Based on findings in animals and its mechanism of action inhibiting insulin-like growth factor 1 receptor (IGF-1R), teprotumumab may cause fetal harm when administered to a pregnant woman. Adequate and well-controlled studies with teprotumumab have not been conducted in pregnant women. There are insufficient data with teprotumumab use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero teprotumumab exposure in cynomolgus monkeys dosed once weekly with teprotumumab throughout pregnancy resulted in external and skeletal abnormalities. Teprotumumab exposure may lead to an increase in fetal loss [see Data]. Therefore, teprotumumab should not be used in pregnancy, and appropriate forms of contraception should be implemented prior to initiation, during treatment and for 6 months following the last dose of teprotumumab. If the patient becomes pregnant during treatment, teprotumumab should be discontinued and the patient advised of the potential risk to the fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
In an abridged pilot embryofetal development study, seven pregnant cynomolgus monkeys were dosed intravenously at one dose level of teprotumumab, 75 mg/kg (2.8-fold the maximum recommended human dose (MRHD) based on AUC) once weekly from gestation day 20 through the end of gestation. The incidence of abortion was higher for the teprotumumab treated group compared to the control group. Teprotumumab caused decreased fetal growth during pregnancy, decreased fetal size and weight at caesarean section, decreased placental weight and size, and decreased amniotic fluid volume. Multiple external and skeletal abnormalities were observed in each exposed fetus, including: misshapen cranium, closely set eyes, micrognathia, pointing and narrowing of the nose, and ossification abnormalities of skull bones, sternebrae, carpals, tarsals and teeth. The test dose, 75 mg/kg of teprotumumab, was the maternal no observed adverse effect level (NOAEL).
Based on mechanism of action inhibiting IGF-1R, postnatal exposure to teprotumumab may cause harm.
There is no information regarding the presence of teprotumumab in human milk, the effects on the breast-fed infant or the effects on milk production.
The carcinogenic potential of teprotumumab has not been evaluated in long-term animal studies.
The genotoxic potential of teprotumumab has not been evaluated.
Fertility studies have not been performed with teprotumumab.
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 safety of teprotumumab was evaluated in two randomized, double-masked, placebo-controlled clinical studies (Study 1 [NCT:01868997] and Study 2 [NCT:03298867]) consisting of 170 patients with Thyroid Eye Disease (84 received teprotumumab and 86 received placebo). Patients were treated with teprotumumab (10 mg/kg for first infusion and 20 mg/kg for the remaining 7 infusions) or placebo given as an intravenous infusion every 3 weeks for a total of 8 infusions. The majority of patients completed 8 infusions (89% of teprotumumab patients and 93% of placebo patients).
The most common adverse reactions (≥5%) that occurred at greater incidence in the teprotumumab group than in the control group during the treatment period of Studies 1 and 2 are summarized in Table 1.
Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with Teprotumumab and Greater Incidence than Placebo:
| Adverse Reactions | Teprotumumab N=84 N (%) | Placebo N=86 N (%) |
|---|---|---|
| Muscle spasms | 21 (25%) | 6 (7%) |
| Nausea | 14 (17%) | 8 (9%) |
| Alopecia | 11 (13%) | 7 (8%) |
| Diarrhea | 10 (12%) | 7 (8%) |
| Fatigue* | 10 (12%) | 6 (7%) |
| Hyperglycemia† | 8 (10%) | 1 (1%) |
| Hearing impairment‡ | 8 (10%) | 0 |
| Dysgeusia | 7 (8%) | 0 |
| Headache | 7 (8%) | 6 (7%) |
| Dry skin | 7 (8%) | 0 |
* Fatigue includes asthenia
† Hyperglycemia includes blood glucose increase
‡ Hearing impairment (includes deafness, eustachian tube dysfunction, hyperacusis, hypoacusis and autophony)
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
In a placebo-controlled study with teprotumumab, 1 of 42 patients treated with placebo had detectable levels of antidrug antibodies in serum. In the same study, none of the 41 patients treated with teprotumumab had detectable levels of antidrug antibodies in serum.
© 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.