Tzield

Tzield (teplizumab-mzwv) is a prescription medicine used for type 1 diabetes to slow the progression from stage 2 to stage 3 in adults and children 1 year of age and older. It is also used in Stage 3 type 1 diabetes to slow the decline in the body's own insulin production in recently diagnosed patients aged 8 to 17 years.

Tzield is administered as a daily infusion for 14 days for stage 2 type 1 diabetes, and two treatment courses of daily infusions for 12 days in patients with stage 3 type 1 diabetes.

Tzield works by targeting overactive immune cells (T cells) that mistakenly attack the insulin-producing beta cells. By binding to a protein called CD3 on these T cells, it slows the immune attack on the pancreas and helps preserve the body's own insulin production for longer, and delays disease progression. Tzield is a CD3-directed antibody.

Tzield is called a disease-modifying therapy as it targets the underlying cause of type 1 diabetes to delay or slow down its progression.

Type 1 diabetes (T1D) is an autoimmune disorder in which your immune system attacks and destroys the insulin-producing cells (beta cells) in the pancreas.

Stage 2 type 1 diabetes in adults and children aged 1 year and older, to delay the onset of Stage 3 type 1 diabetes, with confirmation of:

• at least two positive pancreatic islet cell autoantibodies, and
• blood sugar levels that fluctuate abnormally (dysglycemia) but without overly high blood sugar (hyperglycemia) using an oral glucose tolerance test (OGTT) or alternative test

Stage 3 type 1 diabetes (accelerated approval) in children and adolescents aged 8 to 17 years, recently diagnosed (within the last 8 weeks), to delay the decline in the body's own insulin production, with confirmation of:

• at least one positive pancreatic islet cell autoantibody, and
• Peak C-peptide greater than or equal to 0.2 pmol/mL on a mixed-meal tolerance test or alternative test

Confirmation of clinical benefit in follow-up trials is required for the Stage 3 indication.

Limitations of use

• Safety and effectiveness have not been well established in patients aged 45 years and older with Stage 2 type 1 diabetes
• This medicine is not effective as a disease-modifying therapy in non-autoimmune dysglycemic conditions

Tzield is given by intravenous (IV) infusion by a healthcare provider. The dosing schedule differs depending on the indication:

• Stage 2 type 1 diabetes: one daily infusion for 14 consecutive days (one course)
• Stage 3 type 1 diabetes: one daily infusion for 12 consecutive days, repeated for a second course 6 months later

Pre-medications:

You will be given other medications to help reduce the side effects of fever, headache, muscle and joint pain, or nausea. Medicines may include ibuprofen, naproxen, or other pain relievers such as acetaminophen, an antihistamine, and an anti-nausea medicine.

You should receive all appropriate vaccines before you start using this medicine. Live-attenuated (live) vaccines should be given at least 8 weeks before Tzield treatment. Inactivated (killed) vaccines or mRNA vaccines should be given at least 2 weeks prior to treatment.

You will need regular blood tests before and during treatment with Tzield.

Your treatment may be temporarily or permanently discontinued if you have certain side effects.

Tzield carries a Boxed Warning for serious life-threatening cases of viral reactivation, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation.

Viral Reactivation. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common viruses that may stayinactive in your body after an initial infection. Tzield may cause these viruses to become active again, which, especially in people with a weakened immune system, can become serious and potentially life-threatening. These infections can happen during treatment with Tzield and for up to 2 months after your last dose. Your healthcare provider will test you for active EBV and CMV infections before treatment with Tzield.Contact your healthcare provider right away if you develop symptoms of an infection during or after treatment with Tzield (such as fever, swollen glands, or fatigue)

Other serious side effects that can occur with Tzield include:

• Cytokine Release Syndrome is a serious side effect that may occur during the first 5 days of treatment. Tell your healthcare provider right away if, during treatment, you develop any of these signs and symptoms: feeling unusually tired, fever, headache, nausea, or muscle and joint pain.
• Serious Infections. Treatment with Tzield may lower your immune system's ability to fight infections, which may increase your risk of getting a serious infection. Tzield is not recommended if you currently have a serious infection, or an infection that keeps coming back or does not go away (chronic infection), other than a minor skin infection. Contact your healthcare provider right away if you develop symptoms of an infection during or after treatment with Tzield, such as fever or chills, redness, warmth, or swelling of the skin, feeling tired, cough or shortness of breath, or severe stomach pain or diarrhea.
• Decrease in white blood cells. This medicine may decrease the number of a type of white blood cells (lymphocytes) that can affect your body's ability to fight infections.
• Liver and complete blood counts. Your healthcare provider will do blood tests to check your liver and your complete blood count before you start treatment and during treatment with this medicine.

During and after your treatment, your healthcare provider will check for serious side effects, as well as other side effects, and treat you as needed. Your healthcare provider may temporarily or completely stop your treatment with this medicine if you develop liver problems, have a serious infection, or if your blood counts stay too low.

Tell your doctor if you have:

• a serious infection or an infection that keeps returning or does not go away; or
• recently received or are scheduled to receive a vaccine. This medicine may affect how well a vaccine works. Tell your healthcare provider that you are receiving treatment with this medicine before receiving a vaccine. You should be up to date with all your age-appropriate vaccines before receiving Tzield.

Pregnancy

Tzield may harm an unborn baby. Do not use if you are pregnant or for at least 30 days before a planned pregnancy. Tell your doctor if you become pregnant.

If you become pregnant while taking Tzield, you are encouraged to report your pregnancy to Provention Bio, Inc.’s Adverse Event reporting line at 1-800-633-1610 or visit https://ae.reporting.sanofi.

Breastfeeding

Do not breastfeed while using this medicine. If you are considering breastfeeding, use a breast pump and throw out any milk you collect during treatment with this drug and for at least 20 days after your last dose to minimize drug exposure to a breastfed child.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your medical caregivers if you have signs of cytokine release syndrome (CRS), a serious side effect: fever, chills, trouble breathing, confusion, severe vomiting or diarrhea, fast or irregular heartbeats, or feeling light-headed or very tired.

Tzield may cause serious side effects. Call your doctor at once if you have:

• signs of infection-fever, chills, sore throat, body aches, unusual tiredness, loss of appetite, bruising or bleeding; or
• liver problems-loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects of Tzield may include:

• decrease in white blood cell counts
• vomiting
• rash
• diarrhea
• headache.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tzield is given by intravenous (IV) infusion by a healthcare provider. The dosing schedule differs depending on the indication.

Stage 2 type 1 diabetes - 14-day course (one course total)

Daily infusion for 14 consecutive days (one course), dosed based on body surface area (BSA).

Administered by intravenous infusion over a minimum of:

• 30 minutes in adult and pediatric patients aged 8 years and older
• 2 hours in pediatric patients aged 1 to less than 8 years

Stage 3 Type 1 Diabetes - 12-day course (two courses total)

Treatment should begin as soon as possible after a Stage 3 T1D diagnosis, and no later than 8 weeks from diagnosis. Tzield is administered by intravenous (IV) infusion over a minimum of 30 minutes, once daily for 12 consecutive days, with a second course being administered in 6 months.

A full course of treatment consists of two 12-day courses, dosed based on body surface area (BSA):

Second treatment course: The second 12-day course is given 6 months after the first. If delayed, it should be administered within 6 to 12 months after the first course.

General Dosing Information

• Before starting treatment, obtain a complete blood count and liver enzyme tests.
• Use of this medicine is not recommended in patients with certain laboratory abnormalities.
• Must dilute Tzield in 0.9% Sodium Chloride Injection, USP. See full prescribing information for detailed preparation and administration instructions.
• Premedicate with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, an antihistamine, and/or an antiemetic before each dose for at least the first 5 days of the 14-day treatment course.

Avoid receiving an inactivated, mRNA, and "live" vaccine. The vaccine may not work as well while you are using teplizumab.

Other drugs may affect Tzield, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all other medicines you use. To check for interactions with Tzield, click on the link below.

• Refrigerate Tzield vials at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Store upright. Do not freeze or shake the vials.
• Diluted Tzield. If not used immediately, store the diluted solution at room temperature 15°C to 30°C (59°F to 86°F) and complete infusion within 4 hours of the start of preparation. Discard the diluted solution if not administered within 4 hours of preparation.

Provention Bio, Inc., 55 Broad Street, Red Bank, NJ 07701.

Active ingredient: teplizumab-mzwv.Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80, sodium chloride, and water for injection.