Description for Tepezza
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.
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)]
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.
Table 1: Adverse Reactions Occurring in 5% or More of Patients Treated with TEPEZZA and Greater Incidence than Placebo
|
Adverse Reactions |
TEPEZZA |
Placebo |
|
Muscle spasms |
21 (25%) |
6 (7%) |
|
Nausea |
14 (17%) |
8 (9%) |
|
Alopecia |
11 (13%) |
7 (8%) |
|
Diarrhea |
10 (12%) |
7 (8%) |
|
Fatiguea |
10 (12%) |
6 (7%) |
|
Hyperglycemiab |
8 (10%) |
1 (1%) |
|
Hearing impairmentc |
8 (10%) |
0 |
|
Dysgeusia |
7 (8%) |
0 |
|
Headache |
7 (8%) |
6 (7%) |
|
Dry skin |
7 (8%) |
0 |
|
Weight decreased |
5 (6%) |
0 |
|
Nail disorderd |
4 (5%) |
0 |
|
a Fatigue includes asthenia |
||
In clinical trials, gastrointestinal complaints including exacerbation of preexisting inflammatory bowel disease were reported.
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.
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
Drug Interactions for Tepezza
No information provided.
Warnings for Tepezza
Included as part of the PRECAUTIONS section.
Precautions for Tepezza
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.
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 (6.3)]. Monitor patients for signs and symptoms of IBD. If IBD exacerbation is suspected, discontinue use of TEPEZZA.
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.
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.
NONCLINICAL TOXICOLOGY
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.
Clinical Pharmacology for Tepezza
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.
Pharmacodynamics
No formal pharmacodynamic studies have been conducted with teprotumumab-trbw.
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.
Patient Information for Tepezza
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 Instruct patients to contact their healthcare provider if they experience any signs or symptoms of hearing impairment or any changes in hearing.
Manufactured by:
Horizon Therapeutics
Ireland DAC Dublin, Ireland
U.S. License No. 2022
Patent: https://pat.amgen.com/tepezza/
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