSELUGO?</content> </paragraph> <paragraph>KOSELUGO is a prescription medicine that is used to treat adults and children 1 year of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cause symptoms and cannot be completely removed by surgery.</paragraph> <paragraph>It is not known if KOSELUGO is safe and effective in children under 1 year of age.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Before taking KOSELUGO, tell your healthcare provider about all of your medical conditions, including if you:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>have heart problems.</item> <item> <caption>•</caption>have eye problems.</item> <item> <caption>•</caption>have liver problems.</item> <item> <caption>•</caption>are pregnant or plan to become pregnant. KOSELUGO can harm your unborn baby.</item> </list> <paragraph> <content styleCode="bold">Females who are able to become pregnant:</content> </paragraph> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>∘</caption>Your healthcare provider should check to see if you are pregnant before you begin treatment with KOSELUGO.</item> <item> <caption>∘</caption>You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.</item> <item> <caption>∘</caption>Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with KOSELUGO.</item> </list> </item> </list> <paragraph> <content styleCode="bold">Males with female partners who are able to become pregnant:</content> </paragraph> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>∘</caption>You should use effective birth control (contraception) during treatment with KOSELUGO and for 1 week after your last dose.</item> </list> </item> <item> <caption>•</caption>are breastfeeding or plan to breastfeed. It is not known if KOSELUGO passes into your breast milk.<list listType="unordered"> <item> <caption>∘</caption> <content styleCode="bold">Do not</content> breastfeed during treatment with KOSELUGO and for 1 week after your last dose. </item> <item> <caption>∘</caption>Talk to your healthcare provider about the best way to feed your baby during this time.</item> </list> </item> </list> <paragraph> <content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Certain medicines may affect the way KOSELUGO works.</paragraph> <paragraph>Especially tell your healthcare provider if you are taking a supplement containing vitamin E, aspirin, blood thinners, or other medicines to treat blood clots. KOSELUGO capsules contain vitamin E, which may increase your risk of bleeding.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I take KOSELUGO?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Take or give KOSELUGO exactly as your healthcare provider tells you to.</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> change your dose or stop taking KOSELUGO unless your healthcare provider tells you to.</item> <item> <caption>•</caption>Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area).</item> <item> <caption>•</caption>Take or give KOSELUGO 2 times a day. </item> <item> <caption>•</caption>If you or your child miss a dose of KOSELUGO capsules or KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time.</item> <item> <caption>•</caption>If you or your child vomit after taking a dose of KOSELUGO capsules or KOSELUGO oral granules, <content styleCode="bold">do not</content> take an additional dose. Take the next dose at the regular scheduled time.</item> </list> <paragraph> <content styleCode="bold">KOSELUGO comes in capsules and oral granules.</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">If your healthcare provider prescribes KOSELUGO capsules:</content> <list listType="unordered"> <item> <caption>∘</caption>Take KOSELUGO capsules with or without food.</item> <item> <caption>∘</caption>Swallow KOSELUGO capsules whole. <content styleCode="bold">Do not</content> open, chew, or crush the capsules.</item> <item> <caption>∘</caption>Tell your healthcare provider if you or your child has trouble swallowing capsules.</item> </list> </item> <item> <caption>•</caption> <content styleCode="bold">If your healthcare provider prescribes KOSELUGO oral granules:</content> <list listType="unordered"> <item> <caption>∘</caption> <content styleCode="bold">See the Instructions for Use for the instructions on how to prepare and take or give KOSELUGO oral granules.</content> </item> <item> <caption>∘</caption>Prepare KOSELUGO oral granules by carefully opening the capsule and sprinkling all of the oral granules on a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.</item> <item> <caption>∘</caption>Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose.</item> <item> <caption>∘</caption>If the prepared dose of KOSELUGO oral granules and food mixture is not taken or given within 30 minutes, <content styleCode="bold">do not</content> take or give the prepared dose. Throw away the mixture and prepare a new dose.</item> <item> <caption>∘</caption>If part of a dose is taken or given within 30 minutes of preparing, throw away the remainder of the mixture and do not prepare a new dose. Take or give the full dose within 30 minutes next time.</item> <item> <caption>∘</caption>The KOSELUGO oral granules should flow freely. <content styleCode="bold">Do not</content> use if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens.</item> <item> <caption>∘</caption>Throw away the empty capsule shells after use.</item> <item> <caption>∘</caption> <content styleCode="bold">Do not </content>swallow, chew, or dissolve the capsule shells of KOSELUGO oral granules.</item> <item> <caption>∘</caption> <content styleCode="bold">Do not</content> chew or crush the KOSELUGO oral granules. Do not add oral granules to liquids.</item> <item> <caption>∘</caption> <content styleCode="bold">Do not</content> mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.</item> </list> </item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What should I avoid while taking KOSELUGO?</content> </paragraph> <paragraph>Avoid St John’s wort, grapefruit or grapefruit juice, and Seville orange during treatment with KOSELUGO.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">What are the possible side effects of KOSELUGO?</content> </paragraph> <paragraph> <content styleCode="bold">KOSELUGO can cause serious side effects, including:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Heart problems. </content>KOSELUGO can lower the amount of blood pumped by your heart, which can be severe. Your healthcare provider will do tests before and during treatment with KOSELUGO to check how well your heart is working. Tell your healthcare provider right away if you get any of the following signs or symptoms:</item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>persistent coughing or wheezing</item> <item> <caption>∘</caption>shortness of breath</item> <item> <caption>∘</caption>swelling of your ankles and feet</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>tiredness</item> <item> <caption>∘</caption>increased heart rate</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Eye problems. </content>KOSELUGO can cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get new or worsening vision changes, including:</item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>blurred vision</item> <item> <caption>∘</caption>loss of vision</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>dark spots in your vision (floaters)</item> <item> <caption>∘</caption>other changes to your vision</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Stomach, intestine, and mouth (gastrointestinal) problems.</content> KOSELUGO can cause diarrhea, vomiting, nausea, and mouth sores. Diarrhea can be severe with KOSELUGO. Tell your healthcare provider right away the first time that you get diarrhea during treatment with KOSELUGO. Your healthcare provider may give you medicine to help control your diarrhea and may tell you to drink more fluids.</item> <item> <caption>•</caption> <content styleCode="bold">Skin problems.</content> Koselugo can cause severe skin rashes. Tell your healthcare provider if you get any of the following signs of skin problems:</item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>rash that covers a large area of your body</item> <item> <caption>∘</caption>flat skin rash</item> <item> <caption>∘</caption>raised bumps on your skin</item> <item> <caption>∘</caption>skin bumps that look like acne</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>blisters</item> <item> <caption>∘</caption>peeling skin</item> <item> <caption>∘</caption>itchy rash</item> <item> <caption>∘</caption>hair thinning or hair loss (alopecia)</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Increased level of an enzyme called creatine phosphokinase (CPK) in your blood and muscle problems.</content> Koselugo can cause severe muscle problems. Treatment with KOSELUGO may increase the level of enzyme in your blood called creatine phosphokinase (CPK), which may be a sign of muscle damage. Increased level of CPK in the blood are common during treatment with KOSELUGO and can also be severe. Your healthcare provider should do a blood test to check your blood levels of CPK before and during treatment with KOSELUGO. Tell your healthcare provider right away if you get any of the following signs or symptoms:</paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>∘</caption>muscle aches or pain</item> <item> <caption>∘</caption>muscle spasms and weakness</item> </list> </item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>∘</caption>dark, reddish urine</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph>Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with KOSELUGO if you have any of these side effects.</paragraph> <paragraph> <content styleCode="bold">The most common side effects of KOSELUGO in children include:</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>•</caption>vomiting</item> <item> <caption>•</caption>diarrhea</item> <item> <caption>•</caption>increased level of an enzyme called creatine phosphokinase (CPK) in your blood</item> <item> <caption>•</caption>dry skin</item> </list> </item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>redness around the fingernails</item> <item> <caption>•</caption>nausea</item> <item> <caption>•</caption>skin bumps that look like acne</item> <item> <caption>•</caption>fever</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">The most common side effects of KOSELUGO in adults include:</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>rash</item> <item> <caption>•</caption>diarrhea</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>skin bumps that look like acne</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>These are not all of the possible side effects of KOSELUGO.</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 Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I store KOSELUGO?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Store KOSELUGO capsules and KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C).</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose.</item> <item> <caption>•</caption>Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere.</item> <item> <caption>•</caption>The bottle of KOSELUGO capsules and KOSELUGO oral granules contain a desiccant packet to reduce moisture. <content styleCode="bold">Do not</content> throw away the desiccant packet.</item> <item> <caption>•</caption>Keep KOSELUGO capsules and KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed.</item> </list> <paragraph> <content styleCode="bold">Keep KOSELUGO and all medicines out of the reach of children</content>.</paragraph> </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 KOSELUGO.</content> </paragraph> <paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. <content styleCode="bold">Do not</content> use KOSELUGO for a condition for which it was not prescribed. <content styleCode="bold">Do not</content> give KOSELUGO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KOSELUGO that is written for a healthcare professional.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">What are the ingredients in KOSELUGO?</content> </paragraph> <paragraph> <content styleCode="bold">Active ingredient:</content> selumetinib.</paragraph> <paragraph> <content styleCode="bold">KOSELUGO capsule inactive ingredients:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>The 10 mg and 25 mg capsules contain: vitamin E polyethylene glycol succinate.</item> <item> <caption>•</caption>The 10 mg capsule shell contains: carnauba wax, carrageenan, hypromellose, potassium chloride, purified water, and titanium dioxide.</item> <item> <caption>•</caption>The 10 mg capsule printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac.</item> <item> <caption>•</caption>The 25 mg capsule shell contains: carnauba wax and/or corn starch, carrageenan, FD&C blue 2, ferric oxide yellow, hypromellose, potassium chloride, purified water, and titanium dioxide.</item> <item> <caption>•</caption>The 25 mg capsule printing ink contains: carnauba wax, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, and shellac.</item> </list> <paragraph> <content styleCode="bold">KOSELUGO oral granule inactive ingredients:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>The 5 mg and 7.5 mg uncoated cores contain: glyceryl dibehenate and stearoyl polyoxylglycerides.</item> <item> <caption>•</caption>The 5 mg and 7.5 mg granule coatings contain: acetone, hypromellose acetate succinate, and stearic acid.</item> <item> <caption>•</caption>The 5 mg shell contains: ferric oxide yellow, hypromellose, and titanium dioxide.</item> <item> <caption>•</caption>The 5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.</item> <item> <caption>•</caption>The 7.5 mg shell contains: ferric oxide red, hypromellose, and titanium dioxide.</item> <item> <caption>•</caption>The 7.5 mg printing ink contains: butyl alcohol, dehydrated alcohol, ferric oxide black, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.</item> </list> <paragraph>Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850</paragraph> <paragraph>©AstraZeneca 2025</paragraph> <paragraph>For more information, go to website www.KOSELUGO.com or call 1-800-236-9933</paragraph> </td> </tr> </tbody> </table> <paragraph>This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2025</paragraph> </text> <effectiveTime value="20251119"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_9f68ff60-fa36-42a2-8e4b-13e8d319d821"> <id root="4fb92b32-c893-4124-8fd7-39e3bff7b806"/> <code code="59845-8" codeSystem="2.16.840.1.113883.6.1" displayName="INSTRUCTIONS FOR USE SECTION"/> <title>Instructions for Use </title> <text> <table styleCode="Noautorules" width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">INSTRUCTIONS FOR USE</content> </paragraph> <paragraph> <content styleCode="bold">KOSELUGO<sup>®</sup> (ko-SEL-u-go)</content> </paragraph> <paragraph> <content styleCode="bold">(selumetinib)</content> </paragraph> <paragraph> <content styleCode="bold">oral granules</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>This Instructions for Use contains information on how to take or give KOSELUGO oral granules.</paragraph> <paragraph> <content styleCode="bold">Read this Instructions for Use before taking or giving KOSELUGO oral granules and each time you get a refill. There may be new information</content>. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions about how to take or give KOSELUGO oral granules.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Important Information You Need to Know Before Taking or Giving KOSELUGO oral granules</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>KOSELUGO oral granules come in capsules that must be opened before use. Do not swallow, chew, or dissolve the capsule shells. Do not chew or crush the oral granules. Do not add oral granules to liquids.</item> <item> <caption>•</caption>Take or give KOSELUGO oral granules exactly as your healthcare provider tells you to.</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> change your dose or stop taking KOSELUGO oral granules unless your healthcare provider tells you to.</item> <item> <caption>•</caption>Your healthcare provider will decide on the right dose of KOSELUGO based on your or your child’s weight or size (body surface area).</item> <item> <caption>•</caption>KOSELUGO oral granules come in 2 different strengths: 5 mg and 7.5 mg. Each strength is a different color. Your healthcare provider may prescribe more than 1 strength of KOSELUGO oral granules for your or your child’s dose. Make sure that you understand how many capsules of KOSELUGO oral granules you need and what strengths to take.</item> <item> <caption>•</caption>Your healthcare provider may change the dose, temporarily stop, or permanently stop treatment with KOSELUGO oral granules if you or your child has side effects.</item> <item> <caption>•</caption>Take or give KOSELUGO oral granules 2 times a day.</item> <item> <caption>•</caption>If you or your child miss a dose of KOSELUGO oral granules, take or give the dose as soon as you remember, unless the next dose is due within 6 hours. If your scheduled dose is due within 6 hours, skip the dose and take or give the next dose at the regular time.</item> <item> <caption>•</caption>If you or your child vomits after taking a dose of KOSELUGO oral granules, do not take an additional dose. Take the next dose at the regular scheduled time.</item> <item> <caption>•</caption>For more information about KOSELUGO oral granules, see the Patient Information leaflet.</item> </list> <paragraph> <content styleCode="bold">Supplies needed to prepare a dose of KOSELUGO oral granules</content>:</paragraph> <list listType="unordered"> <item> <caption>•</caption>The prescribed number of KOSELUGO oral granules.</item> <item> <caption>•</caption>Smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry.</item> <item> <caption>•</caption>A spoon or a small cup.</item> <item> <caption>•</caption>A paper towel or plate.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Preparing KOSELUGO oral granules</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 1:</content> Wash and dry your hands thoroughly.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id-1174644363" referencedObject="ID_03426954-711c-4fdc-ad3a-024a36c94f4e"/> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 2:</content> Open the bottle(s) and take out the number of capsule(s) needed for your prescribed dose of KOSELUGO oral granules.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id1074934749" referencedObject="ID_5befa87d-755f-4183-aa03-20038b74865b"/> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 3:</content> Add a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing apple, banana, pear, or strawberry onto the spoon or into a small cup.</paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Do not</content> mix KOSELUGO oral granules in grapefruit or any juice, fruit puree or jam containing Seville orange.</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id-475219627" referencedObject="ID_76d30ac5-4eaf-476c-b745-f5e3ce2b5814"/> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 4:</content> Place the spoon or cup on the paper towel or plate. Carefully open the capsule(s) one at a time and sprinkle the entire contents of the capsule (oral granules) onto the food that is on the spoon or in the small cup.</paragraph> <list listType="unordered"> <item> <caption>•</caption>If you are using a spoon to prepare KOSELUGO oral granules, you may find it easier to prepare and take or give 1 capsule at a time. Repeat Steps 3 to 6 for each capsule until the full dose is taken or given.</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> swallow, chew, or dissolve the capsule shells. <content styleCode="bold">Do not</content> chew or crush the oral granules. <content styleCode="bold">Do not</content> add oral granules to liquids.</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id1476328214" referencedObject="ID_0d7e8298-3193-4487-81c2-c97e6cb6af06"/> <paragraph> <content styleCode="bold">Important:</content> The oral granules should flow freely inside the capsule. <content styleCode="bold">Do not</content> use the capsule if the oral granules are clumped or stuck inside the capsule shell. Contact your pharmacy if this happens.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Taking or giving KOSELUGO oral granules</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 5: </content>Take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose. Swallow the mixture without chewing while seated upright. <content styleCode="bold">Do not</content> save for future use.</paragraph> <paragraph> <content styleCode="bold">Note:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>If you <content styleCode="bold">do not</content> take or give the KOSELUGO oral granules and food mixture within 30 minutes of preparing the dose, <content styleCode="bold">do not</content> take or give the mixture. Throw away the mixture and prepare a new dose.</item> <item> <caption>•</caption>If you take or give part of the mixture within 30 minutes of preparing the dose, throw away the remainder of the mixture and <content styleCode="bold">do not</content> prepare a new dose. Take or give the full dose within 30 minutes next time.</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id-126553113" referencedObject="ID_902bb69e-82b6-4df4-bc22-b93ecf39ece4"/> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Step 6:</content> If you used a cup to prepare KOSELUGO oral granules, add more of the same food into the cup and take or give all of the mixture to make sure you get the full dose.</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <renderMultiMedia ID="id357248881" referencedObject="ID_4c715a3b-7130-482d-9183-0353a5721968"/> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Clean up</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Throw away empty capsule shells, used paper towel, and any spilled oral granules in your household trash.</item> <item> <caption>•</caption>Wash your hands and all the supplies used to take or give KOSELUGO oral granules.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Storing KOSELUGO oral granules</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Store KOSELUGO oral granules at room temperature between 68°F to 77°F (20°C to 25°C).</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> store KOSELUGO oral granules above 86°F (30°C). Store KOSELUGO oral granules in the refrigerator between 36°F to 46°F (2°C to 8°C) if the temperature is above 86°F (30°C). KOSELUGO oral granules may clump together or stick to the capsule shell if the medicine gets too hot, and you may not get your full dose.</item> <item> <caption>•</caption>Keep KOSELUGO oral granules cold in a cooler bag with a cold pack if you need to take it anywhere.</item> <item> <caption>•</caption>The bottle of KOSELUGO oral granules contains a desiccant packet to reduce moisture. <content styleCode="bold">Do not</content> throw away the desiccant packet.</item> <item> <caption>•</caption>Keep KOSELUGO oral granules in its original bottle to protect from light and moisture. Keep the bottle tightly closed.</item> </list> <paragraph> <content styleCode="bold">Keep KOSELUGO and all medicines out of the reach of children.</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Disposing of KOSELUGO oral granules</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Ask your pharmacist how to throw away unused doses, expired medicines, or medicines you no longer use.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850</paragraph> <paragraph>©AstraZeneca 2025</paragraph> <paragraph>For more information, go to website www.KOSELUGO.com or call 1-800-236-9933.</paragraph> </td> </tr> </tbody> </table> <paragraph>This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: Sep/2025</paragraph> </text> <effectiveTime value="20251119"/> <component> <observationMedia ID="ID_03426954-711c-4fdc-ad3a-024a36c94f4e"> <text>Step_1</text> <value mediaType="image/jpeg"> <reference value="Step_1.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_5befa87d-755f-4183-aa03-20038b74865b"> <text>Step_2</text> <value mediaType="image/jpeg"> <reference value="Step_2.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_76d30ac5-4eaf-476c-b745-f5e3ce2b5814"> <text>Step_3</text> <value mediaType="image/jpeg"> <reference value="Step_3.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_0d7e8298-3193-4487-81c2-c97e6cb6af06"> <text>Step_4</text> <value mediaType="image/jpeg"> <reference value="Step_4.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_902bb69e-82b6-4df4-bc22-b93ecf39ece4"> <text>Step_5</text> <value mediaType="image/jpeg"> <reference value="Step_5.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_4c715a3b-7130-482d-9183-0353a5721968"> <text>Step_6</text> <value mediaType="image/jpeg"> <reference value="Step_6.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_ec4954f5-738c-4429-a558-75bdf51e4b88"> <id root="50b66875-1b80-4d5a-8cba-5452bd300e93"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 10mg </title> <text> <paragraph>NDC 0310-0610-28</paragraph> <paragraph>Koselugo<sup>®</sup> </paragraph> <paragraph>(selumetinib)</paragraph> <paragraph>capsules</paragraph> <paragraph>10 mg</paragraph> <paragraph> <content styleCode="bold">Rx only</content> </paragraph> <paragraph>Dispense in original bottle. <content styleCode="bold">Do not remove</content> </paragraph> <paragraph> <content styleCode="bold">desiccant</content>. Protect from moisture.</paragraph> <paragraph>Keep the bottle tightly closed.</paragraph> <paragraph> <content styleCode="bold">28 Capsules</content> AstraZeneca</paragraph> <paragraph> <renderMultiMedia ID="id-2009817514" referencedObject="ID_019f044a-6f5b-4c43-b414-2fa50da8b058"/> </paragraph> </text> <effectiveTime value="20250910"/> <component> <observationMedia ID="ID_019f044a-6f5b-4c43-b414-2fa50da8b058"> <text>10mg 28count</text> <value mediaType="image/jpeg"> <reference value="10mgPDP.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_8487124f-c74a-4976-bad7-cd4e17b3676d"> <id root="24ebf67f-373f-41f5-baee-cd9b87464e55"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 25mg </title> <text> <paragraph>NDC 0310-0625-28</paragraph> <paragraph> <content styleCode="bold">Koselugo<sup>®</sup> </content> </paragraph> <paragraph>(selumetinib)</paragraph> <paragraph>capsules</paragraph> <paragraph>25 mg</paragraph> <paragraph> <content styleCode="bold">Rx only</content> </paragraph> <paragraph>Dispense in original bottle. <content styleCode="bold">Do not remove</content> </paragraph> <paragraph> <content styleCode="bold">desiccant</content>. Protect from moisture.</paragraph> <paragraph>Keep the bottle tightly closed.</paragraph> <paragraph> <content styleCode="bold">28 Capsules</content> AstraZeneca</paragraph> <renderMultiMedia ID="id501093103" referencedObject="ID_6d687f95-6679-4980-84d6-5d28adea2dc0"/> </text> <effectiveTime value="20251119"/> <component> <observationMedia ID="ID_6d687f95-6679-4980-84d6-5d28adea2dc0"> <text>25mg 28ct</text> <value mediaType="image/jpeg"> <reference value="25mgPDP.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_a58f4689-6701-4a9d-ad96-446460ecc772"> <id root="d4e8adad-b32d-4c68-bf7b-4f0b3bfa6fdd"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>Package/Label Display Panel 5 mg </title> <text> <paragraph>NDC 0310-0635-60</paragraph> <paragraph> <content styleCode="bold">Koselugo<sup>®</sup> </content> </paragraph> <paragraph>(selumetinib)</paragraph> <paragraph>Oral granules</paragraph> <paragraph>7.5 mg</paragraph> <paragraph>Sprinkle oral granules on or mix</paragraph> <paragraph>with smooth yogurt or fruit puree.</paragraph> <paragraph>Dispense and store in original </paragraph> <paragraph>bottle <content styleCode="bold">below 25° C (77°F)</content> to</paragraph> <paragraph>protect from light and moisture.</paragraph> <paragraph> <content styleCode="bold">60 Capsules</content> </paragraph> <paragraph> <content styleCode="bold">Rx only </content>Astrazeneca</paragraph> <renderMultiMedia ID="id1630899592" referencedObject="ID_9528a9fb-7cd6-4cbc-91a6-71b7f4bd7a8c"/> </text> <effectiveTime value="20250910"/> <component> <observationMedia ID="ID_9528a9fb-7cd6-4cbc-91a6-71b7f4bd7a8c"> <text>5mg_oral_granules</text> <value mediaType="image/jpeg"> <reference value="5mg_oral_granules.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_5108da7d-ce28-4374-a772-8aaf785bd8a7"> <id root="972f59c2-2ba7-4bac-b483-4113cc69b1d8"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>Package/Label Display Panel 7.5 mg </title> <text> <paragraph>NDC 0310-0640-60</paragraph> <paragraph> <content styleCode="bold">Koselugo<sup>®</sup> </content> </paragraph> <paragraph>(selumetinib)</paragraph> <paragraph>Oral granules</paragraph> <paragraph>7.5 mg</paragraph> <paragraph>Sprinkle oral granules on or mix</paragraph> <paragraph>with smooth yogurt or fruit puree.</paragraph> <paragraph>Dispense and store in original </paragraph> <paragraph>bottle <content styleCode="bold">below 25° C (77°F)</content> to</paragraph> <paragraph>protect from light and moisture.</paragraph> <paragraph> <content styleCode="bold">60 Capsules</content> </paragraph> <paragraph> <content styleCode="bold">Rx only</content> Astrazeneca</paragraph> <renderMultiMedia ID="id1108239510" referencedObject="F60E4249-958E-4E46-A8F1-6DD86E6F2CEF"/> </text> <effectiveTime value="20251119"/> <component> <observationMedia ID="F60E4249-958E-4E46-A8F1-6DD86E6F2CEF"> <text>7_5mg_oral_granules</text> <value mediaType="image/jpeg"> <reference value="7_5mg_oral_granules.jpg"/> </value> </observationMedia> </component> </section>

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The information provided on this site is intended for use by healthcare professionals practicing in the US. The dissemination of this information may be subject to different medical and regulatory requirements in other countries.

This web site is intended to help healthcare professionals practicing in the US and AstraZeneca authorized persons find scientifically balanced, evidence-based information about AstraZeneca drugs, submit a question, ask for field medical follow-up, and explore links to professional and patient support resources.

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This website is only intended for healthcare professionals practicing in the United States and authorized AstraZeneca personnel. AstraZeneca US Headquarters personnel and US Field Medical personnel are authorized to browse and search the database for their own background knowledge and insight. US Field Sales personnel should not access or browse this site. None of the content of this site should be directly linked or distributed without approval.

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