Teplizumab-Mzwv

Description

11 DESCRIPTION Teplizumab-mzwv is a CD3-directed monoclonal antibody (humanized IgG1 kappa) that has a molecular weight of approximately 150 kilodalton (kDa) and is expressed from a recombinant Chinese hamster ovary (CHO) cell line. TZIELD (teplizumab-mzwv) injection is supplied as a sterile, preservative-free, clear and colorless solution in a 2 mg/2 mL (1 mg/mL) single-dose vial for intravenous use. Each mL contains 1 mg of teplizumab-mzwv, dibasic sodium phosphate (0.26 mg), monobasic sodium phosphate (0.98 mg), polysorbate 80 (0.05 mg), sodium chloride (8.78 mg), and water for injection. The pH is 6.1.

What Is Teplizumab-Mzwv Used For?

1 INDICATIONS AND USAGE TZIELD is indicated 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 [see Dosage and Administration ( 2.1 )] . TZIELD is a CD3-directed antibody indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D ( 1 ).

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Confirm Stage 2 T1D by documenting at least two positive pancreatic islet autoantibodies in those who have dysglycemia without overt hyperglycemia using an oral glucose tolerance test (OGTT) or alternative method if appropriate and OGTT is not available ( 2.1 ). In patients who meet criteria for a diagnosis of Stage 2 type 1 diabetes, ensure the clinical history of the patient does not suggest type 2 diabetes ( 2.1 ). Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests. Use of TZIELD is not recommended in patients with certain laboratory abnormalities ( 2.2 ). Must dilute TZIELD in 0.9% Sodium Chloride Injection, USP. See full prescribing information for detailed preparation and administration instructions ( 2.3 , 2.4 , 2.5 ). Premedicate with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and/or (3) an antiemetic before each TZIELD dose for at least the first 5 days of the 14-day treatment course ( 2.3 ). Administer TZIELD by intravenous infusion (over a minimum of 30 minutes) once daily for 14 days. See full prescribing information for the dosing schedule ( 2.4 ). 2.1 Patient Selection Select adult patients and pediatric 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 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. 2.2 Laboratory Evaluation and Vaccination Prior to Initiation Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests. Use of TZIELD is not recommended in patients with [see Warnings and Precautions ( 5 )] : 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 TZIELD [see Warnings and Precautions ( 5.5 )] : 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. 2.3 Important Preparation and Premedication Instructions The following are important preparation and premedication instructions: Must dilute TZIELD prior to use [see Dosage and Administration ( 2.5 )] . Premedicate prior to TZIELD...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the Prescribing Information: Cytokine Release Syndrome [see Warnings and Precautions ( 5.1 )] Serious Infections [see Warnings and Precautions ( 5.2 )] Lymphopenia [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>10%) were lymphopenia, rash, leukopenia and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Provention Bio at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Placebo-Controlled Study in Patients with Stage 2 Type 1 Diabetes The data in Table 1 are derived from the placebo-controlled study (Study TN-10) in patients aged 8 years and older with Stage 2 type 1 diabetes (T1D) [see Clinical Studies ( 14 )] . These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course. Pool of Five Controlled Clinical Studies in Stage 2 Type 1 Diabetes and in an Unapproved Population Adverse reactions in TZIELD-treated patients were also evaluated in a larger pool of adult and pediatric patients who participated in five controlled clinical studies (including Study TN-10 described above): One study in patients with Stage 2 T1D (Study TN-10) [see Clinical Studies ( 14 )] , Three placebo-controlled studies in an unapproved population, One open-label standard-of-care controlled study of TZIELD in an unapproved population. In this pool: 773 patients received TZIELD (44 patients with Stage 2 TID and 729 patients from an unapproved population), and 245 patients received either placebo or standard of care control (32 patients with Stage 2 T1D and 213 patients from an unapproved population). In these studies, 436 patients received a 14-day dosing regimen of TZIELD with a total drug exposure that was comparable to the total drug exposure achieved with the recommended dosage [see Dosage and Administration ( 2.4 )] , 168 patients received a 14-day course of TZIELD with a lower total TZIELD drug exposure, and 169 patients received a 6-day course of TZIELD with a lower total TZIELD drug exposure. The mean age of TZIELD-treated patients was 17.6 years (median 15 years), 62% were <18 years old (40% age 12 to 17; 21% age 8 to 11), and 64% were male. The population was 72% White, 26% Asian, 1% Black or African American, 1% were multiple or unknown race, and <1% American Indian or Alaska Native; 5% were Hispanic or Latino ethnicity. Common Adverse Reactions Table 1 presents common (≥ 5%) adverse reactions that occurred during treatment and through 28 days after the last study drug administration in Study TN-10. Adverse reactions observed in pediatric patients 8 years and older who received TZIELD were consistent with those reported in adult patients in this study. Table 1. Common Adverse Reactions That occurred during treatment and through 28 days after the last study drug administration in Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 Type 1 Diabetes (Study TN-10) Adverse reactions that occurred in 2 or more TZIELD-treated patients Adverse Reaction Placebo N=32 TZIELD N=44 Lymphopenia 6% 73% Rash Composite of rash-related terms including rash erythematous, rash macular, rash papular, rash maculo-papular, rash pruritic 0% 36% Leukopenia 0% 21% Headache 6% 11% Neutropenia 3% 5% Increased alanine aminotransferase 3% 5% Nausea 3% 5% Diarrhea 0% 5% Nasopharyngitis 0% 5% Cytokine Release Syndrome (CRS) In Study TN-10, CRS was reported in 2% of TZIELD-treated patients compared to 0% of placebo-treated patients. Of the 39 TZIELD-treated patients that developed CRS (5% of all TZIELD-treated patients) in the pool of 5...

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 ).

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Available case reports from clinical trials with TZIELD 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-mzwv, monoclonal antibodies can be actively transported across the placenta, and TZIELD may cause immunosuppression in the utero- exposed infant (see Clinical Considerations ). To minimize exposure to a fetus, avoid use of TZIELD during pregnancy and at least 30 days (6 half-lives) prior to planned pregnancy. TZIELD is not active in rodents. In animal reproduction studies, mice were given a surrogate anti-mouse CD3 antibody subcutaneously during organogenesis through lactation. Pups born to dams administered the murine surrogate antibody during pregnancy showed a reduction in the adaptive immune response consistent with the expected pharmacology (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Report pregnancies to Provention Bio, Inc.'s Adverse Event reporting line at 1-800-633-1610. Clinical Considerations Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because teplizumab-mzwv may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to teplizumab-mzwv in utero. There are insufficient data regarding infant serum levels of teplizumab-mzwv at birth and the duration of persistence of teplizumab- mzwv in infant serum after birth to identify a specific timeframe to delay live virus immunizations in infants exposed in utero. Data Animal Data In an embryo-fetal developmental...

8.2 Lactation Risk Summary There are no data on the presence of teplizumab-mzwv 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-mzwv are unknown. Although the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TZIELD and any potential adverse effects on the breastfed child from TZIELD 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 TZIELD administration to minimize drug exposure to a breastfed child.

How Supplied

16 HOW SUPPLIED / STORAGE AND HANDLING TZIELD (teplizumab-mzwv) injection is a clear and colorless solution (2 mg/2 mL (1 mg/mL)) supplied in a single-dose vial as follows: Carton Contents NDC 1 single dose vial NDC 73650-316-01 10 single dose vials NDC 73650-316-10 14 single dose vials NDC 73650-316-14 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. 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 [see Dosage and Administration ( 2.5 )] .