Ibalizumab

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.

Injection: 200 mg/1.33 mL (150 mg/mL) colorless to slightly yellow and clear to slightly opalescent solution with no visible particles in a single-dose vial. Injection: 200 mg/1.33 mL (150 mg/mL) in a single-dose vial.

TROGARZO is contraindicated in patients with a prior hypersensitivity reaction to TROGARZO or any components of the product [see Warnings and Precautions ( 5.1 )]. Prior hypersensitivity reaction to TROGARZO or any components of the product.

Hypersensitivity reactions including infusion-related reactions and anaphylactic reactions have been reported following infusion of TROGARZO. ( 5.1 ) Immune Reconstitution Inflammatory Syndrome (IRIS) has been reported in patients treated with combination antiretroviral therapies. ( 5.2 ) Embryo-Fetal Toxicity: Monitor infants exposed to TROGARZO in utero for signs and symptoms of immunosuppression. ( 5.3 , 8.1 )

5.1 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 [see Contraindications ( 4 ), Adverse Reactions ( 6.2 )].

5.2 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.

5.3 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. [see Use In Specific Populations ( 8.1 )]

The following adverse drug reactions are discussed in other sections of the labeling: Immune Reconstitution Inflammatory Syndrome [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (incidence ≥ 5%) were diarrhea, dizziness, nausea, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact THERA patient support ® at 1-833-23THERA (1-833-238-4372) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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) [see Clinical Pharmacology ( 12.3 )]. 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%

6.2 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 [see Warnings and Precautions ( 5.1 )] . Skin and subcutaneous tissue disorders: pruritus

Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 )

8.1 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.

8.2 Lactation Risk Summary 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 TROGARZO 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 TROGARZO.

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

8.5 Geriatric Use No studies have been conducted with TROGARZO in geriatric patients.

Ibalizumab-uiyk is an HIV-1 antiretroviral drug [see Microbiology ( 12.4 )] .