TZIELD

/ Sanofi Israel Ltd

Patient Selection
Confirm Stage 2 type 1 diabetes by documenting:
*At least two positive pancreatic islet cell autoantibodies
* Dysglycemia without overt hyperglycemia using an oral glucose tolerance
test (if an oral glucose tolerance test is not available, an alternative
method for diagnosing dysglycemia without overt hyperglycemia may be
appropriate)
Ensure the clinical history of the patient does not suggest type 2 diabetes.
Laboratory Evaluation and Vaccination Prior to Initiation
* Prior to initiating this medical product, obtain a complete blood count and liver enzyme tests.
Use of this medical product is not recommended in patients with: Lymphocyte count less than 1,000 lymphocytes/mcL, Hemoglobin less than 10 g/dL, Platelet count less than 150,000 platelets/mcL, Absolute neutrophil count less than 1,500 neutrophils/mcL, Elevated ALT or AST greater than 2 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN, Laboratory or clinical evidence of acute infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV), Active serious infection or chronic active infection other than localized skin infections.
Administer all age-appropriate vaccinations prior to starting: Administer live-attenuated (live) vaccines at least 8 weeks prior to treatment. Administer inactivated (killed) vaccines or mRNA vaccines at least 2 weeks prior to treatment.
The following are important preparation and premedication instructions: Must dilute prior to use. Premedicate prior to infusion for the first 5 days of dosing with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or paracetamol, (2) an antihistamine, and/or (3) an antiemetic. Administer additional doses of premedication if needed.
Recommended Dosage and Administration
Administer by intravenous infusion (over a minimum of 30 minutes), using a body surface area-based dosing, 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.
See prescribing information for full details.

To delay the onset of Stage 3 type 1 diabetes in adults
and pediatric patients 8 years of age and older with Stage 2 type 1
diabetes.

Hypersensitivity to the active substance or to any of the excipients

Cytokine Release Syndrome: Cytokine release syndrome (CRS) has been observed in treated patients. In clinical trials, CRS was reported in 5% of treated patients compared to 0.8% of control-treated patients during the treatment period and through 28 days after the last study drug administration. CRS manifestations in treated patients included fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), and increased total bilirubin. These manifestations typically occurred during the first 5 days of treatment.
To mitigate CRS: Premedicate with antipyretics, antihistamines and/or antiemetics prior to treatment. Monitor liver enzymes and bilirubin during treatment. Discontinue 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 treated patients. In clinical trials, treated patients had a higher rate of serious infections (3.5%) than control- treated patients (2%), including gastroenteritis, cellulitis, pneumonia, abscess, sepsis. recommended in patients with active serious infection or chronic infection other than localized skin infections. Monitor patients for signs and symptoms of infection during and after treatment. If serious infection develops, treat appropriately, and discontinue teplizumab.
Lymphopenia: In clinical trials, 78% of treated patients developed lymphopenia compared to 11% of control-treated patients. For most treated patients 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. Severe lymphopenia (<500 cells per mcL) lasting 1 week or longer occurred in 0.9% of treated patients, and 0.5% of treated patients permanently discontinued this medical product because of lymphopenia. Monitor white blood cell counts during the treatment period. If prolonged severe
lymphopenia (<500 cells per mcL lasting 1 week or longer) develops,
discontinue teplizumab.
Hypersensitivity Reactions: Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred. If severe hypersensitivity reactions occur, discontinue use of teplizumab and treat promptly.
Vaccinations: The safety of immunization with live-attenuated vaccines in treated patients has not been studied. Additionally, teplizumab may interfere with the immune response to vaccination and decrease vaccine efficacy. Administer all age-appropriate vaccinations prior to starting teplizumab. Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to treatment, during treatment, or 6 weeks after completion of treatment. Live-attenuated vaccinations are not recommended within the 8 weeks prior to treatment, during treatment, or up to 52 weeks after treatment.
See prescribing information for full details.

Common (≥ 5%): Lymphopenia, Rash, Leukopenia, Headache, Neutropenia, Increased alanine aminotransferase, Nausea, Diarrhea, Nasopharyngitis.
See prescribing information for full details.

Pregnancy: Available case reports from clinical trials with teplizumab are insufficient to identify a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Although there are no data on teplizumab, monoclonal antibodies can be actively transported across the placenta, and teplizumab may cause immunosuppression in the utero- exposed infant. To minimize exposure to a fetus, avoid use of teplizumab during pregnancy and at least 30 days (6 half-lives) prior to planned pregnancy.
Fetal/Neonatal Adverse Reactions: Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because teplizumab may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to teplizumab in utero. There are insufficient data regarding infant serum levels of teplizumab at birth and the duration of persistence of teplizumab in infant serum after birth to identify a specific timeframe to delay live virus immunizations in infants exposed in utero.
Lactation: There are no data on the presence of teplizumab in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to teplizumab are unknown. Although the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for teplizumab and any potential adverse effects on the breastfed child or from the underlying maternal condition, a lactating woman may interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after teplizumab administration to minimize drug exposure to a breastfed child.

Refrigerate vials at 2°C to 8°C in the original carton to protect from light. Store upright. Do not freeze or shake the vials.
If not used immediately, store the diluted solution at room temperature 15°C to 30°C and complete infusion within 4 hours of the start of preparation. Discard the diluted solution if not administered within 4 hours of preparation