BRIEF SUMMARY

TEPLIZUMIB-(Nov 2022)

Indn- To delay the onset of stage 3 type of 1 diabetic 

Comp-  Injection: 2 mg per 2 mL (1 mg/mL) single-dose vial .Administer  by intravenous infusion (over a minimum of 30 minutes) once daily for 14 days. See full prescribing information for the dosing schedul

ADR- Most common adverse reactions (>10%) were lymphopenia, rash, leukopenia and headache

CI- None.

 WARNINGS -

 Cytokine Release Syndrome (CRS): Premedicate, monitor liver enzymes, discontinue in those that develop elevated ALT or AST more than 5 times the upper limit of normal, and if severe CRS develops consider temporarily pausing dosing

  Serious Infections: Use  is not recommended in patients with active serious infection or chronic infection. Monitor for signs and symptoms of infection during and after  treatment. If a serious infection develops, discontinue 

Pat inform

Serious Infections- Inform patients that  may lower the ability of the immune system to fight infections. Instruct patients to contact their health care provider if they develop any symptoms of infection

Lymphopenia Inform patients that although most -treated patients had mild lymphopenia; a few had severe lymphopenia that required stopping the drug

Hypersensitivity Reactions-  Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking  and seek medical attention promptly if such symptoms occur

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U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 30

Name-        TZIELD

Active  Ingredient -  Teplizumab- mzwv

Pharmacological clssificiation-        To delay the onset of stage 3 type of 1 diabetic                                                                                                                                               

 Date of Approved-         11/18/2022      

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                 TZIELD safely and effectively.                                                                                            See full prescribing information for TZIELD. TZIELD™ (teplizumab-mzwv) injection, for intravenous use

Initial U.S. Approval: 2022

 INDICATIONS AND USAGE

 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

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

 • 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

 • 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

 • Must dilute TZIELD in 0.9% Sodium Chloride Injection, USP. See full prescribing information for detailed preparation and administration instructions 

 • Premedicate with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and/or  an antiemetic before each TZIELD dose for at least the first 5 days of the 14-day treatment course

• Administer TZIELD by intravenous infusion (over a minimum of 30 minutes) once daily for 14 days. See full prescribing information for the dosing schedul

 DOSAGE FORMS AND STRENGTHS-

 Injection: 2 mg per 2 mL (1 mg/mL) single-dose vial 

 ADVERSE REACTIONS-

 Most common adverse reactions (>10%) were lymphopenia, rash, leukopenia and headache

 CONTRAINDICATIONS-

 None.

 WARNINGS AND PRECAUTIONS-

 • Cytokine Release Syndrome (CRS): Premedicate, monitor liver enzymes, discontinue in those that develop elevated ALT or AST more than 5 times the upper limit of normal, and if severe CRS develops consider temporarily pausing dosing

 • Serious Infections: Use of TZIELD is not recommended in patients with active serious infection or chronic infection. Monitor for signs and symptoms of infection during and after TZIELD treatment. If a serious infection develops, discontinue TZIELD

 • 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 TZIELD

• Hypersensitivity Reactions: If severe hypersensitivity reactions occur, discontinue TZIELD and treat promptly

 • Vaccinations: Administer all age-appropriate vaccinations prior to starting TZIELD. See recommendations regarding live-attenuated, inactivated, and mRNA vaccines

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

 • 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

 • 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

 • 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 TZIELD dose for at least the first 5 days of the 14-day treatment course

• Administer TZIELD by intravenous infusion (over a minimum of 30 minutes) once daily for 14 days. See full prescribing information for the dosing schedul

 DOSAGE FORMS AND STRENGTHS-

 Injection: 2 mg per 2 mL (1 mg/mL) single-dose vial 

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Cytokine Release Syndrome Inform patients about the signs and symptoms of CRS

 Serious Infections Inform patients that TZIELD may lower the ability of the immune system to fight infections. Instruct patients to contact their health care provider if they develop any symptoms of infection

Lymphopenia Inform patients that although most TZIELD-treated patients had mild lymphopenia; a few had severe lymphopenia that required stopping TZIELD

[see Warnings and Precautions (5.3)]. Hypersensitivity Reactions Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TZIELD and seek medical attention promptly if such symptoms occur [see Warnings and Precautions (5.4)].

Vaccinations Advise patient to receive all age-appropriate vaccinations prior to starting TZIELD and avoid concurrent use of live, inactivated, and mRNA vaccines with TZIELD [see Warnings and Precautions (5.5)]

. Pregnancy Advise patients to inform their health care provider of a known or suspected pregnancy.

Advise patients who are exposed to TZIELD during pregnancy to contact Provention Bio, Inc.’s Adverse Event reporting line at 1-844-778-2246 [see Use in Specific Populations (8.1)]. Lactation Advise a lactating woman that she 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 infant [see Use in Specific Populations (8.2)].

Manufactured by: Provention Bio, Inc. 55 Broad Street Red Bank, NJ 07701 U.S. License Number: TZIELD is a trademark of Provention Bio, Inc. Copyright © 2022, Provention Bio, Inc. All rights reserve

12 CLINICAL PHARMACOLOGY -

12.1 Mechanism of Action -                                                                                     Teplizumab-mzwv binds to CD3 (a cell surface antigen present on T lymphocytes) and delays the onset of Stage 3 type 1 diabetes in adults and pediatric patients aged 8 years and older with Stage 2 type 1 diabetes. The mechanism may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. Teplizumab-mzwv leads to an increase in the proportion of regulatory T cells and of exhausted CD8+ T cells in peripheral blood.

12.2 Pharmacodynamics Clinical studies have shown that teplizumab-mzwv binds to CD3 molecules on the surface of both CD4+ and CD8+ T cells during treatment, with internalization of the teplizumabmzwv/CD3 complex from the surface of T cells. Pharmacodynamic effects include lymphopenia in the absence of depletion of T cells with a nadir on the 5th day of dosing, during a 14-day course of TZIELD treatment [see Warnings and Precautions (5.3)]. Teplizumab-mzwv exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of teplizumab-mzwv have not been fully characterized.

12.3 Pharmacokinetics Steady state concentrations of teplizumab-mzwv are not expected to be achieved during the 14- day course of TZIELD.

Distribution The central volume of distribution (Vd) of teplizumab-mzwv was 2.27 L in a 60 kg subject. Reference ID: 5079828

Elimination Teplizumab-mzwv showed saturable binding and elimination. The mean (SD) terminal elimination half-life and clearance of teplizumab-mzwv are 4.5 (0.2) days and 2.7 (0.8) L/day in a 60 kg subject, respectively.

Metabolism Teplizumab-mzwv is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations No clinically significant differences in the pharmacokinetics of teplizumab-mzwv were observed based on age (8 to 35 years old), biologic sex, or racial groups (White, Asians). BSA-based dosing normalizes the exposure to teplizumab-mzwv across body weight.

12.6 Immunogenicity The observed incidence of anti-drug antibodies 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 teplizumab-mzwv or of other teplizumab products. In the placebo-controlled study in patients aged 8 years of age and older with Stage 2 type 1 diabetes (Study TN-10) [see Clinical Studies (14)], approximately 57% of TZIELD-treated patients developed anti-teplizumab-mzwv antibodies, 46% of whom developed neutralizing antibodies.

There is insufficient information to characterize the effects of ADA on pharmacokinetics, pharmacodynamics, or effectiveness of TZIELD. There was a higher incidence of rash in TZIELD-treated patients who developed anti-teplizumab-mzwv antibodies compared to those who did not develop anti-teplizumab-mzwv antibodies [see Adverse Reactions (6.1)].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies have been performed to assess the carcinogenic potential of teplizumabmzwv. No studies have been performed to assess the mutagenic potential of teplizumab-mzwv. As an antibody, teplizumab-mzwv is not expected to interact directly with DNA. Fertility and repro

 USE IN SPECIFIC POPULATIONS

1 Pregnancy -                                                                                                                  Risk Summary-                                                                                                      Available case reports from clinical trials with TZIELD are insufficient to identify a drugassociated 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 uteroexposed 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 1-844-778-2246. Reference ID: 5079828 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 teplizumabmzwv 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 toxicity study, pregnant mice were administered a murine surrogate anti-mouse CD3 antibody by subcutaneous injection at dose levels of 0, 0.03, 0.3, or 20 mg/kg on Gestation Days 6, 10, and 14. Increase in post-implantation loss occurred in the 20 mg/kg group, in the presence of maternal toxicity. In a pre- and postnatal development toxicity study in pregnant mice, in which the murine surrogate antibody was administered every 3 days from gestation day 6 through lactation day 19 at doses of 0, 0.3, 3, or 20 mg/kg, no maternal toxicity or increased incidence of postimplantation loss was observed. Reductions in T cell populations and increases in B cells, and a reduction in the adaptive immune response to keyhole limpet hemocyanin (KLH) were observed in the offspring on postnatal days 35 and 84 at 20 mg/kg. The surrogate antibody was present in the offspring serum at level less than 1.5% that of maternal serum at the high dose. A trend towards reduction in fertility was observed in the offspring of dams administered the murine surrogate antibody at 20 mg/kg. The human relevance of this finding is unknown.

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.

8.4 Pediatric Use The safety and effectiveness of TZIELD to delay the onset of Stage 3 type 1 diabetes have been established in pediatric patients 8 years of age and older with Stage 2 type 1 diabetes. Use of TZIELD for this indication is supported by evidence from an adequate and well-controlled study (Study TN-10) in adults and pediatric patients 8 years of age and older (including 29 pediatric Reference ID: 5079828 patients).

Adverse reactions observed in pediatric patients 8 years of age and older who received TZIELD were consistent with those reported in adult patients [see Adverse Reactions (6.1)]. The safety and effectiveness of TZIELD have not been established in pediatric patients younger than 8 years of age.

8.5 Geriatric Use Stage 2 type 1 diabetes is largely a condition that occurs in pediatric and younger adult patients. Clinical studies of TZIELD to delay the onset of Stage 3 T1D did not include patients 65 years of age and older.