TEPEZZA

5 WARNINGS AND PRECAUTIONS Infusion Reactions : If an infusion reaction occurs, interrupt or slow the rate of infusion and use appropriate medical management ( 5.1 ) Inflammatory Bowel Disease (IBD) : Monitor patients; for signs and symptoms of disease, including patients without a history of IBD; discontinue TEPEZZA if IBD exacerbation is suspected ( 5.2 ) Hyperglycemia : Assess patients for elevated blood glucose and symptoms of hyperglycemia prior to infusion and continue to monitor while on treatment with TEPEZZA. Ensure patients with hyperglycemia or preexisting diabetes are under appropriate glycemic control before and while receiving TEPEZZA ( 5.3 ) Hearing Impairment Including Hearing Loss: TEPEZZA may cause severe hearing impairment including hearing loss, which in some cases may be permanent. Assess patients' hearing before, during, and after treatment with TEPEZZA and consider the benefit-risk of treatment with patients ( 5.4 ) 5.1 Infusion Reactions TEPEZZA may cause infusion reactions. Infusion reactions have been reported in approximately 4% of patients treated with TEPEZZA. Signs and symptoms of infusion-related reactions include transient increases in blood pressure, feeling hot, tachycardia, dyspnea, headache and muscular pain. Infusion reactions may occur during any of the infusions or within 1.5 hours after an infusion. Reported infusion reactions are usually mild or moderate in severity and can usually be successfully managed with corticosteroids and antihistamines. In patients who experience an infusion reaction, consideration should be given to pre-medicating with an antihistamine, antipyretic, corticosteroid and/or administering all subsequent infusions at a slower infusion rate. 5.2 Inflammatory Bowel Disease TEPEZZA may cause an exacerbation of inflammatory bowel disease (IBD). IBD has been reported in some patients without a prior diagnosis of IBD [see Adverse Reactions (6.2) ]. Monitor patients for signs and symptoms of IBD. If IBD exacerbation is suspected, discontinue use of TEPEZZA. 5.3 Hyperglycemia Hyperglycemia or increased blood glucose may occur in patients treated with TEPEZZA. In the premarketing clinical trials, 10% of patients (two-thirds of whom had preexisting diabetes or impaired glucose tolerance) experienced hyperglycemia [see Adverse Reactions (6.1) ] . Hyperglycemic events should be controlled with medications for glycemic control, if necessary. Assess patients for elevated blood glucose and symptoms of hyperglycemia prior to infusion and continue to monitor while on treatment with TEPEZZA. Ensure patients with hyperglycemia or preexisting diabetes are under appropriate glycemic control before and while receiving TEPEZZA. 5.4 Hearing Impairment Including Hearing Loss TEPEZZA may cause severe hearing impairment including hearing loss, which in some cases may be permanent. Assess patients' hearing before, during, and after treatment with TEPEZZA and consider the benefit-risk of treatment with patients.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion Reactions [see Warnings and Precautions (5.1) ] Inflammatory Bowel Disease [see Warnings and Precautions (5.2) ] Hyperglycemia [see Warnings and Precautions (5.3) ] Hearing Impairment Including Hearing Loss [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence greater than 5%) are muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dry skin, dysgeusia, headache, weight decreased, and nail disorder ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The safety of TEPEZZA was evaluated in two premarketing randomized, double-masked, placebo-controlled clinical trials (Study 1 [NCT01868997] and Study 2 [NCT03298867]) consisting of 170 patients with Thyroid Eye Disease (84 received TEPEZZA and 86 received placebo). Patients were treated with TEPEZZA (10 mg/kg for first infusion and 20 mg/kg for the remaining 7 infusions) or placebo given as an intravenous infusion every 3 weeks for a total of 8 infusions. The majority of patients completed 8 infusions (89% of TEPEZZA patients and 93% of placebo patients). The most common adverse reactions (≥ 5%) that occurred at greater incidence in the TEPEZZA group than in the control group during the treatment period of Studies 1 and 2 are summarized in Table 1. In addition, menstrual disorders (amenorrhea, metrorrhagia, dysmenorrhea) were reported in approximately 23% (5 of 22 patients) of menstruating women treated with TEPEZZA compared to 4% (1 of 25 patients) treated with placebo in the premarketing clinical trials. Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with TEPEZZA and Greater Incidence than Placebo Adverse Reactions TEPEZZA N = 84 N (%) Placebo N = 86 N (%) Muscle spasms 21 (25%) 6 (7%) Nausea 14 (17%) 8 (9%) Alopecia 11 (13%) 7 (8%) Diarrhea 10 (12%) 7 (8%) Fatigue Fatigue includes asthenia 10 (12%) 6 (7%) Hyperglycemia Hyperglycemia includes blood glucose increase 8 (10%) 1 (1%) Hearing impairment Hearing impairment including hearing loss (deafness, including sensorineural deafness, eustachian tube dysfunction, hyperacusis, hypoacusis, autophony and tinnitus) 8 (10%) 0 Dysgeusia 7 (8%) 0 Headache 7 (8%) 6 (7%) Dry skin 7 (8%) 0 Weight decreased 5 (6%) 0 Nail disorder Nail disorder (includes nail discoloration, nail disorder and onychoclasis) 4 (5%) 0 In clinical trials, gastrointestinal complaints including exacerbation of inflammatory bowel disease were reported. In two postapproval trials, the following were the adverse reactions occurring ≥ 5% of participants treated with TEPEZZA during the double-masked treatment period: muscle spasms (29%), hearing impairment (19%), hyperglycemia (18%) diarrhea (16%), fatigue (13%), headache (13%), alopecia (10%), dry skin (10%), dysgeusia (9%), ear discomfort (9%), and nail disorder (6%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TEPEZZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: bowel perforation, exacerbation of inflammatory bowel disease (IBD), including patients without a prior diagnosis of IBD Metabolism and Nutrition Disorders: diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS) Otologic: severe hearing impairment including hearing loss, which in some cases may be permanent

<table width="75%"><caption>Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with TEPEZZA and Greater Incidence than Placebo</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center">Adverse Reactions</th><th styleCode="Rrule">TEPEZZA N = 84 N (%)</th><th styleCode="Rrule">Placebo N = 86 N (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Muscle spasms</td><td styleCode="Rrule">21 (25%)</td><td styleCode="Rrule">6 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">14 (17%)</td><td styleCode="Rrule">8 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alopecia</td><td styleCode="Rrule">11 (13%)</td><td styleCode="Rrule">7 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">10 (12%)</td><td styleCode="Rrule">7 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue<footnote>Fatigue includes asthenia</footnote></td><td styleCode="Rrule">10 (12%)</td><td styleCode="Rrule">6 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia<footnote>Hyperglycemia includes blood glucose increase</footnote></td><td styleCode="Rrule">8 (10%)</td><td styleCode="Rrule">1 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hearing impairment<footnote>Hearing impairment including hearing loss (deafness, including sensorineural deafness, eustachian tube dysfunction, hyperacusis, hypoacusis, autophony and tinnitus) </footnote></td><td styleCode="Rrule">8 (10%)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dysgeusia</td><td styleCode="Rrule">7 (8%)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">7 (8%)</td><td styleCode="Rrule">6 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry skin</td><td styleCode="Rrule">7 (8%)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight decreased</td><td styleCode="Rrule">5 (6%)</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Nail disorder<footnote>Nail disorder (includes nail discoloration, nail disorder and onychoclasis)</footnote></td><td styleCode="Rrule">4 (5%)</td><td styleCode="Rrule">0</td></tr></tbody></table>