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<title>5 WARNINGS AND PRECAUTIONS </title>
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<caption>•</caption>
<content styleCode="underline">Cardiomyopathy</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 dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">2.2</linkHtml>, <linkHtml href="#ID_8507719d-0e55-4e5a-9823-4366927ade6a">5.1</linkHtml>)</item>
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<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_07a2b215-93b8-49b4-836e-0d7aecab4cb7">2.2</linkHtml>, <linkHtml href="#ID_4cda2ecb-da55-4270-8119-8347e03f9f6f">5.2</linkHtml>) </item>
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<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 dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">2.2</linkHtml>, <linkHtml href="#ID_e543f923-0c3f-4a49-9df4-d2906a5158fc">5.3</linkHtml>)</item>
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<caption>•</caption>
<content styleCode="underline">Skin Toxicity</content>: Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">2.2</linkHtml>, <linkHtml href="#ID_3d97afde-5790-47f3-b9d8-3fda020f31ca">5.4</linkHtml>)</item>
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<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 dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. (<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">2.2</linkHtml>, <linkHtml href="#ID_e1f1a009-725c-454f-8b50-ba6a4b4c6fa9">5.5</linkHtml>) </item>
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<caption>•</caption>
<content styleCode="underline">Increased Vitamin E Levels and Risk of Bleeding</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 coadministered vitamin-K antagonists or anti-platelet agents. (<linkHtml href="#ID_a3787e6a-935c-481e-a590-41bbead8533f">5.6</linkHtml>)</item>
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<title>5.1 Cardiomyopathy </title>
<text>
<paragraph>Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% below baseline, occurred in 23% of 74 pediatric patients who received KOSELUGO in SPRINT <content styleCode="italics">[see <linkHtml href="#ID_041d0db3-a4d3-412b-b4c9-64d43beb1b07">Adverse Reactions (6.1)</linkHtml>]</content>. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients.</paragraph>
<paragraph>Left ventricular dysfunction or decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO. Decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in a pediatric population with NF1 in an expanded access program.</paragraph>
<paragraph>The safety of KOSELUGO has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.</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 <content styleCode="italics">[see <linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">Dosage and Administration (2.2)</linkHtml>]</content>. In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. 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>
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<title>5.2 Ocular Toxicity </title>
<text>
<paragraph>Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 pediatric patients receiving KOSELUGO in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients.</paragraph>
<paragraph>Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (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. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.</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_07a2b215-93b8-49b4-836e-0d7aecab4cb7">Dosage and Administration (2.2)</linkHtml>]</content>.</paragraph>
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<title>5.3 Gastrointestinal Toxicity </title>
<text>
<paragraph>Diarrhea occurred in 77% of 74 pediatric patients who received KOSELUGO in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days and the median duration was 2 days.</paragraph>
<paragraph>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. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent.</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_07a2b215-93b8-49b4-836e-0d7aecab4cb7">Dosage and Administration (2.2)</linkHtml>]</content>.</paragraph>
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<title>5.4 Skin Toxicity </title>
<text>
<paragraph>Rash occurred in 91% of 74 pediatric patients who received KOSELUGO in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients.</paragraph>
<paragraph>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. </paragraph>
<paragraph>Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">Dosage and Administration (2.2)</linkHtml>
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<content styleCode="italics">]</content>.</paragraph>
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<title>5.5 Increased Creatine Phosphokinase </title>
<text>
<paragraph>Increased creatine phosphokinase (CPK) occurred in 76% of 74 pediatric patients who received KOSELUGO in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued KOSELUGO for myalgia.</paragraph>
<paragraph>Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent. </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 </content>
<content styleCode="italics">
<linkHtml href="#ID_07a2b215-93b8-49b4-836e-0d7aecab4cb7">Dosage and Administration (2.2)</linkHtml>
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<content styleCode="italics">]</content>.</paragraph>
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<section ID="ID_a3787e6a-935c-481e-a590-41bbead8533f">
<id root="e747f544-914a-4cc0-b2e9-5e8780cafa07"/>
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<title>5.6 Increased Levels of Vitamin E and Risk of Bleeding </title>
<text>
<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 coadministered vitamin-K antagonists or anti-platelet antagonists with KOSELUGO. 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<content styleCode="italics"> [see <linkHtml href="#ID_fd9c62fb-6be4-4ea6-ab10-702c5d333cb3">Drug Interactions (7.1)</linkHtml>].</content>
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<title>5.7 Embryo-Fetal Toxicity </title>
<text>
<paragraph>Based on findings from animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. 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_2a780ab1-fbae-4574-b194-359e15e5cfbe">8.3)</linkHtml>]</content>.</paragraph>
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