TZIELD is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients 1 year 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 adult and pediatric patients 1 year of age and older with Stage 2 T1D ( 1 ).
Contraindications
None. None. ( 4 ).
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 ( 5.2 ). 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 ( 5.3 ). 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 ( 5.4 ). Hypersensitivity Reactions: If severe hypersensitivity reactions occur, discontinue TZIELD and treat promptly ( 5.5 ). Vaccinations: Administer all age-appropriate vaccinations prior to starting TZIELD.
See recommendations regarding live-attenuated, inactivated, and mRNA vaccines ( 5.6 ).
5.1Viral Reactivation
Serious, life-threatening cases of viral reactivation, including EBV and CMV have been reported with TZIELD. During and within 2 months of TZIELD treatment, if primary infection or reactivation of EBV or CMV occurs, it may present with increased severity, including EBV-associated lymphoproliferative disease and organ failure. Patients who are immunocompromised, including patients with Down syndrome, may be at increased risk.
The majority of serious viral reactivation cases occurred in patients who continued TZIELD despite persistent, severe lymphopenia [see Warnings and Precautions 5.4 ]. Prior to initiating treatment with TZIELD, evaluate patients for active EBV and CMV infection and confirm undetectable viral load (e.g., PCR testing). TZIELD is not recommended in patients with laboratory or clinical evidence of active EBV or CMV infection [see Dosage and Administration (2.2) ].
During treatment with TZIELD, regularly monitor lymphocyte counts [see Dosage and Administration (2.6) , Warnings and Precautions (5.4) ] and monitor patients for signs and symptoms of viral reactivation during treatment and for at least 2 months following the last infusion. If viral reactivation is suspected, discontinue TZIELD and obtain viral load (e.g., PCR) promptly. Consider appropriate expert consultation for diagnostic testing recommendations as some diagnostic tests may give inaccurate results in immunosuppressed patients.
If viral reactivation is confirmed, permanently discontinue TZIELD [see Dosage and Administration (2.6) ]. Consider appropriate expert consultation for the management of severe viral reactivation.
5.2Cytokine Release Syndrome
Cytokine release syndrome (CRS) has been observed in TZIELD-treated patients. In clinical trials, CRS was reported in 5% of TZIELD-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 TZIELD-treated patients included fever, nausea (with or without vomiting), fatigue, headache, myalgia, arthralgia, increased ALT, increased AST, and increased total bilirubin.
These manifestations typically occurred during the first 5 days of TZIELD treatment [see Adverse Reactions (6.1) ] . To mitigate CRS: Premedicate with antipyretics, antihistamines and/or antiemetics prior to TZIELD treatment [see Dosage and Administration (2.3) ]. Monitor liver enzymes and bilirubin during treatment. Discontinue TZIELD 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 in TZIELD-treated patients with antipyretics, antihistamines and/or antiemetics. If severe CRS develops, consider: Temporarily pausing TZIELD dosing for 1–2 days and if symptoms have resolved or significantly improved, subsequently administering the remaining doses on consecutive days to complete the full 14-day course or Discontinuing TZIELD treatment .
5.3Serious Infections Bacterial
and viral infections have occurred in TZIELD-treated patients. In clinical trials, TZIELD-treated patients had a higher rate of serious infections (3.5%) than control-treated patients (2%), including gastroenteritis, cellulitis, pneumonia, abscess, sepsis [see Adverse Reactions (6.1) ]. Use of TZIELD 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 TZIELD treatment. If serious infection develops, treat appropriately, and discontinue TZIELD.
5.4Lymphopenia
In clinical trials, 78% of TZIELD-treated patients developed lymphopenia compared to 11% of control-treated patients. For most TZIELD-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 TZIELD-treated patients, and 0.5% of TZIELD-treated patients permanently discontinued TZIELD because of lymphopenia [see Adverse Reactions (6.1) ].
Obtain a CBC prior to starting TZIELD and monitor white blood cell counts during TZIELD treatment. If prolonged severe lymphopenia (<500 cells per mcL lasting 1 week or longer) develops, permanently discontinue TZIELD.
5.5Hypersensitivity Reactions
Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in TZIELD-treated patients [see Adverse Reactions (6.1) ]. If severe hypersensitivity reactions occur, discontinue use of TZIELD and treat promptly.
5.6Vaccinations
The safety of immunization with live-attenuated vaccines in TZIELD-treated patients has not been studied. Additionally, TZIELD may interfere with the immune response to vaccination and decrease vaccine efficacy. Administer all age-appropriate vaccinations prior to starting TZIELD [see Dosage and Administration (2.2) ]. Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to TZIELD treatment, during treatment, or up to 6 weeks after completion of treatment.
Live-attenuated vaccinations are not recommended within the 8 weeks prior to starting TZIELD treatment, during treatment, or up to 52 weeks after treatment.
Pregnancy and breastfeeding
8.1Pregnancy 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 in nonclinical studies, 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 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 or visit https://ae.reporting.sanofi. 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 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 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.
Adverse reactions
The following serious adverse reactions are described elsewhere in the Prescribing Information: Viral Reactivation [see Warnings and Precautions (5.1) ] Cytokine Release Syndrome [see Warnings and Precautions (5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Lymphopenia [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions were lymphopenia, vomiting, rash, leukopenia, diarrhea 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
6.1Clinical 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 Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 T1D The data in Table 1 are derived from the placebo-controlled study (Study TN-10) in adult and pediatric patients aged 8 years and older with Stage 2 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 T1D and for an Unapproved Use 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 less than18 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 less than1% 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 T1D (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 clinical trials, 13% of the CRS cases were serious adverse reactions [see Warnings and Precautions (5.2) ] . Liver transaminase elevations were observed in 56% of TZIELD-treated patients who experienced CRS: 64% were up to 2.5 times ULN, 32% were more than 2.5 to 5 times ULN, and 4.5% were 5–10 times ULN. Serious Infections In Study TN-10, serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) were reported in 9% (4/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients any time during or after the first dose of study treatment.
Rash and Hypersensitivity Reactions Hypersensitivity reactions were reported with TZIELD in Study TN-10. Serum sickness was observed in 2% (1/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients. The patient who developed serum sickness had a prior history of positive anti-nuclear antibody and presented with arthralgias and elevated c-reactive protein and low C4 complement five days after completing their course of TZIELD; illness resolved in 2.5 months.
In the pool of 5 clinical trials of patients: Anaphylaxis (with hypoxia and bronchospasm) was observed in one TZIELD-treated patient who was hospitalized. Angioedema (periorbital and facial) was observed in 0.3% TZIELD-treated patients, compared to 0% in control-treated patients. Peripheral and generalized edema was reported in 1.6% of TZIELD-treated patients and 0% of control-treated patients. Rash was observed in 48% of TZIELD-treated patients compared to 15% in control-treated patients, with 33 excess cases of rash per 100 patients.
The majority of rashes observed with TZIELD treatment were not serious and resolved without intervention; although 0.3% (2/773) of TZIELD-treated patients had a serious rash compared to 0% (0/245) of placebo- treated patients. Urticaria was reported in 1.9% of TZIELD-treated patients and in 1.2% of control-treated patients. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In Study TN-10, rash occurred in 39% of TZIELD-treated patients who developed anti- teplizumab-mzwv antibodies and in 33% of TZIELD-treated patients who did not develop anti- teplizumab-mzwv antibodies [see Clinical Pharmacology (12.6) ].
Open Label Study in Pediatric Patients Age 1 to Less Than 8 Years with Stage 2 T1D The safety of TZIELD was evaluated in a non-randomized, single arm, open-label, multicenter study in 23 pediatric patients age 1 to less than 8 years with Stage 2 T1D ( PETITE-T1D Study; NCT05757713)[see Clinical Pharmacology (12.3) ]. In this trial, 87% completed the full 14-day treatment course. The median age was 4.9 years (1 patient was less than 2 years old; 52% were 2 to less than 5 years old; 44% were 5 to less than 8 years old; range 1.7 to 6.8 years) and 52% were female.
The majority of the population (96%) was White and one patient (4%) was Asian; 3 patients (13%) were Hispanic or Latino ethnicity. At baseline, 87% of participants had a first-degree relative with T1D. The majority (87%) were positive for 3 or more diabetes-related autoantibodies. The most common autoantibodies were anti-insulin (87%), anti-ICA (85%), anti-GAD65 (83%), anti-ZnT8 (74%), and anti-IA2 (68%). The median HbA1c was 5.5%.
Overall, the safety profile of TZIELD observed in pediatric patients less than 8 years of age with Stage 2 T1D was consistent with that observed in patients 8 years of age and older with Stage 2 T1D. The most common adverse reactions that occurred in patients less than 8 years of age were vomiting (52%) and diarrhea (30%). Other Adverse Reactions in Adult and Pediatric Patients Age 1 Year and Older with Stage 2 T1D Lymphopenia In Study TN-10, lymphopenia was reported in 73% of TZIELD-treated patients compared to 6% of placebo-treated patients.
The average lymphocyte count nadir occurred at Day 5 of treatment, with recovery and return to baseline by Week 6 [see Warning
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
TEPLIZUMAB-MZWV 2MG/2ML(1MG/ML)
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761183.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
