Teplizumab-mzwv (Monograph)

Brand name: Tzield
Drug class: Antidiabetic Agents, Miscellaneous

Introduction

Teplizumab-mzwv is a CD3-directed humanized IgG1 kappa antibody.

Uses for Teplizumab-mzwv

Teplizumab-mzwv has the following uses:

Teplizumab-mzwv is 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.

Teplizumab-mzwv Dosage and Administration

General

Teplizumab-mzwv is available in the following dosage form(s) and strength(s):

• Injection: 2 mg per 2 mL (1 mg/mL) in a single-dose vial for IV infusion after dilution.

• Confirm Stage 2 T1D by documenting at least two positive pancreatic islet cell 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 T1D, ensure the clinical history of the patient does not suggest type 2 diabetes.

• Prior to initiating teplizumab-mzwv, obtain a complete blood count and liver enzyme tests. Use of teplizumab-mzwv is not recommended in patients with certain laboratory abnormalities.

• Premedicate with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and/or (3) an antiemetic before each teplizumab-mzwv infusion for at least the first 5 days of the 14-day treatment course.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration in Pediatric Patients ≥8 Years of Age

• Must dilute teplizumab-mzwv in 0.9% sodium chloride injection, USP prior to use. See full prescribing information for detailed preparation and administration instructions.

• Administer teplizumab-mzwv by intravenous infusion (over a minimum of 30 minutes) once daily for 14 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

Adults

Dosage and Administration

• Must dilute teplizumab-mzwv in 0.9% sodium chloride injection, USP prior to use. See full prescribing information for detailed preparation and administration instructions.

• Administer teplizumab-mzwv by intravenous infusion (over a minimum of 30 minutes) once daily for 14 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

Related/similar drugs

Lantus, Tresiba, Levemir, Basaglar, Novolog, Toujeo

Cautions for Teplizumab-mzwv

Contraindications

• None.

Warnings/Precautions

Cytokine Release Syndrome

Cytokine release syndrome (CRS) has been observed in patients treated with teplizumab-mzwv. In clinical trials, CRS was reported in 5% of patients treated with teplizumab-mzwv compared to 0.8% of control patients during the treatment period and through 28 days after the last study drug administration. CRS manifestations in teplizumab-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 teplizumab-mzwv treatment.

To mitigate CRS, premedicate with antipyretics, antihistamines and/or antiemetics prior to teplizumab-mzwv treatment. Monitor liver enzymes during treatment. Discontinue teplizumab-mzwv 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 teplizumab-mzwv. In clinical trials, teplizumab-treated patients had a higher rate of serious infections (3.5%) than control patients (2%), including gastroenteritis, cellulitis, pneumonia, abscess, sepsis. Use of teplizumab-mzwv is not 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 teplizumab-mzwv treatment. If serious infection develops, treat appropriately and discontinue teplizumab-mzwv.

Lymphopenia

In clinical trials, 78% of patients treated with teplizumab-mzwv developed lymphopenia compared to 11% of control patients. For most teplizumab-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 teplizumab-treated patients, and 0.5% of these patients permanently discontinued therapy 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-mzwv.

Hypersensitivity Reactions

Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in patients treated with teplizumab-mzwv. If severe hypersensitivity reactions occur, discontinue use of teplizumab-mzwv and treat promptly.

Vaccinations

The safety of immunization with live-attenuated vaccines in patients treated with teplizumab-mzwv has not been studied. Additionally, teplizumab-mzwv may interfere with the immune response to vaccination and decrease vaccine efficacy.

Administer all age-appropriate vaccinations prior to starting teplizumab-mzwv. Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to teplizumab-mzwv treatment, during treatment, or 6 weeks after completion of treatment. Live-attenuated vaccinations are not recommended within the 8 weeks prior to teplizumab-mzwv treatment, during treatment, or up to 52 weeks after treatment.

Specific Populations

Pregnancy

Available case reports from clinical trials with teplizumab-mzwv 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 teplizumab-mzwv may cause immunosuppression in the utero-exposed infant. To minimize exposure to a fetus, avoid use of teplizumab-mzwv during pregnancy and at least 30 days (6 half-lives) prior to planned pregnancy.

Teplizumab-mzwv 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.

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.

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.

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 post-implantation 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 a 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.

Lactation

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 teplizumab-mzwv and any potential adverse effects on the breastfed child from teplizumab-mzwv 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-mzwv administration to minimize drug exposure to a breastfed child.

Pediatric Use

The safety and effectiveness of teplizumab-mzwv 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 teplizumab-mzwv 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 patients). Adverse reactions observed in pediatric patients 8 years of age and older who received teplizumab-mzwv were consistent with those reported in adult patients.

The safety and effectiveness of teplizumab-mzwv have not been established in pediatric patients younger than 8 years of age.

Geriatric Use

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

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.

• Inform patients about the signs and symptoms of cytokine release syndrome (CRS).

• Inform patients that teplizumab-mzwv 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.

• Inform patients that although most teplizumab-mzwv-treated patients had mild lymphopenia, a few had severe lymphopenia that required stopping teplizumab-mzwv.

• Advise patients of the symptoms of hypersensitivity reactions and instruct them to stop taking teplizumab-mzwv and seek medical attention promptly if such symptoms occur.

• Advise patients to receive all age-appropriate vaccinations prior to starting teplizumab-mzwv and avoid concurrent use of live inactivated and mRNA vaccines with teplizumab-mzwv.

• Advise patients to inform their health care provider of a known or suspected pregnancy. Advise patients who are exposed to teplizumab-mzwv during pregnancy to contact Provention Bio, Inc.’s Adverse Event reporting line at 1-844-778-2246.

• Advise a lactating woman that she may interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after teplizumab-mzwv administration to minimize drug exposure to a breastfed infant.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• What is Tzeild?
• How does Tzield work?
• How effective is Tzield?
• How is Tzield administered?

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