PRINCIPAL DISPLAY PANEL - 500 mg Vial Carton

NDC-75987-130-15

TEPEZZA®
(teprotumumab-trbw)
for Injection

500 mg/vial

For Intravenous Infusion Only
Reconstitute and Further Dilute Prior to Use

Single-dose vial. Discard unused portion.

Rx Only

5 WARNINGS AND PRECAUTIONS

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 Exacerbation of Preexisting Inflammatory Bowel Disease

TEPEZZA may cause an exacerbation of preexisting inflammatory bowel disease (IBD). Monitor patients with IBD for flare of disease. If IBD exacerbation is suspected, consider discontinuation of TEPEZZA.

5.3 Hyperglycemia

Hyperglycemia or increased blood glucose may occur in patients treated with TEPEZZA. In clinical trials, 10% of patients (two thirds of whom had pre- existing diabetes or impaired glucose tolerance) experienced hyperglycemia. 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 pre-existing 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.

2 DOSAGE AND ADMINISTRATION

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 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 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 0.9% Sodium Chloride, USP volume withdrawn.

Step 4: Withdraw the required volume from the reconstituted TEPEZZA vial(s) based on the patient's weight (in kg) and transfer into an intravenous bag containing 0.9% Sodium Chloride Solution, USP to prepare a diluted solution with a total volume of 100 mL (for less than 1800 mg dose) or 250 mL (for 1800 mg and greater dose). Mix diluted solution by gentle inversion. Do not shake.

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. If refrigerated prior to administration, allow the diluted solution to reach room temperature prior to infusion.

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 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 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.

Do not administer as an intravenous push or bolus. TEPEZZA should not be infused concomitantly with other agents.

12 CLINICAL PHARMACOLOGY

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.

12.2 Pharmacodynamics

No formal pharmacodynamic studies have been conducted with teprotumumab-trbw.

12.3 Pharmacokinetics

The pharmacokinetics of teprotumumab-trbw was described by a two compartment population PK model based on data from 40 patients with Thyroid Eye Disease receiving an initial intravenous infusion of 10 mg/kg, followed by infusions of 20 mg/kg TEPEZZA every 3 weeks in one clinical trial. Following this regimen, the mean (± standard deviation) estimates for steady-state area under the concentration curve (AUC), peak (Cmax), and trough (Ctrough) concentrations of teprotumumab-trbw were 138 (± 34) mg∙hr/mL, 632 (± 139) mcg/mL, and 176 (± 56) mcg/mL, respectively.

Distribution

Following the recommended TEPEZZA dosing regimen, the population PK estimated mean (± standard deviation) for central and peripheral volume of distribution of teprotumumab-trbw were 3.26 (±0.87) L and 4.32 (± 0.67) L, respectively. The mean (± standard deviation) estimated inter-compartment clearance was 0.74 (± 0.16) L/day.

Elimination

Following the recommended TEPEZZA dosing regimen, the population PK estimated mean (± standard deviation) for the clearance of teprotumumab-trbw was 0.27 (± 0.08) L/day and for the elimination half-life was 20 (± 5) days.

Metabolism

Metabolism of teprotumumab-trbw has not been fully characterized. However, teprotumumab-trbw is expected to undergo metabolism via proteolysis.

Specific Populations

No clinically significant differences in the pharmacokinetics of teprotumumab- trbw were observed following administration of TEPEZZA based on patient's age (18-80 years), gender, race/ethnicity (103 White, 10 Black, and 3 Asian), weight (46-169 kg), mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min estimated by Cockcroft-Gault Equation), bilirubin levels (2.7-24.3 mcmol/L), aspartate aminotransferase (AST) levels (11-221 U/L), or alanine aminotransferase (ALT) levels (7-174 U/L). The effect of hepatic impairment on the pharmacokinetics of teprotumumab-trbw is unknown.

Drug Interactions

No studies evaluating the drug interaction potential of TEPEZZA have been conducted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of TEPEZZA has not been evaluated in long-term animal studies.

Mutagenesis

The genotoxic potential of TEPEZZA has not been evaluated.

Impairment of Fertility

Fertility studies have not been performed with TEPEZZA.

17 PATIENT COUNSELING INFORMATION

Embryo-Fetal Toxicity

• Advise females of reproductive potential that TEPEZZA can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
• Educate and counsel females of reproductive potential about the need to use effective contraception prior to initiation, during treatment with TEPEZZA and for 6 months after the last dose of TEPEZZA.

Infusion-related reactions

• Advise patients that TEPEZZA may cause infusion reactions that can occur at any time. Instruct patients to recognize the signs and symptoms of infusion reaction and to contact their healthcare provider immediately for signs or symptoms of potential infusion-related reactions.

Exacerbation of Preexisting Inflammatory Bowel Disease

• Advise patients on the risk of inflammatory bowel disease (IBD) and to seek medical advice immediately if they experience diarrhea, with or without blood or rectal bleeding, associated with abdominal pain or cramping/colic, urgency, tenesmus or incontinence.

Hyperglycemia

• Advise patients on the risk of hyperglycemia and, if diabetic, discuss with healthcare provider to adjust glycemic control measures including medications as appropriate. Encourage compliance with glycemic control.

Hearing Impairment Including Hearing Loss

• Advise patients that TEPEZZA may cause severe hearing impairment including hearing loss, which in some cases may be permanent. Instruct patients to contact their healthcare provider if they experience any signs or symptoms of hearing impairment or any changes in hearing.