2.1 Recommended Dosage

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.

The loading dose of TROGARZO is administered as a diluted intravenous infusion (IV infusion). Maintenance doses of TROGARZO may be administered as a diluted IV infusion or undiluted intravenous push (IV push).

Patients should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.

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

2.2 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.

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 (2oC to 8oC, 36oF to 46oF) 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.

2.3 Administration

TROGARZO solution should be administered by a trained medical professional.

Administer TROGARZO intravenously (as an IV infusion or IV push) in the cephalic vein of the patient’s right or left arm. If this vein is not accessible, an appropriate vein located elsewhere can be used.

The duration of the first infusion (loading dose) should be no less than 30 minutes. If no infusion-associated adverse reactions have occurred, subsequent maintenance doses can be administered as an IV infusion in no less than 15 minutes or as an IV push over a 30-second period.

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 administration for at least the first infusion (loading dose). 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.

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)]

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 2 shows the frequency of adverse reactions occurring in 5% or more of subjects.

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 3 shows the frequency of laboratory abnormalities (≥ Grade 3) in Trial TMB-301.

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

8.1 Pregnancy

8.2 Lactation

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.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

A clear trend was identified between exposure and response rate for the Phase 2b trial (TMB-202) which studied two different intravenous doses given at two different dosing intervals (every 4 weeks vs. every 2 weeks). The recommended intravenous dosing regimen consisting of a 2,000 mg loading dose followed by a maintenance dose of 800 mg every 2 weeks was selected on the basis of these results.

12.3 Pharmacokinetics

Ibalizumab-uiyk administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of ibalizumab-uiyk as 0.5 to 1.5-hour infusions, the area under the concentration-time curve increased in a greater than dose-proportional manner, clearance decreased from 9.54 to 0.36 mL/h/kg and elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg. The volume of distribution of ibalizumab-uiyk was approximately that of serum volume, at 4.8 L.

Following the recommended dose regimen (a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks), ibalizumab-uiyk concentrations reached steady-state levels after the first 800 mg maintenance dose with mean concentrations over 30 mcg/mL throughout the dosing interval. Among HIV-infected subjects, the pharmacokinetic data from Trial TMB-302 demonstrated that ibalizumab-uiyk Ctrough and AUC0-tau values between IV push administration and IV infusion administration for maintenance dose were similar. The Cmax values were 25% higher for IV push compared to the IV infusion administration. The increase in Cmax is not considered clinically relevant.

Specific Populations
A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates (age, body weight, sex, baseline CD4+ cell count) on ibalizumab-uiyk pharmacokinetics. The result suggests that ibalizumab-uiyk concentration decreases as body weight increases; however, the effect is unlikely to impact virologic outcome and does not warrant a dose adjustment.

Pediatric/Geriatric Patients: Ibalizumab-uiyk pharmacokinetics have not been evaluated in pediatric or geriatric patients [see Use in Specific Populations (8.4, 8.5)].

Renal/Hepatic Impairment: No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of ibalizumab-uiyk. Renal impairment is not anticipated to impact the pharmacokinetics of ibalizumab-uiyk.

Drug Interaction studies
No drug interaction studies have been conducted with ibalizumab-uiyk. Based on ibalizumab-uiyk’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.

12.4 Microbiology

12.6 Immunogenicity

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 TROGARZO 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, mutagenesis, and fertility studies with ibalizumab-uiyk have not been conducted.

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 [SD] age: 50.5 [11.0] years). At Baseline, median viral load and CD4+ T cell counts were 35,350 copies/mL and 73 cells/mm3, 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 log10 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 log10 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 4 below.

p < 0.0001 based on McNemars test comparing the proportion of subjects achieving ≥ 0.5 log10 decrease in viral load at the end of the control and functional monotherapy periods.

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 log10 reduction in viral load, and 48% of subjects had a ≥ 2 log10 reduction in viral load at Week 25. An increase in the mean and median number of CD4+ T-cells (44 cells/mm3 and 17 cells/mm3, respectively) was observed from Baseline to Week 25. Week 25 outcomes are shown in Table 5 and Table 6.

TROGARZO (ibalizumab-uiyk) injection is a sterile colorless to slightly yellow and clear to slightly opalescent solution with no visible particles for intravenous administration (by IV infusion or IV push). It is packaged in a single-dose 2 mL clear glass vial containing 200 mg/1.33 mL (150 mg/mL) of ibalizumab-uiyk. TROGARZO is not made with natural rubber latex.

TROGARZO is available in a carton containing two single-dose vials (NDC 62064-122-02).

Store vials under refrigeration at 2 to 8ºC (36-46 ºF). Do not freeze and protect from light.

Once diluted, the TROGARZO solution should be administered immediately [see Dosage and Administration (2.2)].

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