Teplizumab is a CD3-directed monoclonal antibody FDA-approved to delay the onset of stage 3 type 1 diabetes in adult and pediatric patients 8 years and older with stage 2 type 1 diabetes. In a randomized, double-blind, placebo-controlled trial of 76 patients 8 to 49 years with stage 2 type 1 diabetes, the median time from randomization to stage 3 type 1 diabetes diagnosis was 50 months in the teplizumab group and 25 months in the placebo group. With a median follow-up time of 51 months, teplizumab therapy resulted in a statistically significant delay in the development of stage 3 type 1 diabetes, hazard ratio 0.41 (95% CI: 0.22 to 0.78; p = 0.0066). Teplizumab is associated with increased risk of cytokine release syndrome; premedication and hepatic enzyme monitoring is recommended. Additionally, there are increased risks of serious infection, mild and moderate hepatic enzyme elevations, and decreases in lymphocytes; laboratory monitoring is necessary.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit. The solution is clear and colorless.
-Premedicate with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, an antihistamine, and/or an antiemetic prior to infusion for the first 5 days. If needed, administer additional doses of premedication.
-Missed dose: Do NOT administer 2 doses on the same day. If a planned infusion is missed, resume dosing by administering all remaining doses on consecutive days to complete the 14-day treatment course.
Intravenous Administration
Dilution
-Teplizumab must be diluted prior to use.
-Prepare either a sterile glass vial or polyvinylchloride (PVC) infusion bag with 18 mL of 0.9% Sodium Chloride Injection.
-Remove 2 mL of teplizumab from the vial and slowly add to the 18 mL of 0.9% Sodium Chloride Injection. Gently mix by slowly inverting the vial or rocking the infusion bag. The resulting 20 mL diluted solution contains 100 mcg/mL of teplizumab.
-Using a syringe, withdraw the volume of diluted teplizumab solution required for that day's calculated dose from the 100 mcg/mL solution.
-Slowly add the contents of the syringe containing diluted teplizumab solution to a 25 mL 0.9% Sodium Chloride Injection PVC infusion bag. Gently mix by rocking the infusion bag. Do NOT shake.
-Discard unused portion of the remaining diluted teplizumab solution in the sterile glass vial or PVC infusion bag.
-Storage: Begin the teplizumab infusion within 2 hours of preparation. If not used immediately, store the infusion solution at room temperature between 15 and 30 degrees C (59 to 86 degrees F). Complete the infusion within 4 hours of the start of preparation. Discard the infusion solution if not administered within 4 hours of preparation.
Intermittent IV Infusion
-Administer teplizumab by IV infusion over a minimum of 30 minutes.
Cytokine release syndrome (CRS) has been reported with teplizumab; manifestations typically occur during the first 5 days of treatment. In clinical trials, CRS was reported in 5% of teplizumab-treated patients compared to 0.8% of control-treated patients. Of the teplizumab-treated patients who developed CRS, 13% were serious adverse reactions. CRS manifestations in teplizumab-treated patients included fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and increased bilirubin. Liver transaminase elevations were observed in 56% of teplizumab-treated patients who experienced CRS. Specifically, 64% were up to 2.5 times the upper limit of normal (ULN), 32% were more than 2.5 to 5 times the ULN, and 4.5% were 5 to 10 times the ULN. To reduce the risk of CRS, premedicate with antipyretics, antihistamines, and/or antiemetics prior to teplizumab administration. Monitor liver transaminases and serum bilirubin at baseline and during treatment as clinically indicated. Discontinue teplizumab in patients who develop elevated ALT or AST more than 5 times the ULN or bilirubin more than 3 times the ULN. For severe CRS, consider temporarily pausing dosing for 1 to 2 days (and administer the remaining doses to complete the full 14-day course on consecutive days) or discontinuing treatment.
In clinical trials, lymphopenia was reported in 73% to 78% of teplizumab-treated patients; severe lymphopenia (less than 500 cells/mcL lasting 1 week or longer) occurred in 0.9% of teplizumab-treated patients. Of the patients with severe lymphopenia, 0.5% permanently discontinued teplizumab therapy. For most teplizumab-treated patients who develop lymphopenia, lymphocyte concentrations began to recover after the fifth day of treatment and returned to baseline by Week 6 without dose interruption. Leukopenia (21%) and neutropenia (5% to 7%) were also reported during clinical trials. Anemia was reported in 27% of teplizumab-treated patients compared to 21% of patients receiving placebo. Thrombocytopenia was reported in 13% of teplizumab-treated patients compared to 5% of patients receiving placebo. Anemia and thrombocytopenia recovery occurred within 2 to 4 weeks of treatment. In clinical trials, 1.8% of teplizumab-treated patients discontinued treatment due to hemoglobin less than 8.5 g/dL (or a decrease of more than 2 g/dL to a value less than 10 g/dL) and 1% discontinued teplizumab due to a platelet count less than 50,000 platelets/mcL. Evaluate complete blood cell counts at baseline and periodically during treatment. Therapy discontinuation may be necessary in patients who develop prolonged severe lymphopenia.
During clinical trials, acute hypersensitivity reactions have been reported in teplizumab-treated patients. If severe hypersensitivity reactions occur, discontinue use of teplizumab and treat promptly. Rash, including erythematous rash, macular rash, papular rash, maculopapular rash, and pruritic rash, was reported in 36% to 44% of teplizumab-treated patients compared to 0% to 15% of patients receiving placebo or control, with 33 excess cases of rash per 100 patients. The majority of rashes observed with teplizumab treatment were not serious and resolved without intervention; however, 0.3% of teplizumab-treated patients compared to 0% of patients receiving placebo experienced a serious rash. Serum sickness was reported in 2% of teplizumab-treated patients compared to 0% of patients receiving placebo. The patient who developed serum sickness had a prior history of positive anti-nuclear antibody and presented with arthralgias, elevated c-reactive protein, and low C4 complement 5 days after completing teplizumab therapy. The illness resolved in 2.5 months. Anaphylaxis, with hypoxia and bronchospasm, was observed in 1 teplizumab-treated patient who was hospitalized. Angioedema (periorbital and facial) was observed in 0.3% of teplizumab-treated patients compared to 0% of patients receiving placebo. Peripheral edema and generalized edema were reported in 1.6% of teplizumab-treated patients compared to 0% of patients receiving placebo. Urticaria was reported in 1.9% of teplizumab-treated patients compared to 1.2% of control-treated patients. Vomiting and bronchospasm were also reported as acute hypersensitivity reactions.
Elevated hepatic enzymes were observed in teplizumab-treated patients, both in patients with cytokine release syndrome (CRS) and in patients without CRS. Monitor liver transaminases and serum bilirubin at baseline and during treatment as clinically indicated. Discontinue teplizumab in patients who develop elevated alanine aminotransferase (ALT) or aspartate amiontransferase (AST) more than 5 times the upper limit of normal (ULN) or bilirubin more than 3 times the ULN. In clinical trials, elevated hepatic enzymes were reported in 25% of teplizumab-treated patients compared to 11% of patients receiving placebo. Increased ALT of 3 times the ULN was reported in 5% of teplizumab-treated patients. Most hepatic enzyme elevations were transient and resolved 1 to 2 weeks after treatment; 98% resolved by follow-up week 14.
In clinical trials, headache was reported in 11% of teplizumab-treated patients compared to 6% of patients receiving placebo.
Serious bacterial infection and viral infection have been reported with teplizumab therapy including gastroenteritis, cellulitis, pneumonia, abscess, and sepsis. If serious infection develops, treat appropriately, and discontinue teplizumab. In clinical trials, serious infections occurred in 3.5% of teplizumab-treated patients compared to 2% of control-treated patients. Naso-pharyngitis was reported in 5% of teplizumab-treated patients compared to 0% of patients receiving placebo.
In clinical trials, diarrhea was reported in 5% of teplizumab-treated patients compared to 0% of patients receiving placebo. Nausea was reported in 5% of teplizumab-treated patients compared to 3% of patients receiving placebo.
In clinical trials, decreased bicarbonate (metabolic acidosis) was reported in 15% of teplizumab-treated patients compared to 7% of patients receiving placebo. Decreased blood calcium (hypocalcemia) was reported in 19% of teplizumab-treated patients compared to 13% of patients receiving placebo.
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation. In a placebo-controlled trial in patients 8 years and older with stage 2 type 1 diabetes, anti-drug antibodies (ADAs) were observed in approximately 57% of teplizumab-treated patients, 46% of whom developed neutralizing antibodies. There is insufficient information to characterize the effects of ADAs on pharmacokinetics, pharmacodynamics, or effectiveness of teplizumab. The incidence of rash was higher in teplizumab-treated patients with anti-teplizumab antibody development compared to those who did not develop ADAs. Rash occurred in 39% of teplizumab-treated patients who developed anti-teplizumab antibodies compared to 33% of teplizumab-treated patients who did not develop anti-teplizumab antibodies.
Cytokine release syndrome (CRS) has been reported with teplizumab; manifestations typically occur during the first 5 days of treatment. CRS manifestations in teplizumab-treated patients include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and increased bilirubin. To reduce the risk of CRS, premedicate with antipyretics, antihistamines, and/or antiemetics prior to teplizumab administration. Monitor liver transaminases and serum bilirubin at baseline and during treatment as clinically indicated. Discontinue teplizumab in patients who develop elevated ALT or AST more than 5 times the upper limit of normal (ULN) or bilirubin more than 3 times the ULN. Treat symptoms of CRS with antipyretics, antihistamines, and/or antiemetics. For severe CRS, consider temporarily pausing dosing for 1 to 2 days (and administer the remaining doses to complete the full 14-day course on consecutive days) or discontinuing treatment.
Teplizumab therapy is not recommended in patients with active serious infection or chronic infection, other than localized skin infections, or in patients with laboratory or clinical evidence of acute infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV). Serious bacterial infection and viral infection have been reported with teplizumab therapy including gastroenteritis, cellulitis, pneumonia, abscess, and sepsis. Monitor patients for signs and symptoms of infection prior to and during teplizumab therapy. If serious infection develops, treat appropriately, and discontinue teplizumab.
Hematologic toxicity (e.g., anemia, lymphopenia, leukopenia, neutropenia, and thrombocytopenia) has been reported with teplizumab therapy. Evaluate complete blood cell counts at baseline and periodically during treatment. Teplizumab therapy is not recommended in patients with hemoglobin less than 10 g/dL, lymphocyte count less than 1,000 lymphocytes/mcL, platelet count less than 150,000 platelets/mcL, and absolute neutrophil count less than 1,500 neutrophils/mcL. For most teplizumab-treated patients who develop lymphopenia, lymphocyte concentrations began to recover after the fifth day of treatment and return to pre-treatment values within 2 weeks after treatment completion without dose interruption. Monitor white blood cell counts during the treatment period. Therapy discontinuation may be necessary in patients who develop prolonged severe lymphopenia (less than 500 cells/mcL lasting 1 week or longer).
The safety of vaccination with live-attenuated vaccines in teplizumab-treated patients has not been studied. Additionally, teplizumab may interfere with the immune response to vaccination and decrease vaccine efficacy. Administer all age-appropriate vaccinations prior to teplizumab therapy. Inactivated or mRNA vaccinations are not recommended within 2 weeks prior to teplizumab treatment, during treatment, or 6 weeks after completion of treatment. Live-attenuated vaccinations are not recommended within the 8 weeks prior to teplizumab treatment, during treatment, or up to 52 weeks after treatment. Consider risks and benefits before administering live vaccines to neonates or infants with in utero exposure to teplizumab. The data are insufficient regarding infant serum concentrations of teplizumab at birth and the duration of persistence of teplizumab in infant serum after birth to establish a specific timeframe to delay live virus immunizations in infants exposed in utero.
Elevated hepatic enzymes have been reported with teplizumab therapy. Monitor liver transaminases and serum bilirubin at baseline and during treatment as clinically indicated. Teplizumab therapy is not recommended in patients with hepatic disease whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations are greater than 2 times the upper limit of normal (ULN) or bilirubin concentration is greater than 1.5 times the ULN. Discontinue teplizumab in patients who develop elevated ALT or AST more than 5 times the ULN or bilirubin more than 3 times the ULN.
Available case reports from clinical trials with teplizumab use during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are no available data with teplizumab use during pregnancy; however, monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Teplizumab may cause immunosuppression in the utero-exposed neonate. To minimize exposure to a fetus, avoid use of teplizumab during pregnancy and at least 30 days (6 half-lives) prior to planned pregnancy. Teplizumab is not active in rodents. In animal reproduction studies, mice were given a surrogate anti-mouse CD3 antibody subcutaneously during organogenesis through lactation; immune function was impaired in offspring consistent with the expected pharmacology. Report pregnancies to Provention Bio, Inc.'s Adverse Event reporting line at 1-844-778-2246.
There are no data on the presence of teplizumab in human or animal milk, the effects on a breast-fed infant, or the effects on milk production. Monoclonal antibodies and endogenous maternal IgG are excreted in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the infant is unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for teplizumab and any potential adverse effects on the breast-fed infant from teplizumab or from the underlying maternal condition. A lactating woman may interrupt breast-feeding and pump and discard breast milk during treatment and for 20 days after teplizumab administration to minimize drug exposure to a breast-feeding infant.
General Dosing Information
-Confirm stage 2 type 1 diabetes diagnosis with documentation of the following:
--At least 2 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 patient's clinical history does not suggest type 2 diabetes.
For type 1 diabetes mellitus prophylaxis or delay in the onset of stage 3 type 1 diabetes mellitus in persons with stage 2 type 1 diabetes mellitus:
Intravenous dosage:
Adults: 65 mcg/m2/dose IV once daily on day 1, then 125 mcg/m2/dose IV once daily on day 2, then 250 mcg/m2/dose IV once daily on day 3, then 500 mcg/m2/dose IV once daily on day 4, and then 1,030 mcg/m2/dose IV once daily on days 5 through 14.
Children and Adolescents 8 to 17 years: 65 mcg/m2/dose IV once daily on day 1, then 125 mcg/m2/dose IV once daily on day 2, then 250 mcg/m2/dose IV once daily on day 3, then 500 mcg/m2/dose IV once daily on day 4, and then 1,030 mcg/m2/dose IV once daily on days 5 through 14.
Maximum Dosage Limits:
-Adults
1,030 mcg/m2/day IV.
-Geriatric
1,030 mcg/m2/day IV.
-Adolescents
1,030 mcg/m2/day IV.
-Children
8 to 12 years: 1,030 mcg/m2/day IV.
1 to 7 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Teplizumab therapy is not recommended in patients with hepatic disease whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations are greater than 2 times the upper limit of normal (ULN) or bilirubin concentration is greater than 1.5 times the ULN.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Teplizumab products.
Teplizumab binds to CD3, a cell surface antigen on T lymphocytes, on the surface of both CD4+ and CD8+ T cells during treatment with internalization of the teplizumab/CD3 complex from the surface of T cells. Teplizumab's mechanism may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. Teplizumab increases the proportion of regulatory T cells and exhausted CD8+ T cells in peripheral blood.
Teplizumab is administered by intravenous infusion. During a 14-day course of teplizumab, lymphopenia, in the absence of depletion of T cells, occurred with a nadir on the fifth day of dosing. Steady-state concentrations are not expected to be achieved during the 14-day course of teplizumab. The central volume of distribution (Vd) is 2.27 L in a 60 kg patient. Teplizumab binding and elimination are saturable. The mean terminal elimination half-life and clearance of teplizumab are 4.5 days and 2.7 L/day in a 60 kg patient, respectively. Teplizumab is expected to be metabolized into small peptides by catabolic pathways.
Affected cytochrome P450 isoenzymes: none
-Special Populations
Pediatrics
No clinically significant differences in the pharmacokinetics of teplizumab were observed based on age in patients 8 to 35 years.
Gender Differences
No clinically significant differences in the pharmacokinetics of teplizumab were observed based on sex.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of teplizumab were observed based on ethnicity.
Obesity
BSA-based dosing normalizes the exposure to teplizumab across body weight.