No.2 - Teprotumumab- (TEPEZZA) - (Jan  2020

 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 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 medications as appropriate.

Encourage compliance with glycemic control.

Manufactured by: Horizon Therapeutics Ireland DAC Dublin, Ireland U.S. License No. 2022

Distributed by: Horizon Therapeutics USA, Inc. Lake Forest, IL 60045

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TEPEZZA                safely and effectively.

See full prescribing information for TEPEZZA. TEPEZZA (teprotumumab-trbw) for injection, for intravenous use

Initial U.S. Approval: 2020

INDICATIONS AND USAGE

 TEPEZZA is an insulin-like growth factor-1 receptor inhibitor indicated for the treatment of Thyroid Eye Disease 

ADVERSE REACTIONS

 Most common adverse reactions (incidence greater than 5%) are muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dry skin, dysgeusia and headache

CONTRAINDICATIONS

 None

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 

Hyperglycemia: Monitor glucose levels in all patients; treat hyperglycemia with glycemic control medications

DOSAGE AND ADMINISTRATION

 Initiate dosing with 10 mg/kg for first infusion, followed by 20 mg/kg every 3 weeks for 7 additional infusions 

 Administer TEPEZZA by intravenous infusion over 60 to 90 minutes -

DOSAGE FORMS AND STRENGTHS

 For Injection: 500 mg lyophilized powder in a single-dose vial for reconstitution

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 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 glycem

Manufactured by: Horizon Therapeutics Ireland DAC Dublin, Ireland U.S. License No. 2022 Distributed by: Horizon Therapeutics USA, Inc. Lake Forest, IL 600

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 two clinical trials.

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 14 Reference ID: 4547685 BLA 761143 Page 15 (±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 Carcinogen

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary

Based on findings in animals and its mechanism of action inhibiting insulin-like growth factor 1 receptor (IGF-1R), TEPEZZA may cause fetal harm when administered to a pregnant woman.

Adequate and well-controlled studies with TEPEZZA have not been conducted in pregnant women.

There are insufficient data with TEPEZZA use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero teprotumumab exposure in cynomolgus monkeys dosed once weekly with teprotumumab throughout pregnancy resulted in external and skeletal abnormalities. Teprotumumab exposure may lead to an increase in fetal loss [see Data].

Therefore, TEPEZZA should not be used in pregnancy, and appropriate forms of contraception should be implemented prior to initiation, during treatment and for 6 months following the last dose of TEPEZZA. If the patient becomes pregnant during treatment,

TEPEZZA should be discontinued and the patient advised of the potential risk to the fetus. 12 Reference ID: 4547685 BLA 761143 Page 13

The background rate of major birth defects and miscarriage is unknown for the indicated population.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Data Animal Data In an abridged pilot embryofetal development study, seven pregnant cynomolgus monkeys were dosed intravenously at one dose level of teprotumumab, 75 mg/kg (2.8-fold the maximum recommended human dose (MRHD) based on AUC) once weekly from gestation day 20 through the end of gestation.

The incidence of abortion was higher for the teprotumumab treated group compared to the control group. Teprotumumab caused decreased fetal growth during pregnancy, decreased fetal size and weight at caesarean section, decreased placental weight and size, and decreased amniotic fluid volume. Multiple external and skeletal abnormalities were observed in each exposed fetus, including: misshapen cranium, closely set eyes, micrognathia, pointing and narrowing of the nose, and ossification abnormalities of skull bones, sternebrae, carpals, tarsals and teeth. The test dose, 75 mg/kg of teprotumumab, was the maternal no observed adverse effect level (NOAEL). Based on mechanism of action inhibiting IGF-1R, postnatal exposure to teprotumumab may cause harm.

8.2 Lactation Risk Summary There is no information regarding the presence of TEPEZZA in human milk, the effects on the breast-fed infant or the effects on milk production.

8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action inhibiting IGF-1R, TEPEZZA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception prior to initiation, during treatment with TEPEZZA and for 6 months after the last dose of TEPEZZA. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 13 Reference ID: 4547685 BLA 761143 Page 14

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). 10

OVERDOSAGE No information is available for patients who have received an overdosage.

11 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 a