Drug Detail:Tepezza (Teprotumumab [ tep-roe-toom-ue-mab ])
Drug Class: Growth hormone receptor blockers
Highlights of Prescribing Information
TEPEZZA (teprotumumab-trbw) for injection, for intravenous use
Initial U.S. Approval: 2020
Recent Major Changes
| Indications and Usage (1) | 4/2023 |
| Warnings, and Precautions, | |
| Hyperglycemia (5.3) | 12/2022 |
| Hearing Impairment Including Hearing Loss (5.4) | 7/2023 |
Indications and Usage for Tepezza
TEPEZZA is an insulin-like growth factor-1 receptor inhibitor indicated for the treatment of Thyroid Eye Disease (1)
Tepezza 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)
Dosage Forms and Strengths
For Injection: 500 mg lyophilized powder in a single-dose vial for reconstitution (3)
Contraindications
None (4)
Warnings and Precautions
- Infusion Reactions: If an infusion reaction occurs, interrupt or slow the rate of infusion and use appropriate medical management (5.1)
- Exacerbation of Preexisting Inflammatory Bowel Disease (IBD): Monitor patients with preexisting IBD for flare of disease; discontinue TEPEZZA if IBD worsens (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 pre-existing 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)
Adverse Reactions/Side Effects
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 Horizon at 1-866-479-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use In Specific Populations
Females of Reproductive Potential: Appropriate forms of contraception should be implemented prior to initiation, during treatment and for 6 months following the last dose of TEPEZZA (8.3)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 7/2023
Full Prescribing Information
1. Indications and Usage for Tepezza
TEPEZZA is indicated for the treatment of Thyroid Eye Disease regardless of Thyroid Eye Disease activity or duration.
2. Tepezza 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.
3. Dosage Forms and Strengths
For injection (intravenous infusion): 500 mg of teprotumumab as a white to off-white lyophilized powder in a single-dose vial for reconstitution and dilution.
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.
6. Adverse Reactions/Side Effects
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Infusion Reactions [see Warnings and Precautions (5.1)]
- Exacerbation of Preexisting 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)]
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 randomized, double-masked, placebo-controlled clinical studies (Study 1 [NCT:01868997] and Study 2 [NCT:03298867]) 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 clinical trials.
| 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* | 10 (12%) | 6 (7%) |
| Hyperglycemia† | 8 (10%) | 1 (1%) |
| Hearing impairment‡ | 8 (10%) | 0 |
| Dysgeusia | 7 (8%) | 0 |
| Headache | 7 (8%) | 6 (7%) |
| Dry skin | 7 (8%) | 0 |
| Weight decreased | 5 (6%) | 0 |
| Nail disorder§ | 4 (5%) | 0 |
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
In a placebo-controlled study with TEPEZZA, 1 of 42 patients treated with placebo had detectable levels of antidrug antibodies in serum. In the same study, none of the 41 patients treated with TEPEZZA had detectable levels of antidrug antibodies in serum.
6.3 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.
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. Use In Specific Populations
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).
11. Tepezza Description
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 contains 500 mg of teprotumumab-trbw, L-histidine (7.45 mg), L-histidine hydrochloride monohydrate (31.8 mg), polysorbate 20 (1 mg), and trehalose dihydrate (946 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.
12. Tepezza - 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.
12.3 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.
14. Clinical Studies
TEPEZZA was evaluated in 2 randomized, double-masked, placebo-controlled studies in 171 patients with Thyroid Eye Disease: Study 1 (NCT01868997) and Study 2 (NCT03298867). Patients were randomized to receive TEPEZZA or placebo in a 1:1 ratio. Patients were given intravenous infusions (10 mg/kg for first infusion and 20 mg/kg for the remaining 7 infusions) every 3 weeks for a total of 8 infusions. Patients had a clinical diagnosis of Thyroid Eye Disease with symptoms and were euthyroid or had thyroxine and free triiodothyronine levels less than 50% above or below normal limits. Prior surgical treatment for Thyroid Eye Disease was not permitted. Proptosis ranged from 16 to 33 mm and 125 patients (73%) had diplopia at baseline.
A total of 84 patients were randomized to TEPEZZA and 87 patients were randomized to placebo. The median age was 52 years (range 20 to 79 years), 86% were White, 9% were Black or African-American, 4% were Asian and 1% identified as Other. The majority (73%) were female. At baseline, 27% of patients were smokers.
The proptosis responder rate at week 24 was defined as the percentage of patients with ≥2 mm reduction in proptosis in the study eye from baseline, without deterioration in the non-study eye (≥2 mm increase) in proptosis. Additional evaluations included signs and symptoms of Thyroid Eye Disease including pain, gaze evoked orbital pain, swelling, eyelid erythema, redness, chemosis, inflammation, clinical activity score and assessments of functional vision and patient appearance. Results for proptosis are found in Table 2.
| Study 1 | Study 2 | |||||
|---|---|---|---|---|---|---|
| Teprotumumab (N=42) | Placebo (N=45) | Difference (95% CI) | Teprotumumab (N=41) | Placebo (N=42) | Difference (95% CI) |
|
|
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| Proptosis responder rate at week 24, % (n) * | 71% (30) | 20% (9) | 51% (33, 69) | 83% (34) | 10% (4) | 73% (59, 88) |
| Proptosis (mm) average change from baseline through week 24, LS Mean (SE) † | -2.5 (0.2) | -0.2 (0.2) | -2.3 (-2.8, -1.8) | -2.8 (0.2) | -0.5 (0.2) | -2.3 (-2.8, -1.8) |
In Study 2, improvement of proptosis as measured by mean change from Baseline was observed as early as 6 weeks and continued to improve through week 24 as shown in Figure 1. Similar results were seen in Study 1.
Figure 1. Change from Baseline in Proptosis over 24 Weeks in Study 2
P<0.01 at each timepoint
TEPEZZA also led to improvement in the less severely impacted "fellow" eye.
Diplopia (double vision) was evaluated in a subgroup of patients that had diplopia at baseline in Study 1 and 2. Results are shown in Table 3.
| Parameter | TEPEZZA (n=66) | Placebo (n=59) |
|---|---|---|
| P<0.01 | ||
|
||
| Diplopia | ||
| Responder rate* at week 24, % (n) | 53% (35) | 25% (15) |
Following discontinuation of treatment in Study 1, 53% of patients (16 of 30 patients) who were proptosis responders at week 24 maintained proptosis response 51 weeks after the last TEPEZZA infusion. 67% of patients (12 of 18) who were diplopia responders at week 24 maintained diplopia response 51 weeks after the last TEPEZZA infusion.
16. How is Tepezza supplied
TEPEZZA (teprotumumab-trbw) for injection is a sterile, preservative-free, white to off-white lyophilized powder available as follows:
| Carton containing one 500 mg single-dose vial | NDC 75987-130-15 |
| TEPEZZA
teprotumumab injection, powder, lyophilized, for solution |
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| Labeler - Horizon Therapeutics USA, Inc. (033470838) |
