No adequate human data are available to establish whether or not ibalizumab poses a risk to pregnancy outcomes. Animal reproductive toxicology studies with ibalizumab-uiyk have not been conducted. Monoclonal antibodies, such as ibalizumab-uiyk, are transported across the placenta as pregnancy progresses; therefore, ibalizumab-uiyk has the potential to be transmitted from the mother to the developing fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection.
No data are available regarding the presence of ibalizumab in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is present in human milk, although published data indicate that antibodies in breast milk do not enter the neonatal or infant circulation system in substantial amounts. Because of the potential for HIV-1 transmission, instruct mothers not to breastfeed if they are receiving ibalizumab.
Carcinogenesis, mutagenesis, and reproductive toxicology studies with ibalizumab-uiyk have not been conducted.
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.
A total of 292 patients with HIV-1 infection have been exposed to ibalizumab IV infusion.
The primary safety assessment of ibalizumab is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of ibalizumab which enrolled 40 heavily treatment-experienced subjects with multidrug resistant HIV-1 on a failing HIV treatment regimen. Subjects received a single 2,000 mg IV loading dose of ibalizumab followed seven days later by the initiation of an optimized background regimen (OBR) including at least one agent to which the subject’s virus was susceptible. Two weeks after the ibalizumab loading dose, 800 mg of ibalizumab was administered IV. The IV administration of ibalizumab 800 mg was continued every 2 weeks through Week 25.
The most common adverse reactions (all Grades) reported in at least 5% of subjects were diarrhea, dizziness, nausea, and rash. Table 2 shows the frequency of adverse reactions occurring in 5% or more of subjects.
Table 2. Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving Ibalizumab and Optimized Background Regimen for 23 Weeks in Trial TMB-301:
| % Subjects N=40 | |
|---|---|
| Diarrhea | 8% |
| Dizziness | 8% |
| Nausea | 5% |
| Rash* | 5% |
* Includes pooled terms “rash”, “rash erythematous”, “rash generalized”, “rash macular”, “rash maculopapular”, and "rash papular"
Most (90%) of the adverse reactions reported were mild or moderate in severity. Two subjects experienced severe adverse reactions: one subject had a severe rash and one subject developed immune reconstitution inflammatory syndrome manifested as an exacerbation of progressive multifocal leukoencephalopathy.
Table 3 shows the frequency of laboratory abnormalities (≥ Grade 3) in Trial TMB-301.
Table 3. Selected Laboratory Abnormalities (≥ Grade 3) in Trial TMB-301:
| % Subjects N=40 | |
|---|---|
| Bilirubin (≥2.6 x ULN) | 5% |
| Direct Bilirubin (> ULN) | 3% |
| Creatinine (>1.8 x ULN or 1.5 x baseline) | 10% |
| Blood Glucose (>250 mg/dL) | 3% |
| Lipase (>3.0 x ULN) | 5% |
| Uric Acid (>12 mg/dL) | 3% |
| Hemoglobin (<8.5 g/dL) | 3% |
| Platelets (<50,000/mm³) | 3% |
| Leukocytes (<1.5 × 109 cells/L) | 5% |
| Neutrophils (<0.6 × 109 cells/L) | 5% |
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. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ibalizumab-uiyk in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
All subjects enrolled in clinical trial TMB-301 and trial TMB-202 (a Phase 2b clinical trial that studied ibalizumab administered intravenously as 2,000 mg every 4 weeks or 800 mg every 2 weeks; the safety and effectiveness of this dosing regimen has not been established), were tested for the presence of anti-ibalizumab antibodies throughout their participation. One sample tested positive with low titer anti-ibalizumab antibodies. No adverse reaction or reduced efficacy was attributed to the positive sample reported in this subject.
The following adverse reactions have been identified during post‐approval use of ibalizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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