Trogarzo Drug Information

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.

Recommended Dosage

The recommended dosage regimen is a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks administered as a diluted intravenous infusion (IV infusion) or undiluted intravenous push (IV push). TROGARZO is available in a single-dose, 2 mL vial containing 150 mg/mL of ibalizumab-uiyk. Each vial delivers approximately 1.33 mL containing 200 mg of ibalizumab-uiyk.

Dose modifications of TROGARZO are not required when administered with any other antiretroviral or any other treatments.

Preparation

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard vial if solution is cloudy, if there is pronounced discoloration or if there is foreign particulate matter. See Table 1 for the appropriate number of vials required to prepare both the loading dose of 2,000 mg and the maintenance doses of 800 mg.

Table 1. Recommended TROGARZO solution for IV infusion or IV push should be prepared by a trained medical professional using aseptic technique as follows: For intravenous infusion For administration as an IV infusion, the appropriate number of vials are diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. • Remove the flip-off cap from the single-dose vial and wipe the stopper with an alcohol swab. • Insert sterile syringe needle into the vial through the center of the stopper and withdraw 1.33 mL from each vial (NOTE: a small residual amount may remain in the vial, discard unused portion) and transfer into a 250 mL intravenous bag of 0.9% Sodium Chloride Injection, USP. Other intravenous diluents must not be used to prepare the TROGARZO solution for infusion. • Once diluted, the TROGARZO solution should be administered immediately. • If not administered immediately, store the diluted TROGARZO solution at room temperature (20°C to 25°C, 68°F to 77°F) for up to 4 hours, or refrigerated (2°C to 8°C, 36°F to 46°F) for up to 24 hours.

If refrigerated, allow the diluted TROGARZO solution to stand at room temperature (20°C to 25°C, 68°F to 77°F) for at least 30 minutes but no more than 4 hours prior to administration. • Discard partially used vials or empty vials of TROGARZO and any unused portion of the diluted TROGARZO solution. For intravenous push For administration as an IV push, undiluted TROGARZO solution is administered. • Allow the vials to stand at room temperature for approximately 5 minutes. • Remove the flip-off cap from the single-dose vial and wipe the stopper with an alcohol swab. • Insert sterile syringe needle into the vial through the center of the stopper and withdraw 1.33 mL from each vial (NOTE: a small residual amount may remain in the vial, discard unused portion). • The undiluted TROGARZO solution should be administered immediately. • Discard partially used vials or empty vials of TROGARZO and any unused portion of the undiluted TROGARZO solution.

Administration

Administer TROGARZO intravenously (as an IV infusion or IV push) in the cephalic vein of the patients right or left arm. If this vein is not accessible, an appropriate vein located elsewhere can be used. Table 2 outlines the duration of IV infusion or IV push for the loading dose and maintenance dose.

Table 2. Duration of IV Infusion or IV Push After the IV infusion is complete, flush with 30 mL of 0.9% Sodium Chloride Injection, USP. After the IV push is complete, flush with 2 to 5 mL of 0.9% Sodium Chloride Injection, USP.

All patients must be observed for 1 hour after completion of TROGARZO loading dose as an IV infusion or IV push. If the patient does not experience an infusion-associated adverse reaction, the post-administration observation time for the subsequent maintenance doses (IV infusion or IV push) can be reduced to 15 minutes. If a maintenance dose (800 mg) of TROGARZO is missed by 3 days or longer beyond the scheduled dosing day, a loading dose (2,000 mg) should be administered as early as possible.

Resume maintenance dosing (800 mg) every 14 days thereafter.

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 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

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

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.

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 The safety and effectiveness of TROGARZO in pediatric patients have not been established.

TROGARZO is contraindicated in patients with a prior hypersensitivity reaction to TROGARZO or any components of the product.