Teprotumumab

12.1 Mechanism of Action Teprotumumab-trbw's mechanism of action in patients with Thyroid Eye Disease has not been fully characterized. Teprotumumab-trbw binds to IGF-1R and blocks its activation and signaling.

1 INDICATIONS AND USAGE TEPEZZA is indicated for the treatment of Thyroid Eye Disease regardless of Thyroid Eye Disease activity or duration. TEPEZZA is an insulin-like growth factor-1 receptor inhibitor indicated for the treatment of Thyroid Eye Disease ( 1 )

2 DOSAGE AND ADMINISTRATION Initiate dosing with 10 mg/kg for first infusion, followed by 20 mg/kg every 3 weeks for 7 additional infusions ( 2.1 ) Administer TEPEZZA by intravenous infusion over 60 to 90 minutes ( 2.3 ) 2.1 Recommended Dosing The recommended dose of TEPEZZA is an intravenous infusion of 10 mg/kg for the initial dose followed by an intravenous infusion of 20 mg/kg every three weeks for 7 additional infusions. 2.2 Reconstitution and Preparation Step 1: Calculate the dose (mg) and determine the number of vials needed for the 10 or 20 mg/kg dosage based on patient weight. Each TEPEZZA vial contains 500 mg of the teprotumumab antibody. Step 2: Using appropriate aseptic technique, reconstitute each TEPEZZA vial with 10 mL of Sterile Water for Injection, USP. Ensure that the stream of diluent is not directed onto the lyophilized powder, which has a cake-like appearance. Do not shake, but gently swirl the solution by rotating the vial until the lyophilized powder is dissolved. The reconstituted solution has a total volume of 10.5 mL. Withdraw 10.5 mL of reconstituted solution to obtain 500 mg. After reconstitution, the final concentration is 47.6 mg/mL. Step 3: The reconstituted TEPEZZA solution must be further diluted in 0.9% Sodium Chloride Injection, USP prior to infusion. To prepare the diluted solution, use 100 mL infusion bags for a dose less than 1800 mg, and 250 mL infusion bags for a dose equal to or greater than 1800 mg. To maintain a constant volume in the infusion bag, a sterile syringe and needle should be used to remove the volume equivalent to the amount of the reconstituted TEPEZZA solution to be placed into the infusion bag. Discard the volume of 0.9% Sodium Chloride Injection, USP withdrawn. Step 4: Withdraw the required volume from the reconstituted TEPEZZA vial(s) based on the patient's weight (in kg) and transfer into the intravenous bag containing 0.9% Sodium Chloride Injection, USP. Mix diluted solution by gentle inversion. Do not shake. If refrigerated prior to administration, allow the diluted solution to reach room temperature prior to infusion. The product does not contain any preservative. The combined storage time of reconstituted TEPEZZA solution in the vial and the diluted solution in the infusion bag containing 0.9% Sodium Chloride Injection, USP is a total of 4 hours at room temperature 20°C to 25°C (68°F to 77°F) or up to 48 hours under refrigerated conditions 2°C to 8°C (36°F to 46°F) protected from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Upon reconstitution, TEPEZZA is a nearly colorless or slightly brown, clear to opalescent solution which is free of foreign particulate matter. Discard the solution if any particulate matter or discoloration are observed. Do not freeze the reconstituted or diluted solution. Discard vial(s) and all unused contents. No incompatibilities between TEPEZZA and polyethylene (PE), polyvinyl chloride (PVC), polyurethane (PUR) or polyolefin (PO) bags and intravenous administration sets have been observed. 2.3 Administration Administer the diluted solution intravenously over at least 90 minutes for the first two infusions. If well tolerated, the minimum time for subsequent infusions can be reduced to 60 minutes. If not well tolerated, the minimum time for subsequent infusions should remain at 90 minutes, and pre-medication is recommended for subsequent infusions. Do not administer as an intravenous push or bolus. TEPEZZA should not be infused concomitantly with other agents.

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