Available case reports from clinical trials with teplizumab 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 may cause immunosuppression in the utero-exposed infant (see Clinical Considerations). 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. 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.
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 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.
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 and any potential adverse effects on the breastfed child from teplizumab 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 administration to minimize drug exposure to a breastfed child.
No long-term studies have been performed to assess the carcinogenic potential of teplizumab-mzwv.
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 reproductive performance were unaffected in female and male mice that received a murine surrogate anti-mouse CD3 antibody administered by the subcutaneous route at doses up to 20 mg/kg.
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.
The data in the table below are derived from the placebo-controlled study (Study TN-10) in patients aged 8 years and older with Stage 2 type 1 diabetes (T1D). These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course.
Adverse reactions in teplizumab-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):
In this pool:
In these studies, 436 patients received a 14-day dosing regimen of teplizumab with a total drug exposure that was comparable to the total drug exposure achieved with the recommended dosage, 168 patients received a 14-day course of teplizumab with a lower total teplizumab drug exposure, and 169 patients received a 6-day course of teplizumab with a lower total teplizumab drug exposure. The mean age of teplizumab-treated patients was 17.6 years (median 15 years), 62% were <18 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 <1% American Indian or Alaska Native; 5% were Hispanic or Latino ethnicity.
The following table 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 teplizumab were consistent with those reported in adult patients in this study.
Common Adverse Reactions* in Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 Type 1 Diabetes (Study TN-10)†:
| Adverse Reaction | Placebo N=32 | Teplizumab N=44 |
|---|---|---|
| Lymphopenia | 6% | 73% |
| Rash‡ | 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% |
* That occurred during treatment and through 28 days after the last study drug administration
† Adverse reactions that occurred in 2 or more teplizumab-treated patients
‡ Composite of rash-related terms including rash erythematous, rash macular, rash papular, rash maculo-papular, rash pruritic
In Study TN-10, CRS was reported in 2% of teplizumab-treated patients compared to 0% of placebo-treated patients.
Of the 39 teplizumab-treated patients that developed CRS (5% of all teplizumab-treated patients) in the pool of 5 clinical trials, 13% of the CRS cases were serious adverse reactions. Liver transaminase elevations were observed in 56% of teplizumab-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.
In Study TN-10, serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) were reported in 9% (4/44) of teplizumab-treated patients compared to 0% (0/32) of placebo-treated patients any time during or after the first dose of study treatment.
Hypersensitivity reactions were reported with teplizumab in Study TN-10. Serum sickness was observed in 2% (1/44) of teplizumab-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 teplizumab; illness resolved in 2.5 months.
In the pool of 5 clinical trials of patients:
In Study TN-10, rash occurred in 39% of teplizumab-treated patients who developed anti- teplizumab-mzwv antibodies and in 33% of teplizumab-treated patients who did not develop anti-teplizumab-mzwv antibodies.
In Study TN-10, lymphopenia was reported in 73% of teplizumab-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.
In Study TN-10, neutropenia was observed in 7% of teplizumab-treated patients compared to 3% of placebo-treated patients.
In the pool of 5 clinical trials of patients, anemia was reported in 27% of teplizumab-treated patients compared to 21% of placebo-treated patients, and thrombocytopenia was reported in 13% of teplizumab-treated patients compared to 5% of placebo-treated patients during the 14-day treatment course; 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 platelet count less than 50,000 platelets/mcL.
Liver enzyme elevations were observed in teplizumab-treated patients, both in the context of CRS and in patients without CRS. In the pool of 5 clinical trials, elevated aminotransferases were reported in 25% of teplizumab-treated patients compared to 11% of placebo-treated patients during the 14-day treatment course. On laboratory analysis, 5.1% of teplizumab-treated patients experienced a peak ALT more than 3 times the ULN compared to 0.8% of control-treated patients. Most liver enzyme elevations were transient and resolved 1-2 weeks after treatment; 98% resolved by follow-up week 14.
In the pool of 5 clinical trials, other laboratory abnormalities including decreased bicarbonate (15% in teplizumab-treated patients, compared to 7% in placebo-treated patients) and decreased blood calcium (19% in teplizumab-treated patients, compared to 13% in placebo-treated patients) were noted.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
