TEPROTUMUMAB: 150 Adverse Event Reports & Safety Profile

Teprotumumab-trbw, an insulin-like growth factor-1 receptor inhibitor (IGF-1R), is a fully human IgG1 monoclonal antibody produced in Chinese hamster ovary (CHO-DG44) cells. It has a molecular weight of approximately 148 kilodaltons. TEPEZZA (teprotumumab-trbw) for injection is supplied as a sterile, preservative-free, white to off-white, lyophilized powder for intravenous infusion. Each single-dose vial delivers 500 mg of teprotumumab-trbw, histidine (7.82 mg), L-histidine hydrochloride monohydrate (33.43 mg), polysorbate 20 (1.05 mg), and trehalose (898.43 mg). After reconstitution with 10 mL of Sterile Water for Injection, USP, the final concentration is 47.6 mg/mL with a pH of 5.5.

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 )

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.

None. None ( 4 )

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

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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&apos; hearing before, during, and after treatment with TEPEZZA and consider the benefit-risk of treatment with patients.