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 Discard the volume of 0.9% Sodium Chloride Injection, USP withdrawn.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.

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.

6.1 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.

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

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Of the 171 patients in the two randomized trials, 15% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age).

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.

12.6 Immunogenicity

The observed incidence of anti-drug antibody is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibody in the studies described below with the incidence of anti-drug antibodies in other studies, including those of TEPEZZA.

In a randomized placebo-controlled study, HZNP-TEP-301, where active TED patients were administered placebo or TEPEZZA over a 24-week period, 2.4% (1 of 42) of placebo and 0% (0 of 41) of TEPEZZA treated patients tested positive for anti-teprotumumab antibodies at post-baseline visits.

Because of the low occurrence of anti-teprotumumab antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of teprotumumab products is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Subgroups

Examination of age and gender subgroups did not identify differences in response to TEPEZZA among these subgroups. Reduction in proptosis was similar between smokers and non-smokers in both studies.

Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton until time of use to protect from light. Do not freeze.

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.

Inflammatory Bowel Disease

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