Trogarzo Drug Information
Generic name: IBALIZUMAB
CD4-directed Blocking Antibody [EPC] Human Immunodeficiency Virus 1 Post-attachment Fusion Inhibitor [EPC]
Uses of Trogarzo
TROGARZO, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. TROGARZO, a CD4-directed post-attachment HIV-1 inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.
Dosage & Administration of Trogarzo
| IV Infusion (Diluted) | IV Push (Undiluted) | |
| Loading Dose 2,000 mg | Over at least 30 minutes | |
| Maintenance Dose 800 mg | Over at least 15 minutes |
Side Effects of Trogarzo
Clinical Trial Experience
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 350 subjects have been exposed to TROGARZO in the ibalizumab clinical development program, including 45 subjects who received TROGARZO through expanded access programs. A total of 19 subjects received TROGARZO via IV push.
The safety profile of TROGARZO administered via IV push (Trial TMB-302) was similar to that seen with IV infusion administration (Trial TMB-301). Trial TMB-301 The primary safety assessment of TROGARZO is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of TROGARZO 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 TROGARZO 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 TROGARZO loading dose, 800 mg of TROGARZO was administered IV. The IV administration of TROGARZO 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 3 shows the frequency of adverse reactions occurring in 5% or more of subjects. Table 3. Adverse Reactions (All Grades) Reported in ≥ 5% of Subjects Receiving TROGARZO and Optimized Background Regimen for 23 Weeks in Trial TMB-301 % Subjects N=40 Diarrhea 8% Dizziness 8% Nausea 5% Rash Includes pooled terms “rash”, “rash erythematous”, “rash generalized”, “rash macular”, “rash maculopapular”, and “rash papular” 5% 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.
Laboratory Abnormalities Table 4 shows the frequency of laboratory abnormalities (≥ Grade 3) in Trial TMB-301. Table 4. 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/mm 3 ) 3% Leukocytes (< 1.5 x 10 9 cells/L) 5% Neutrophils (< 0.6 x 10 9 cells/L) 5%
Postmarketing Experience
The following adverse reactions have been identified during post‐approval use of TROGARZO. 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. Immune system disorders: hypersensitivity reactions including infusion-related reactions and anaphylactic reactions have been reported . Skin and subcutaneous tissue disorders: pruritus
Warnings & Cautions for Trogarzo
Hypersensitivity Including Infusion-Related and Anaphylactic Reactions Hypersensitivity reactions including infusion-related reactions and
anaphylactic reactions have been reported following infusion of TROGARZO during post-approval use. Symptoms may include dyspnea, angioedema, wheezing, chest pain, chest tightness, cough, hot flush, nausea, and vomiting. If signs and symptoms of an anaphylactic or other clinically significant hypersensitivity reaction occur, immediately discontinue administration of TROGARZO and initiate appropriate treatment.
The use of TROGARZO is contraindicated in patients with known hypersensitivity with TROGARZO.
Immune Reconstitution Inflammatory Syndrome Immune reconstitution inflammatory syndrome has been reported in
one patient treated with TROGARZO in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.
Embryo-Fetal Toxicity
Based on animal data, TROGARZO may cause reversible immunosuppression (CD4+ T cell and B cell lymphocytopenia) in infants born to mothers exposed to TROGARZO during pregnancy. Immune phenotyping of the peripheral blood and expert consultation are recommended to provide guidance regarding monitoring and management of exposed infants based on the degree of immunosuppression observed. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.
Pregnancy Safety for Trogarzo
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiretrovirals during pregnancy. This registry does not include Trogarzo, but likely includes patients’ concomitant antiretroviral drugs. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263. Risk Summary Based on animal data, ibalizumab-uiyk use during pregnancy may cause reversible immunosuppression (CD4+ T cell and B cell lymphocytopenia) in infants exposed to ibalizumab-uiyk in utero.
Immunoglobulin G (IgG) antibodies, such as ibalizumab-uiyk, are transported across the placenta in significant amounts, especially near term; therefore, ibalizumab-uiyk has the potential to be transferred from the mother to the developing fetus (see Clinical Considerations). There are no available data on ibalizumab-uiyk use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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. In a reproductive study in monkeys, reversible decreases in CD4+ T cells and B cells and increases in CD8+ T cells were observed within the first 4 weeks after birth in infants born to pregnant monkeys receiving ibalizumab-uiyk intravenously ( see Data ). Lymphocyte counts returned to near normal levels by 3 months of age. One infant monkey died from a systemic viral infection that may be related to ibalizumab-uiyk-induced immunosuppression.
No malformations or premature births were observed in this study. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G (IgG) antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Administration of TROGARZO during pregnancy may affect immune responses in the in utero-exposed infant.
For infants with perinatal exposure to TROGARZO, immune phenotyping of the peripheral blood, including CD4+ T cell and B cell counts, is recommended. Expert consultation is also recommended to provide guidance on monitoring and management (e.g., need for antibiotic or immunoprophylaxis) of exposed infants based on the degree of immunosuppression observed. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.
Data Animal Data In an enhanced pre- and post-natal development (ePPND) study, pregnant cynomolgus monkeys were administered intravenous doses of either vehicle or 110 mg/kg ibalizumab-uiyk every week from Gestation Day 20-22 (GD 20-22) until parturition on GD 160 ± 10. Significant changes in infant monkey immune cell levels on Postnatal Day (PND) 14 (mean decreases of 78% in CD4+ T cells and 46% in B cells and increases of 2.3-fold in CD8+ T cells) and PND 28 (mean decreases of 73% in CD4+ T cells and increases of 2.2-fold in CD8+ T cells), attributed to in utero ibalizumab-uiyk exposure, were observed relative to concurrent controls. The lymphocyte changes correlated with infant ibalizumab-uiyk serum concentrations and appeared to return to near normal levels between PND 28-91, when ibalizumab-uiyk concentrations were nearly undetectable. Although ibalizumab-uiyk exposure in these infant monkeys may be significantly higher than in human infants following in utero exposure at the recommended human maintenance dose, the risk of ibalizumab-uiyk-induced immunosuppression in human infants is possible.
No meaningful differences in infant monkey lymphocyte counts were observed on PND 180. Further, no differences in immune cell function were observed in a T cell-dependent response assay conducted on PND 138 to 180 ± 2 following immunization of the infant monkeys with keyhole limpet hemocyanin. One treatment-group infant monkey died on PND 24 from a systemic viral infection with secondary superficial bacterial infection which was acquired during the postnatal period. Despite the low incidence (1 of 20 infants), the death may be related to ibalizumab-uiyk-induced immunosuppression.
Decreases in CD4+ T cells (93%), and B cells (92%) were observed in this infant on PND 14, and decreased cellularity was observed in the spleen, thymus and mandibular lymph node. Unlike the rest of the ibalizumab-exposed infant monkey population, this infant also exhibited a decrease in CD8+ T cells of 71% on PND 14. Body weight was also decreased in this infant between PND 14 and 24. No structural abnormalities were observed among the ibalizumab-uiyk-exposed infants. In addition, no maternal toxicities, including no changes in maternal lymphocyte subsets or effects on embryo-fetal survival, were observed.
Pediatric Use of Trogarzo
Pediatric Use The safety and effectiveness of TROGARZO in pediatric patients have not been established.
Contraindications for Trogarzo
is contraindicated in patients with a prior hypersensitivity reaction to TROGARZO or any components of the product. Prior hypersensitivity reaction to TROGARZO or any components of the product.
Clinical Studies of Trogarzo
- Trial TMB-301: Trial TMB-301 was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected subjects with multidrug resistant HIV-1. Subjects were required to have a viral load greater than 1,000 copies/mL and documented resistance to at least one antiretroviral medication from each of three classes of antiretroviral medications as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed (i.e., in the last 8 weeks) therapy.
- The trial was composed of three discrete periods: Control period (Day 0 to Day 6) : Subjects were either monitored on their current failing therapy or received no therapy if they had failed and discontinued treatment within the 8 weeks preceding screening. This was an observational period to establish baseline HIV viral load.
- Functional monotherapy period (Day 7 to Day 13): All subjects received a 2,000 mg loading dose of TROGARZO on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of TROGARZO. This period was to establish the virologic activity of TROGARZO.
- Maintenance period (Day 14 to Week 25): On Day 14 of the treatment period, viral load was assessed for the primary endpoint, and thereafter the background regimen was optimized to include at least one drug to which the subjects virus was susceptible. The use of an investigational drug(s) as a component of the optimized background regimen was allowed. Beginning at Day 21, an 800 mg maintenance dose of TROGARZO was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of TROGARZO when used in combination with an optimized background regimen. The majority of subjects in Trial TMB-301 were male (85%), white (55%) and between 23 and 65 years of age (mean age: 50.5 years). At Baseline, median viral load and CD4 + T cell counts were 35,350 copies/mL and 73 cells/mm 3, respectively.
- The subjects were heavily treatment-experienced: 53% of participants had been treated with 10 or more antiretroviral drugs prior to trial enrollment; 98% percent had been treated with NRTIs, 98% with PIs, 80% with NNRTIs, 78% with INSTIs, 30% with gp41 fusion inhibitors, and 20% with CCR5 co-receptor antagonists. The primary efficacy endpoint was the proportion of subjects achieving a 0.5 log 10 decrease in viral load from the beginning to the end of the "Functional monotherapy period" as compared to the proportion of subjects achieving a 0.5 log 10 decrease from the beginning to the end of the "Control period", as defined above. The results of the primary endpoint analysis are shown in Table 5 below. Table 5. Proportion of Subjects Achieving a 0.5 log 10 Decrease in Viral Load at the End of the Control and Functional Monotherapy Periods Proportion of Subjects Achieving a 0.5 log 10 Decrease in Viral Load N=40 95% CI exact 95% confidence interval. p < 0.0001 based on McNemars test comparing the proportion of subjects achieving 0.5 log 10 decrease in viral load at the end of the control and functional monotherapy periods. End of Control Period 3% (0.06%, 13%) End of Functional Monotherapy Period 83% (67%, 93%) At Week 25, viral load <50 and <200 HIV-1 RNA copies/mL was achieved in 43% and 50% of subjects, respectively. Fifty-five percent of subjects had a 1 log 10 reduction in viral load, and 48% of subjects had a 2 log 10 reduction in viral load at Week 25. An increase in the mean and median number of CD4 + T-cells (44 cells/mm 3 and 17 cells/mm 3, respectively) was observed from Baseline to Week 25. Week 25 outcomes are shown in Table 6 and Table 7. Table 6. Trial TMB 301 Virologic Outcomes (Snapshot Algorithm) at Week 25 TROGARZO (N=40) HIV RNA < 50 copies/mL at Week 25 HIV RNA 50 copies/mL at Week 25* included subjects who had ≥ 50 copies/mL in the Week 25 window, subjects who discontinued study drug due to lack of efficacy, and subjects who discontinued study drug for reasons other than an AE, death and at the time of discontinuation had a viral value ≥ 50 copies/mL 43% 45% HIV RNA < 200 copies/mL at Week 25 HIV RNA 200 copies/mL at Week 25 included subjects who had ≥ 200 copies/mL in the Week 25 window, subjects who discontinued study drug due to lack of efficacy, and subjects who discontinued study drug for reasons other than an AE, death and at the time of discontinuation had a viral value ≥ 200 copies/mL 50% 38% No virologic data at Week 25 Discontinued due to AE or death 13% Table 7. Virologic Response at Week 25 by Baseline CD4 Cell count, Viral Load, Integrase Inhibitor Resistance and OSS OSS Overall Susceptibility Score. The OSS indicates the number of fully active drugs in a subjects OBR based on both current and available historical resistance test results. Demonstrating drug susceptibility by both genotypic and phenotypic testing was required, when testing by both methods was technically feasible. As an example, an OSS of 2 would indicate that the HIV-1 isolate tested was fully susceptible to two drugs in the OBR. Subjects achieving <50 HIV-1 RNA copies/mL (%) Subjects achieving <200 HIV-1 RNA copies/mL (%) CD4 Cell Counts <50 (n=17) 50-200 (n=10) >200 (n=13) 18 60 62 24 70 69 Viral Load 100,000 (n=33) >100,000 (n=7) 49 14 58 14 Resistance With INSTI Resistance (n=27) Without INSTI Resistance (n=13) 41 46 44 62 OSS 0 (n=5) 1 (n=12) 2 (n=18) 3 (n=3) 4 (n=2) 20 42 50 33 50 20 50 61 33 50
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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