Teplizumab

Tzield is indicated to delay the onset of Stage 3 type 1 diabetes in adult and paediatric patients 8 years of age and older with Stage 2 type 1 diabetes (T1D).

Patient Selection Select adult and paediatric patients 8 years of age and older for Tzield treatment who have a diagnosis of Stage 2 type 1 diabetes. • Confirm Stage 2 type 1 diabetes by documenting: • At least two positive pancreatic islet cell autoantibodies • Dysglycaemia without overt hyperglycaemia • Ensure the clinical history of the patient does not suggest type 2 diabetes.

Laboratory Evaluation and Vaccination Prior to Initiation • Prior to initiating Tzield obtain a complete blood count and liver enzyme tests. 4): o Administer live-attenuated (live) vaccines at least 8 weeks prior to treatment. o Administer inactivated (killed) vaccines or mRNA vaccines at least 2 weeks prior to treatment.

4). Administer additional doses of premedication if needed. Posology Administer Tzield by intravenous infusion (over a minimum of 30 minutes), using a body surface area-based dosing (BSA), once daily for 14 consecutive days as follows: • Day 1: 65 mcg/m2 • Day 2: 125 mcg/m2 • Day 3: 250 mcg/m2 • Day 4: 500 mcg/m2 • Days 5 through 14: 1,030 mcg/m2 Do not administer two doses on the same day.

Missed Dose(s) If a planned Tzield infusion is missed, resume dosing by administering all remaining doses on consecutive days to complete the 14-day treatment course. Special populations Elderly patients Clinical studies of Tzield did not include patients 65 years of age and older.

Paediatric patients The safety and efficacy of Tzield in children younger than 8 years of age has not been established. No data are available. Method of administration Administer Tzield by intravenous infusion over a minimum of 30 minutes.

Do not administer two doses on the same day. 6.

Summary of safety profile Adverse reactions in patients treated with Tzield were evaluated in a pool of adult and paediatric patients who participated in five controlled clinical studies (one study in patients with Stage 2 T1D [Study TN-10], three placebo-controlled studies in an unapproved population (Stage 3 T1D), and one open-label standard-of-care controlled study of Tzield in an unapproved population (Stage 3 T1D)).

Lymphopenia, leukopenia, neutropenia, blood bicarbonate decreased, and rash were the most frequently reported adverse reactions, which occurred at a higher frequency in the teplizumab group compared to the control group. Tabulated list of adverse reactions The adverse reactions occurring in ≥5% of patients in the pooled safety analysis of clinical studies are shown in Table 1 per System Organ Class presented by frequency categories: very common: (≥1/10), common: (≥1/100 to <1/10), uncommon: (≥1/1000 to <1/100), rare: (≥1/10,000 to <1/1000), very rare: (<1/10,000), not known: (cannot be estimated from the available data).

Table 1. Adverse reactions occurring in ≥5% of patients in the pooled safety analysis of clinical studies. System Organ Class Frequency Category Very common Common Not known Blood and lymphatic system disorders Lymphopenia, Leukopenia, Neutropenia, Haemoglobin decreased, Thrombocytopenia Immune system disorders Cytokine release syndrome Nervous system disorders Headache Respiratory, thoracic and mediastinal disorders Nasopharyngitis Gastrointestinal disorders Nausea Diarrhoea Vomiting Skin and subcutaneous tissue disorders Rash, Pruritus Urticaria Rash Pruritic General disorders and administration site conditions Pyrexia Chills Fatigue, Pain, Illness Investigations Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood bicarbonate decreased, Blood calcium decreased Description of selected adverse reactions Cytokine Release Syndrome (CRS) In Study TN-10, CRS was reported in 2% of patients treated with Tzield compared to 0% of patients in the placebo group.

4). 5% were 5-10 times ULN. Serious Infections In Study TN-10, serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) were reported in 9% (4/44) of patients treated with Tzield compared to 0% (0/32) of patients treated with placebo any time during or after the first dose of study treatment.

Lymphopenia In Study TN-10, lymphopenia was reported in 73% of patients treated with Tzield compared to 6% of patients in the placebo group. 4). Rash and Hypersensitivity Reactions Hypersensitivity reactions were reported with Tzield in Study TN-10.

Serum sickness was observed in 2% (1/44) of patients treated with Tzield compared to 0% (0/32) of patients in the placebo group. 5 months. In the pool of 5 clinical trials of patients: • Anaphylaxis (with hypoxia and bronchospasm) was observed in one patient treated with Tzield who was hospitalised.

3% patients treated with Tzield, compared to 0% of patients in the control group. 6% of patients treated with Tzield and 0% of patients in the control group. • Rash was observed in 35% of patients treated with Tzield compared to 10% of patients in the control group.

3% (2/791) of patients treated with Tzield had a serious rash compared to 0% (0/245) of patients in the placebo group. 2% of patients in the control group. Other Adverse Reactions Haemoglobin Decreased and Thrombocytopenia In the pool of 5 clinical trials of patients, haemoglobin decreased was reported in 28% of patients treated with Tzield compared to 22% of patients in the placebo group, and thrombocytopenia was reported in 22% of patients treated with Tzield compared to 10% of patients in the placebo group during the 14-day treatment course; recovery occurred within 2 to 4 weeks of treatment.

5% of patients treated with Tzield discontinued treatment due to haemoglobin less than 85 g/L (or a decrease of more than 20 g/L to a value less than 100 g/L), and 1% discontinued Tzield due to platelet count less than 50 x 109 platelets/L.

Liver Enzyme and Bilirubin Elevations Liver enzyme and bilirubin elevations were observed in patients treated with Tzield, both in the context of CRS and in patients without CRS. 8% of patients in the control group. Most liver enzyme elevations were transient and resolved 1-2 weeks after treatment; 98% resolved by follow-up week 14.

Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of Tzield or of other teplizumab products.

In the placebo-controlled study in […]

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Teizeild is indicated to delay the onset of stage 3 type 1 diabetes (T1D) in adult and paediatric patients 8 years of age and older with stage 2 T1D.

Teizeild should be administered by a healthcare professional with access to appropriate medical support to manage potential severe adverse reactions. Laboratory evaluation and vaccination prior to initiation • Prior to initiating Teizeild, a complete blood count and liver enzyme tests should be obtained.

4 for detailed guidance). 4). Additional doses of premedication should be administered if needed. Posology Teizeild should be administered by intravenous infusion (over a minimum of 30 minutes), using a body surface area (BSA)-based dosing, once daily for 14 consecutive days as follows: • Day 1: 65 micrograms/m2 • Day 2: 125 micrograms/m2 • Day 3: 250 micrograms/m2 • Day 4: 500 micrograms/m2 • Days 5 through 14: 1 030 micrograms/m2 Missed dose(s) If a planned Teizeild infusion is missed, dosing should be resumed by administering all remaining doses on consecutive days to complete the 14-day treatment course.

Treatment discontinuation Temporary treatment discontinuation may be required according to the severity of laboratory abnormalities. Based on clinical judgment, treatment should be paused if platelet count, neutrophil count, or haemoglobin level decreases significantly.

Dose interruption should not exceed 3 days. g. if dosing is missed on Days 4 and 5, dosing may restart at Day 6 with the dosing level specified for Day 4). 8. Special populations Elderly Clinical studies did not include elderly patients (65 years of age and older).

2). 2). 2). Paediatric population The safety and efficacy of Teizeild in children younger than 8 years of age have not been established. Method of administration Teizeild should be administered by intravenous infusion over a minimum of 30 minutes.

Two doses should not be administered on the same day. 6 and at the end of the package leaflet.

8. Special populations Elderly Clinical studies did not include elderly patients (65 years of age and older). 2). 2). 2). Paediatric population The safety and efficacy of Teizeild in children younger than 8 years of age have not been established.

Method of administration Teizeild should be administered by intravenous infusion over a minimum of 30 minutes. Two doses should not be administered on the same day. 6 and at the end of the package leaflet. 1. 8). CRS symptoms included fever, nausea, fatigue, headache, myalgia, arthralgia, increased ALT, increased AST, and increased total bilirubin.

8). 2). • liver enzymes and bilirubin should be monitored during treatment, more frequently within the first week. Treatment should be discontinued in patients who develop elevated ALT or AST more than 5 times the upper limit of normal (ULN) or bilirubin more than 3 times ULN.

• Symptoms of CRS should be treated with antipyretics, antihistamines and/or antiemetics. If severe CRS develops, temporarily pausing dosing for 1-2 days should be considered (and the remaining doses to complete the full 14-day course should be administered on consecutive days).

If CRS does not improve or if CRS recurs despite the pause, discontinuing treatment may be warranted. 8). Use of Teizeild is not recommended in patients with active serious infection or chronic infection other than localised skin infections.

Patients should be monitored for signs and symptoms of infection during and after treatment. If serious infection develops, appropriate treatment should be provided and Teizeild should be discontinued. Lymphopenia In clinical studies, 75% of patients treated with Teizeild developed lymphopenia.

8). White blood cell counts should be monitored during the treatment period. 8). Hypersensitivity reactions Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in patients treated with Teizeild.

8). If severe hypersensitivity reactions occur, Teizeild should be discontinued and treatment should be provided promptly. Vaccinations The safety of immunisation with live-attenuated vaccines in patients treated with Teizeild has not been studied.

Additionally, Teizeild may interfere with the immune response to vaccination and decrease vaccine efficacy. 2). • Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to treatment, during treatment, or up to 6 weeks after completion of treatment.

• Live-attenuated vaccinations are not recommended within the 8 weeks prior to starting treatment, during treatment, or up to 52 weeks after completion of treatment. Glucose monitoring Blood glucose as well as signs and symptoms of hypoglycaemia or hyperglycaemia should be monitored and diabetes managed according to current practice guidelines.

g. diabetes secondary to medicinal products or surgery, monogenic diabetes). Educational/Safety advice tools Healthcare professionals involved in the management of patients treated with Teizeild must be familiar with the guides available for the safe use of this medicinal product and inform patients about the potential risks associated with the use of Teizeild.

• Guide for risk minimisation for Healthcare Professionals: Healthcare Professional Guide • Guide for risk minimisation for Patients: Patient Guide – to be provided to patients by healthcare professionals Excipients with known effect Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

6). 05 mg/mL. Polysorbates may cause allergic reactions. 5 Interaction with other medicinal products and other forms of interaction No drug interaction studies have been performed. Teizeild should be administered with caution in patients with concomitant medicinal products that are associated with significant liver abnormalities, cytopenias […]

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