TZIELD

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.

Cytokine Release Syndrome Cytokine Release Syndrome (CRS) has been observed in patients treated with Tzield. In clinical trials, CRS was reported in 6% of patients treated with Tzield compared to 1% of patients in the control group during the treatment period and through 28 days after the last study drug administration.

CRS manifestations in patients treated with Tzield included fever, nausea, fatigue, headache, myalgia, arthralgia, increased ALT, increased AST, and increased total bilirubin. 8). 2). • Monitor liver enzymes and bilirubin during treatment.

Discontinue Tzield treatment 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. • Treat symptoms of CRS with antipyretics, antihistamines and/or antiemetics.

If severe CRS develops, consider temporarily pausing dosing for 1-2 days (and administer the remaining doses to complete the full 14-day course on consecutive days) or discontinuing treatment. Serious Infections Bacterial and viral infections have occurred in patients treated with Tzield.

8). Use of Tzield is not recommended in patients with active serious infection or chronic infection other than localised skin infections. Monitor patients for signs and symptoms of infection during and after Tzield treatment. If serious infection develops, treat appropriately, and discontinue Tzield.

Lymphopenia In clinical trials, 80% of patients treated with Tzield developed lymphopenia compared to 17% of patients in the control group. For most patients treated with Tzield who experienced lymphopenia, lymphocyte levels began to recover after the fifth day of treatment and returned to pre-treatment values within two weeks after treatment completion and without dose interruption.

8). Monitor white blood cell counts during the treatment period. 5 x 109 cells/L lasting 1 week or longer) develops, discontinue Tzield. 8). If severe hypersensitivity reactions occur, discontinue use of Tzield and treat promptly. Vaccinations The safety of immunisation with live-attenuated vaccines in patients treated with Tzield has not been studied.

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