Teplizumab
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WARNING: Viral Reactivation Serious, life-threatening cases of viral reactivation, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation have been reported with TZIELD. Patients who are immunocompromised are at increased risk. Serious cases have also been reported in adults with higher body surface area or comorbid conditions, such as adrenal insufficiency or cardiovascular disease. The majority of serious cases occurred in patients who continued TZIELD treatment despite persistent, severe lymphopenia. Severe lymphopenia may be prolonged in adults. ( 5.1 , 5.4 ) Test patients for active EBV and CMV infection prior to starting treatment.
TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection). Adhere to lymphocyte count monitoring requirements and discontinuation recommendations. Monitor patients for signs and symptoms of viral reactivation following TZIELD treatment and for at least 2 months following the last infusion. If viral reactivation is suspected, discontinue TZIELD. ( 2.6 , 4 , 5.1 , 5.4 ) WARNING: Viral Reactivation Serious, life-threatening cases of viral reactivation, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation have been reported with TZIELD. Patients who are immunocompromised are at increased risk.
Serious cases have also been reported in adults with higher body surface area or comorbid conditions, such as adrenal insufficiency or cardiovascular disease. The majority of serious cases occurred in patients who continued TZIELD treatment despite persistent, severe lymphopenia. Severe lymphopenia may be prolonged in adults. ( 5.1 , 5.4 ) Test patients for active EBV and CMV infection prior to starting treatment. TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection). Adhere to lymphocyte count monitoring requirements and discontinuation recommendations.
Monitor patients for signs and symptoms of viral reactivation following TZIELD treatment and for at least 2 months following the last infusion. If viral reactivation is suspected, discontinue TZIELD. ( 2.6 , 4 , 5.1 , 5.4 )
CD3-directed Antibody
Dosing in kidney impairment
The duration of severe lymphopenia following TZIELD treatment may be prolonged in adults [see Warnings and Precautions ]. Serious cases have also been reported in adults with higher body surface area or comorbid conditions, such as adrenal insufficiency or cardiovascular disease. Prior to initiating treatment with TZIELD, evaluate patients for active EBV and CMV infection and confirm absence of active infection on assessment of viral load (e.g., PCR).
Preparation and administration
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Important Premedication Instructions Prior to each of the first 5 days of TZIELD infusion [see Warnings and Precautions ] : Premedicate with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen Premedicate with an antihistamine, and Consider premedication with an antiemetic If needed, administer additional premedication doses.
Recommended Dosage and Administration Body Surface Area Dosage Calculation The dosage of TZIELD is based on body surface (BSA) area, which is calculated using the Mosteller formula, below: Using the patient's BSA, calculate the dose based on treatment day: Dose (mcg) = Daily dosage (mcg/m 2 ) × BSA (m 2 ) Recommended Dosage and Administration in Patients with Stage 2 T1D Administer TZIELD once daily for 14 consecutive days using BSA-based dosing per the schedule below: [See table below.] Administer TZIELD 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 [see Clinical Pharmacology ] .
Recommended Dosage and Administration in Patients with Stage 3 T1D Initiate treatment as soon as possible following Stage 3 T1D diagnosis but no later than 8 weeks from diagnosis. Administer TZIELD by intravenous infusion over a minimum of 30 minutes, once daily for 12 consecutive days for each treatment course, for a total of two treatment courses, using the BSA-based dosing schedule below: [See table below.] Second treatment Course: Administer the second 12-day treatment course 6 months after the first treatment course.
If the second course is delayed, administer the second treatment course within 6 to 12 months after the first treatment course. Image
Recommendations Regarding Missed Doses If a planned TZIELD infusion is missed, administer the missed dose as soon as possible and all remaining doses on consecutive days to complete the 14 total dose regimen in patients with Stage 2 T1D or each of the two 12-day treatment courses in patients with Stage 3 T1D. Do not administer two doses on the same day.
Preparation and Administration Instructions Read this entire section carefully before preparing TZIELD. Must dilute TZIELD prior to use. This requires the preparation of 100 mcg/mL dilution followed by the preparation of an infusion solution. Start the infusion after preparation is complete. If the TZIELD infusion solution is not used immediately, store as instructed per corresponding infusion preparation method.
The following are preparation and administration instructions based on BSA dosing requirements [see Dosage and Administration ] : TZIELD 100 mcg/mL Dilution Preparation: Prior to dilution, inspect TZIELD visually before use (the supplied solution is clear and colorless). Do not use TZIELD if particulate matter or coloration is seen.
Prepare TZIELD using aseptic technique. Each vial is intended for one-time use only, discard any unused portion. If the calculated dose is: 2,000 mcg or less, then prepare: One sterile syringe (polypropylene (PP), polycarbonate (PC) or glass) or One sterile glass vial with 18 mL of 0.9% Sodium Chloride Injection or One ≤50 mL polyvinylchloride (PVC) with di-(2-ethylhexyl)phthalate (DEHP) infusion bag with 18 mL of 0.9% Sodium Chloride Injection.
Greater than 2,000 mcg, then prepare: Two sterile syringes (PP, PC or glass) or Two sterile glass vials with 18 mL of 0.9% Sodium Chloride Injection or Two ≤50 mL PVC with DEHP infusion bags with 18 mL of 0.9% Sodium Chloride Injection. Remove the cap from the TZIELD vial – this is the preparation start time. Remove 2 mL of TZIELD from the single-dose vial and slowly add to the sterile syringes (PP, PC or glass), glass vial or PVC with DEHP infusion bag containing 18 mL of 0.9% Sodium Chloride Injection.
Mix gently by slowly swirling the vial or rocking the infusion bag or syringe. The resulting 20 mL diluted TZIELD solution contains 100 mcg/mL of teplizumab-mzwv. If preparing a dose greater than 2,000 mcg, repeat the above process with second TZIELD vial and the glass vial, or PVC with DEHP infusion bag or syringe (PP, PC or glass) containing 18 mL of 0.9% Sodium Chloride Injection.
TZIELD Infusion Solution Preparation: Calculate the volume of TZIELD 100 mcg/mL dilution needed for the infusion. Volume of 100 mcg/mL dilution (mL) = Dose (mcg) 100 mcg/mL There are two different methods for preparation of the infusion: infusion bag (Method 1) or syringe (Method 2, for syringe pump infusion). Use the appropriate steps below depending on the selected method.
Method 1: Infusion bag for intravenous administration: Using an appropriately sized syringe [see Compatible Materials for Administration ] , withdraw the volume of TZIELD 100 mcg/mL dilution required for that day's calculated dose (for a calculated dose 2,000 mcg or less) or from both prepared 100 mcg/mL dilutions (for a calculated dose more than 2,000 mcg) [see TZIELD 100 mcg/mL Dilution Preparation ] .
Discard unused portion of remaining TZIELD dilution in the syringe, sterile glass vial or PVC with DEHP infusion bag. Slowly add contents of the syringe containing the TZIELD dose to a PVC with DEHP infusion bag containing 25 mL of 0.9% Sodium Chloride Injection ( for a calculated dose more than 2,000 mcg, add the cumulative volume for the calculated dose to a single infusion bag ).
Gently rock the infusion bag to ensure that the solution mixes sufficiently. Do not shake. Infusion bag administration: Prime the IV infusion set with the TZIELD infusion solution. Do not waste any infusion solution during the priming process. Infusion administration has a minimum duration 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 Rate may be slowed for patient's tolerability.
After infusion, flush the IV set with a volume of 0.9% Sodium Chloride Injection greater than or equal to the priming volume, to ensure full dose is administered. Same infusion rate should be used for flushing. If the TZIELD infusion solution is not used immediately, store at room temperature between 15°C to 25°C (59°F to 77°F).
Discard if the infusion is unable to be completed within 6 hours of preparation. Method 2: Syringe for intravenous infusion via syringe pump: Requires an appropriately sized sterile syringe (up to 60 mL) [i.e., infusion syringe] which is compatible with available syringe pump. The syringe pump should support rates as low as 1 mL/hour [see Compatible Materials for Administration ] .
The final concentration range is 15 mcg/mL to 60 mcg/mL with a maximum infusion volume of 60 mL. To fit technical constraints of syringe pump, a lower volume may be used as long as the concentration is between 15 mcg/mL and 60 mcg/mL. If the calculated dose is: 900 mcg or less: Calculate the maximum volume that can be administered for the calculated dose (based on treatment day, dose and patient BSA) using a minimum infusion concentration of 15 mcg/mL. [See table below.] Calculate the volume of 0.9% Sodium Chloride Injection to be added to the infusion syringe: Volume 0.9% Sodium Chloride Injection (mL) = Volume Infusion (mL) - Volume 100 mcg/mL dilution (mL) Greater than 900 mcg: the maximum infusion volume is capped at 60 mL.
Volume 0.9% Sodium Chloride Injection (mL) = 60 mL - Volume 100 mcg/mL dilution (mL) For all doses: Measure the appropriate volume of 0.9% Sodium Chloride Injection from above calculation into the infusion syringe. Using an appropriately sized syringe, withdraw the volume of TZIELD 100 mcg/mL dilution [see Compatible Materials for Administration ] required for that day's calculated dose (for a calculated dose 2,000 mcg or less) and add it to the infusion syringe.
For a calculated dose more than 2,000 mcg, add the cumulative volume from both prepared 100 mcg/mL dilutions to a single infusion syringe [see TZIELD 100 mcg/mL Dilution Preparation ] . Gently rock the infusion syringe to ensure that the solution mixes sufficiently. Do not shake. Syringe administration: Prime the IV extension set with the TZIELD infusion solution.
Do not waste any infusion solution during the priming process. Attach infusion syringe to a syringe pump. The infusion must be administered 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 Do not manually push the syringe. Infusion administration rate may be slowed for patient's tolerability.
After infusion, flush the IV extension set with a volume of 0.9% Sodium Chloride Injection greater than or equal to the priming volume at the same infusion rate to ensure full dose is administered. If the TZIELD infusion solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 12 hours, followed by a maximum of 6 hours at room temperature between 15°C to 25°C (59°F to 77°F) which includes infusion time.
Discard if the infusion is unable to be completed within 15 hours of preparation.
Compatible Materials for Administration Compatibility has been demonstrated with the materials listed in Table 1. Other materials should not be used. [See table below.] Use of in-line filter is not recommended. If necessary, use a polyethylene sulfone (PES) filter. Do not use light protected (colored) infusion sets.
| Volume of 100 mcg/mL dilution (mL) = | Dose (mcg) | ||
| 100 mcg/mL |
| VolumeInfusion (mL) | = | Dose (mcg) |
| Minimum infusion concentration 15 mcg/mL |
| Step | Equipment | Product Contact Material |
|---|---|---|
| Abbreviations: PP=polypropylene, PC=polycarbonate, PVC with DEHP=polyvinylchloride with di-(2-ethylhexyl)phthalate, PE=polyethylene. | ||
| Initial dilution | Containers | PP, PC, glass, PVC with DEHP IV bag |
| Syringes | PP, PC, glass | |
| Infusion with IV bags | IV bags | PVC with DEHP for all doses EVA bags for doses ≥ 240 mcg |
| Infusion sets | PVC with DEHP | |
| Infusion with syringe pump | Infusion dilution container | Syringe: PP, PC |
| Syringes | PP, PC | |
| Infusion/extension sets | PE, PVC with or without DEHP | |
Contraindications
4 CONTRAINDICATIONS TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection) [see Warnings and Precautions (5.1) ]. TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection) ( 4 ).
Pregnancy and lactation
Pregnancy
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 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…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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