4.1. Therapeutic indications

TEPEZZA is indicated in adults for the treatment of moderate to severe Thyroid Eye Disease (TED) (see section 5.1).

4.2. Posology and method of administration

TEPEZZA must be administered as an intravenous infusion via an infusion pump.

TEPEZZA must be administered by a healthcare professional and under the supervision of a physician experienced in the diagnosis and treatment of TED with access to appropriate medical support to manage potential severe reactions such as serious infusion-related reactions.

Posology

TEPEZZA dosing is based on the patient's actual body weight. The recommended dose of TEPEZZA is 10 mg/kg of body weight for the initial dose followed by 20 mg/kg of body weight for 7 additional doses given once every three weeks as an intravenous infusion.

For the first 2 infusions, the diluted solution is administered as an intravenous infusion over at least 90 minutes. If well tolerated, infusions 3 to 8 can be administered over 60 minutes every three weeks. Available data suggest that clinical response is usually achieved within 8 doses of treatment.

Recommended pre-medication

For patients experiencing immediate hypersensitivity reactions or infusion-related reactions during the first two infusions of TEPEZZA, pre-medication with an antihistamine, antipyretic, corticosteroid products and/or administering all subsequent infusions at a slower infusion rate is recommended (see section 4.4).

Special populations

Elderly

Based on the available clinical data, no dose adjustment is considered necessary in patients over 65 years old (see section 5.2). There is no data in those over 80 years of age.

Renal impairment

No clinically significant differences in the pharmacokinetics of TEPEZZA were observed following administration of TEPEZZA to patients with mild to moderate renal impairment (see section 5.2).

No dose adjustment is considered necessary in patients with mild to moderate renal impairment.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of TEPEZZA is unknown. However, no clinically significant differences in the pharmacokinetics of TEPEZZA were observed following administration of TEPEZZA to patients with elevated bilirubin levels aspartate aminotransferase (AST) levels, or alanine aminotransferase (ALT) levels (see section 5.2).

Paediatric population

The safety and efficacy of TEPEZZA in children < 18 years of age has not been established. No data are available (see section 5.1).

Method of administration

• TEPEZZA must be administered as an intravenous infusion via an infusion pump.

• Prior to infusion:

- TEPEZZA must be reconstituted with water for injections

- The reconstituted TEPEZZA solution must be further diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion, prior to infusion

• TEPEZZA must not be co-administered with other medicinal products through the same infusion line.

• TEPEZZA must not be administered as an intravenous push or bolus.

• For the first 2 infusions, administer the diluted solution intravenously over at least 90 minutes. 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, the rate of infusion should be reduced and pre-medication is recommended for subsequent infusions.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infusion-related reactions

TEPEZZA may cause infusion reactions. Infusion reactions have been reported in approximately 4% of patients treated with TEPEZZA (see section 4.8). Patients should be advised to contact their healthcare professionals if they experience signs and symptoms of infusion-related reactions including but not limited to transient increases in blood pressure, feeling hot, tachycardia, dyspnoea, headache and muscular pain. Patients should be monitored closely throughout the infusion and for 90 minutes after completion of the infusion. Based on the severity of the infusion-related reaction, TEPEZZA infusion should be interrupted or discontinued, and appropriate medical management should be instituted. 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. For patients who experience an anaphylactic reaction, discontinue TEPEZZA immediately and permanently.

Hyperglycaemia

Hyperglycaemia or increased blood glucose may occur in patients treated with TEPEZZA. In double ‑masked TED clinical trials, 13.2% of patients (80% of whom had pre-existing diabetes or impaired glucose tolerance) experienced hyperglycaemia. Adverse events associated with hyperglycaemia may include diabetes mellitus, diabetic ketoacidosis, glucose tolerance impaired, glycosylated haemoglobin increased and a hyperosmolar hyperglycaemic state. Hyperglycaemic events should be managed with medications for glycaemic control, if necessary.

Assess patients for elevated blood glucose and symptoms of hyperglycaemia prior to infusion and continue to monitor while on treatment with TEPEZZA. Ensure patients with hyperglycaemia or pre‑existing diabetes are under appropriate glycaemic control before and while receiving TEPEZZA (see section 4.8). Blood glucose monitoring is recommended for 6 months after completion of treatment with teprotumumab.

Hearing impairment

TEPEZZA may cause severe hearing impairment including hearing loss, which in some cases may be permanent. Events associated with hearing impairment including hearing loss (reported as deafness, including neurosensory hypoacusis, deafness unilateral, eustachian tube dysfunction, eustachian tube patulous, hyperacusis, hypoacusis, autophony, tinnitus and tympanic membrane disorder), have been observed in clinical trials (13.8%) and post-marketing experience with TEPEZZA (see section 4.8).

Assess patients' hearing before, during and after treatment with TEPEZZA.

For patients with pre-existing hearing impairment, the benefit-risk of treatment should be considered.

The benefit-risk of continuing treatment with TEPEZZA should be reconsidered in patients who experience severe hearing impairment during the treatment. Patients should be advised to stop smoking and avoid high intensity noises during treatment with TEPEZZA.

Patients should be advised to report symptoms of altered hearing promptly to their healthcare professional.

Exacerbation of pre-existing inflammatory bowel disease (IBD)

TEPEZZA may cause an exacerbation of pre-existing inflammatory bowel disease (IBD). Monitor patients with IBD for flare of disease. If IBD exacerbation is suspected, consider discontinuation of TEPEZZA. Patients with pre-existing inflammatory bowel disease were excluded from clinical studies (see section 4.8).

Concomitant therapies

Caution is needed when co-administering TEPEZZA in patients who are receiving concomitant therapies known to cause ototoxicity (e.g. aminoglycosides, vancomycin, platinum containing chemotherapeutic medicinal products, loop diuretics) due to the potential risk of additive effects on hearing impairment.

Information about excipients

This medicine contains 1.05 mg of polysorbate 20 in each 10.5 mL reconstituted volume. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Since TEPEZZA is cleared from the circulation by proteolytic catabolism, no metabolic interactions with other medicinal products are expected.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception

Women of childbearing potential should use highly effective contraception while receiving TEPEZZA and for 6 months after the last administration of TEPEZZA.

Pregnancy

There are no adequate data from the use of teprotumumab in pregnant women. No human developmental and reproductive studies were conducted with teprotumumab.

Studies in animals have shown developmental toxicity (see section 5.3).

Based on the mechanism of action inhibiting IGF-1R and the teratogenic effects observed in animal developmental studies, TEPEZZA may cause congenital malformations such as foetal growth retardation and developmental anomalies when administered during pregnancy (see section 5.3). Therefore, TEPEZZA is contraindicated during pregnancy (see section 4.3).

If a patient becomes pregnant while taking TEPEZZA, therapy should be discontinued, and the patient advised of the potential risk to the foetus.

Breast-feeding

It is unknown whether teprotumumab is excreted in human milk. There are no data on the use of TEPEZZA in breast-feeding women and a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from TEPEZZA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effects of TEPEZZA in humans are unknown. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

TEPEZZA has the potential to have a minor influence on the ability to drive and use machines because fatigue and headaches have been reported with the use of TEPEZZA (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions observed in clinical trials are; muscle spasms (27.6%), diarrhoea (14.5%), hearing impairment (13.8%), alopecia (13.2%), hyperglycaemia (13.2%), fatigue (12.5%), nausea (10.5%), headache (10.5%), dry skin (9.9%), dysgeusia (8.6%), COVID-19 (6.6%), ear discomfort (6.6%) and nail disorder (5.9%).

The most common serious adverse reactions are; diarrhoea, inflammatory bowel disease, infusion ‑related reaction.

Tabulated list of adverse reactions

The adverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the medicinal product, such as the disease, other medicines or unrelated causes.

Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed below in table 1. The adverse reactions are listed by MedDRA System Organ Class and by frequency. The frequencies of adverse reactions is based on 4 placebo-controlled studies with 285 patients. Patients were exposed to teprotumumab for a median of 148 days.

Frequencies are defined according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

Table 1. Adverse reactions

MedDRA system organ class

Very common

(> 1/10)

Common

(> 1/100 to < 1/10)

Uncommon

(> 1/1 000 to < 1/100)

Rare

(> 1/10 000 to < 1/1 000)

Not known/cannot be estimated from available data

Infections and infestations

COVID-19

Metabolism and nutrition disorders

Hyperglycaemia1

Diabetic ketoacidosis

Hyperosmolar hyperglycaemic state2

Nervous system disorders

Headache

Dysgeusia

Ear and labyrinth disorders

Ear discomfort, Autophony, Deafness, Eustachian tube dysfunction, Eustachian tube patulous, Hypoacusis, Neurosensory hypoacusis, Tinnitus

Conductive deafness, Deafness unilateral, Hyperacusis, Tympanic membrane disorder

Gastrointestinal disorders

Diarrhoea

Nausea

Inflammatory bowel disease1

Skin and subcutaneous tissue disorders

Alopecia

Dry skin

Nail bed disorder, Nail discoloration, Onychoclasis

Ingrowing nail

Musculoskeletal and connective tissue disorders

Muscle spasms

Reproductive system and breast disorders

Amenorrhea, Hypomenorrhea, Dysmenorrhea, Irregular menstruation, Heavy menstrual bleeding

General disorders and administration site conditions

Fatigue

Investigations

Weight decreased

Injury, poisoning and procedural complications

Infusion ‑related reaction 1

1 See below description of selected adverse reactions

2 Observed in the post-marketing setting – frequency cannot be estimated from the available data.

Description of selected adverse reactions

Infusion-related reactions

Infusion-related reactions were usually mild or moderate in intensity and can be successfully managed with antihistamines and/or corticosteroids, if needed. No infusion-related reactions in TED trials were reported as anaphylactic reactions. See sections 4.2 and 4.4 for action to be taken in case of infusion ‑related reactions.

Inflammatory bowel disease (IBD)

In study TED01RV, a teprotumumab-treated participant, who had a pre-existing IBD, experienced severe diarrhoea. This serious adverse reaction (0.7%) led to the discontinuation of treatment, see section 4.4.

Hyperglycaemia

In clinical trials, all hyperglycaemia events reported in teprotumumab-treated patients were mild or moderate in severity. In the completed clinical trials, all events resolved. The mean time to onset of hyperglycaemia events was 67.8 days (range: 1 to 169 days) from first infusion of TEPEZZA. One serious event of Diabetic ketoacidosis was reported in a patient from the placebo group who received a single dose of TEPEZZA. This event was severe and resolved. The time to onset for this event was 20 days. Recommendations for management of hyperglycaemia are provided in section 4.4.

Hearing impairment

In clinical trials, the majority of hearing impairment events reported in teprotumumab-treated patients were mild or moderate in severity. The mean time to onset of hearing impairment events was 77.9 days (range: 3 to 153 days). One serious event of conductive deafness was reported for a teprotumumab-treated patient. This event was severe, led to discontinuation of Teprotumumab and did not resolve. The time to onset for this event was 152 days.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no known antidote for teprotumumab overdose. Treatment consists of discontinuation of the medicinal product and supportive therapy.