TEPEZZA Powder for concentrate for solution for infusion Ref.[115480] Active ingredients: Teprotumumab

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

Teprotumumab may cause infusion reactions. Infusion reactions have been reported in approximately 4% of patients treated with teprotumumab (see section 4.8).

Infusion reactions may occur during any of the infusions or within 90 minutes after an infusion. Patients should be monitored closely throughout the infusion and for 90 minutes after completion of infusion.

Following the monitoring period, patients should be advised to contact their healthcare professionals if symptoms of infusion-related reactions, including transient hypertension, feeling hot, tachycardia, dyspnoea, headache, abdominal pain, muscular pain, palpitations, rash, haptic hallucinations, sleep paralysis, nasal congestion, urticaria, or diarrhoea occur.

Based on the severity of the infusion-related reaction, 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.

Hearing impairment

Teprotumumab 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, neurosensory hypoacusis, deafness unilateral, eustachian tube dysfunction, eustachian tube patulous, hyperacusis, hypoacusis, autophony and tinnitus and tympanic membrane disorder) have been observed in clinical trials (13.8%) and post-marketing experience with teprotumumab (see section 4.8).

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

For patients with pre-existing hearing impairment, worsening of hearing impairment symptoms during or after the completion of the treatment with teprotumumab can occur. The benefit-risk of treatment should be considered in these patients.

Patient's hearing should be assessed using audiometry before starting treatment (first infusion), during treatment (around the third or fourth infusion) and after completing treatment with teprotumumab. If a patient experiences subjective hearing changes during treatment, additional audiometric assessments are recommended, as necessary. It is advised to monitor for hearing changes in all patients for 6 months after completion of treatment. Prolonged follow-up may be needed for patients who develop hearing changes, at the discretion of the treating physician.

It should be strongly considered to discontinue teprotumumab in patients experiencing hearing loss that requires intervention, limits their ability to self-care, or is considered profound.

Concomitant therapies

Caution is needed when co-administering teprotumumab 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.

No interaction has been identified between teprotumumab and medicinal products that are known to cause muscle spasms (e.g. anti-thyroid drugs, fluoroquinolones, statins) (see section 4.5).

Hyperglycaemia

Hyperglycaemia may occur in patients treated with teprotumumab. Events associated with hyperglycaemia include blood glucose increased, diabetes mellitus, glucose tolerance impaired and glycosylated haemoglobin increased. In double-blind TED clinical trials, 13.2% of patients (80% of whom had pre-existing pre-diabetes or pre-existing diabetes mellitus) experienced hyperglycaemia or events associated with hyperglycaemia. One patient developed diabetic ketoacidosis. In the post-marketing setting, cases of hyperosmolar hyperglycaemic state have also been observed in patients with pre-diabetes and diabetes (see section 4.8).

Hyperglycaemia and related events should be managed with medicinal products for glycaemic control, if necessary. Patients must be assessed for elevated blood glucose and symptoms of hyperglycaemia prior to infusion and must be monitored while on treatment with teprotumumab. Patients with hyperglycaemia or pre-existing diabetes must be under appropriate glycaemic control before and while receiving teprotumumab (see section 4.8). Blood glucose monitoring is recommended for 6 months after completion of treatment with teprotumumab.

Exacerbation of pre-existing inflammatory bowel disease (IBD)

Teprotumumab may cause an exacerbation of pre-existing inflammatory bowel disease (IBD). Patients with IBD should be monitored for flare of disease. If IBD exacerbation is suspected, discontinuation of treatment should be considered. Patients with pre-existing inflammatory bowel disease were excluded from clinical studies (see section 4.8).

Contraception

Women of childbearing potential should use effective contraception during and for at least 6 months, after the last administration of teprotumumab (see section 4.6).

Additional precautions for use

Patients should be advised to stop smoking and avoid high intensity noises during treatment with teprotumumab. Additionally, blood pressure should be appropriately controlled before and while receiving teprotumumab.

Educational materials

All physicians who intend to prescribe TEPEZZA must ensure that they have received and are familiar with the healthcare professional educational material. Physicians must discuss the benefits and risks of this medicinal product with the patient and provide them with the patient guide. Patients should be instructed to seek immediate medical attention if they experience any signs or symptoms of hearing impairment during therapy. Women of childbearing potential must use effective contraception during treatment and should contact their treating physician immediately if they become pregnant.

Excipient with known effect

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

No interaction studies have been performed.

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

Women of childbearing potential/contraception

Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) prior to initiation, during treatment and for 6 months after the last administration of teprotumumab.

Pregnancy

There are no adequate data from the use of teprotumumab in pregnant women.

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

Based on the mechanism of action inhibiting insulin like growth factor-1 receptor (IGF-1R) and the teratogenic effects observed in animal developmental studies, teprotumumab 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. Teprotumumab induced developmental toxicity in animals (see section 5.3). Thus, as a precautionary measure, teprotumumab should not be used during breast-feeding.

Fertility

Studies to evaluate the effect of teprotumumab on fertility in humans have not been performed. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3). Among female participants of childbearing potential, menstrual disorders (Amenorrhea, Dysmenorrhoea, Heavy menstrual bleeding, Hypomenorrhoea, Menstruation irregular) have been reported during clinical trials (see section 4.8).

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

Summary of the safety profile

The most common adverse reactions are muscle spasms (27.6%), diarrhoea (14.5%), alopecia (13.2%), hyperglycaemia (13.2%), fatigue (12.5%), nausea (10.5%) and headache (10.5%).

The most important serious adverse reactions that have been reported are diabetic ketoacidosis (0.7%), conductive deafness (0.7%), deafness (1.3%), deafness unilateral (0.7%),diarrhoea (0.7%), infusion-related reaction (0.7%), diabetes mellitus (2.6%), and inflammatory bowel disease (0.7%), (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed below in table 1. The frequencies of adverse reactions are based on 4 placebo-controlled studies with 285 patients (teprotumumab = 152 patients; placebo = 133 patients). Patients were exposed to teprotumumab for a median of 148 days. 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 treatments or unrelated causes.

The adverse reactions are listed by MedDRA System Organ Class and by frequency. 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse reactions:

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 observed in 3.9% patients treated with teprotumumab and all were mild or moderate in intensity and transient and were successfully managed with antihistamines and/or corticosteroids, if needed. See sections 4.2 and 4.4 for action to be taken in case of infusion-related reactions.

Hearing impairment

In clinical studies, hearing impairment includes hearing loss [hypoacusis (5.3%), tinnitus (3.3%), deafness (1.3%), neurosensory hypoacusis (1.3%) and deafness unilateral (0.7%), eustachian tube dysfunction (1.3%), eustachian tube patulous (1.3%), autophony (1.3%), hyperacusis (0.7%) and tympanic membrane disorder (0.7%)]. One patient (0.7%) with pre-existing hearing impairment reported an event of neurosensory hypoacusis, which led to the discontinuation of teprotumumab. Additionally, one patient (0.7%) with pre-existing hearing impairment reported a serious event of conductive deafness, also resulting in the discontinuation of teprotumumab. For clinical management of hearing impairment, see section 4.4.

Hyperglycaemia

In clinical studies, hyperglycaemia (5.3%) and events associated with hyperglycaemia including blood glucose increased (3.3%), diabetes mellitus (2.6%), glucose tolerance impaired (1.3%), glycosylated haemoglobin increased (2.0%) were mild or moderate in severity and managed as needed with treatments used for glycaemic control. One event of diabetic ketoacidosis (0.7%) was reported in clinical studies for a patient who received a single-dose of teprotumumab. Post-marketing cases of hyperosmolar hyperglycaemic state have been reported. The events of diabetes mellitus, diabetic ketoacidosis, and hyperosmolar hyperglycaemic state all occurred in patients with pre-existing diabetes or pre-existing pre-diabetes, and other co-morbidities. Patients with diabetes or pre-diabetes at baseline may experience increased hyperglycaemic excursion, as insulin and IGF-1 receptors are homologous and share downstream signalling pathways. Recommendations for management of hyperglycaemia are provided in section 4.4.

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.

Alopecia and madarosis

In clinical studies, 13.2% of patients treated with teprotumumab experienced alopecia, and 2.0% experienced madarosis. Most cases were mild. Patients may experience unresolved hair loss after completing teprotumumab treatment.

Muscle spasms

In clinical studies, muscle spasms were the most commonly reported adverse events, occurring in 27.6% of patients. Some of these events developed greater than 4 months after the last infusion and lasted for more than 3 months. The majority of the events were mild, transient, self-limiting and were manageable without the need for interruption of teprotumumab treatment.

Onychoclasis

In clinical studies, onychoclasis was reported in 2.0% of patients and some of these events lasted for more than 3 months.

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 the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.