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Ibalizumab-uiyk Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 10. MECHANISM OF ACTION
3. DOSAGE AND ADMINISTRATION 11. PHARMACODYNAMICS
4. CONTRAINDICATIONS 12. PHARMACOKINETICS
5. WARNINGS AND PRECAUTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
6. ADVERSE REACTIONS  

 

1. DESCRIPTION

Ibalizumab-uiyk is a CD4-directed post-attachment HIV-1 inhibitor.

Ibalizumab-uiyk is a CD4 domain 2-directed humanized monoclonal antibody of immunoglobulin G (IgG) isotype 4 with a molecular weight of approximately 150 kDa. Ibalizumab-uiyk is produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells.

Ibalizumab-uiyk injection is a sterile, colorless to slightly yellow and clear to slightly opalescent solution with no visible particles in a single-dose vial for intravenous infusion. Each single-dose vial delivers approximately 1.33 mL containing 200 mg of ibalizumab-uiyk, and contains the following inactive ingredients: 10 mM L-histidine (2.06 mg), 0.045% polysorbate 80 (0.60 mg), 52 mM sodium chloride (4.04 mg) and 5.2% sucrose (69.2 mg). Ibalizumab-uiyk solution has a pH of 6.0 and contains no preservative.

2. INDICATIONS AND USAGE

Ibalizumab-uiyk, 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.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

Ibalizumab-uiyk 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.

Ibalizumab-uiyk is administered intravenously (IV), after diluting the appropriate number of vials in 250 mL of 0.9% Sodium Chloride Injection, USP. 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 ibalizumab-uiyk are not required when administered with any other antiretroviral or any other treatments.

3.2 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.

Table 1. Recommended Ibalizumab-uiyk Dose and Number Vials Per Administration

Ibalizumab-uiyk solution for infusion should be prepared by a trained medical professional using aseptic technique as follows:

• Remove the flip-off cap from the single-dose vial and wipe 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 ibalizumab-uiyk solution for infusion.

• Once diluted, the ibalizumab-uiyk solution should be administered immediately.

• If not administered immediately, store the diluted ibalizumab-uiyk 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 ibalizumab-uiyk 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 ibalizumab-uiyk and any unused portion of the diluted ibalizumab-uiyk solution.

3.3 Administration

Diluted ibalizumab-uiyk solution should be administered by a trained medical professional.

Administer ibalizumab-uiyk as an IV infusion 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. Do not administer ibalizumab-uiyk as an intravenous push or bolus.

The duration of the first infusion (loading dose) should be no less than 30 minutes. If no infusion-associated adverse reactions have occurred, the duration of the subsequent infusions (maintenance doses) can be decreased to no less than 15 minutes.

After the infusion is complete, flush with 30 mL of 0.9% Sodium Chloride Injection, USP.

All patients must be observed for 1 hour after completion of ibalizumab-uiyk administration for at least the first infusion. If the patient does not experience an infusion-associated adverse reaction, the post-infusion observation time can be reduced to 15 minutes thereafter.

If a maintenance dose (800 mg) of ibalizumab-uiyk 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.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in one patient treated with ibalizumab-uiyk 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.

6. ADVERSE REACTIONS

The following adverse drug reactions are discussed in other sections of the labeling:

• Immune Reconstitution Inflammatory Syndrome [see Warnings and Precautions (5.1)]

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 292 patients with HIV-1 infection have been exposed to ibalizumab-uiyk IV infusion.

Trial TMB-301

The primary safety assessment of ibalizumab-uiyk is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of ibalizumab-uiyk 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-uiyk 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-uiyk loading dose, 800 mg of ibalizumab-uiyk was administered IV. The IV administration of ibalizumab-uiyk 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-uiyk and Optimized Background Regimen for 23 Weeks in Trial TMB-301

*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.

Laboratory Abnormalities

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

6.2 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 ibalizumab-uiyk 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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ibalizumab-uiyk during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.

Risk Summary

No adequate human data are available to establish whether or not ibalizumab-uiyk 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.

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 ibalizumab-uiyk 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-uiyk.

8.4 Pediatric Use

The safety and effectiveness of ibalizumab-uiyk in pediatric patients have not been established.

8.5 Geriatric Use

No studies have been conducted with ibalizumab-uiyk in geriatric patients.

10. MECHANISM OF ACTION

Ibalizumab-uiyk is an HIV-1 antiretroviral drug.

Ibalizumab-uiyk, a recombinant humanized monoclonal antibody, blocks HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4 and interfering with post-attachment steps required for the entry of HIV-1 virus particles into host cells and preventing the viral transmission that occurs via cell-cell fusion.

Ibalizumab-uiyk Does Not Impact CD4 Function

The binding specificity of ibalizumab-uiyk to domain 2 of CD4 allows ibalizumab-uiyk to block viral entry into host cells without causing immunosuppression. Epitope mapping studies indicate that ibalizumab-uiyk binds to a conformational epitope located primarily in domain 2 of the extracellular portion of the CD4 receptor. This epitope is positioned on the surface of CD4 opposite to the site in domain 1 that is required for CD4 binding of the MHC class II molecules and therefore does not interfere with CD4-mediated immune functions. Additionally, ibalizumab-uiyk does not interfere with gp120 attachment to CD4.

Antiviral Activity

Ibalizumab-uiyk inhibits the replication of CCR5-and CXCR4-tropic laboratory strains and primary isolates of HIV-1 in phytohemagglutinin stimulated peripheral blood lymphocytes. The median EC50 value (50% effective concentration) for ibalizumab-uiyk against HIV-1 group M isolates (subtypes A, B, C, D, E, or O) was 8 ng/mL (n = 15, range of 0.4 to 600 ng/mL) in cell culture, with lower susceptibility observed in macrophage-tropic HIV-1 strains (BaL, JR-CSF, YU2, and ADA-M). In a single-cycle infection assay, ibalizumab-uiyk inhibited 17 clinical isolates of subtypeB with a median EC50 value of 12 ng/mL (range of 8.8 to 16.9 ng/mL;mean12 ± 3 ng/mL)and a median maximum percentage inhibition (MPI) of 97% (range of 89 to 99%; mean 97 ± 3%). Three CCR5-tropic clinical isolates from subtypes B, C, and D, were inhibited with EC50 values ranging from 59-66 ng/mL and 3 CXCR4-tropic clinical isolates from subtypes B, C, and D, with EC50 values ranging from 44-59 ng/mL.

Antiviral Activity in Combination with Other Antiviral Agents

No antagonism was observed when PBMCs or MAGI-CCR5 cells infected with the subtype B Ba-L or ADA variants of HIV-1 were incubated with ibalizumab-uiyk in combination with the CCR5 co-receptor antagonist maraviroc or when PBMCs infected with the subtype B HT/92/599 variant of HIV-1 were incubated with ibalizumab-uiyk in combination with the gp41 fusion inhibitor enfuvirtide; a nonnucleoside reverse transcriptase inhibitor (efavirenz); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, tenofovir, or zidovudine); or a protease inhibitor (atazanavir).

Antiviral Activity in Antiretroviral-Resistant Virus

Subjects enrolled in TMB-301 were heavily treatment-experienced subjects infected with multidrug resistant HIV-1. Ibalizumab-uiyk inhibited 38 baseline isolates at a median EC50 value of 31 ng/mL (range of 13 to 212 ng/mL; mean 39 ± 35 ng/mL) with a median MPI of 97% (range of 41-100%; mean 91 ± 14%). For 10 subjects in TMB-301 who failed treatment, at the time of failure the median ibalizumab-uiyk EC50 value was 566 ng/mL (range of 148 to >54,900 ng/mL; mean 11,768 ± 21,650 ng/mL) representing an EC50 value shift of >18-fold. For the HIV-1 derived from the same subjects, the median MPI was 55% (range of 43-72%; mean 56 ± 8%) representing a 42 percentage point reduction.

Decreased Susceptibility

Decreased susceptibility to ibalizumab-uiyk, as defined by a decrease in MPI, has been observed in some subjects experiencing virologic failure and may be associated with genotypic changes in the HIV-1 envelope coding sequence that results in the loss of potential N-linked glycosylation sites (PNGS) in the V5 loop of gp120. The clinical significance of decreased susceptibility to ibalizumab-uiyk has not been established.

Cross-Resistance

Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab-uiyk and any of the approved classes of anti-retroviral drugs (CCR5 co-receptor antagonists, gp41 fusion inhibitors, integrase strand transfer inhibitors [INSTIs], non-nucleos(t)ide reverse transcriptase inhibitors [NNRTIs], nucleos(t)ide reverse transcriptase inhibitors [NRTIs], or protease inhibitors [PIs]). Ibalizumab-uiyk is active against HIV-1 resistant to all approved antiretroviral agents and exhibits antiretroviral activity against R5-tropic, X4-tropic, and dual-tropic HIV-1.

Decreased susceptibility to ibalizumab-uiyk following multiple dose administrations of ibalizumab-uiyk has been observed in some subjects. Cell culture studies performed with HIV-1 variants with reduced susceptibility to ibalizumab-uiyk indicate that phenotypic changes associated with resistance to ibalizumab-uiyk do not alter susceptibility to other approved agents and do not result in the selection of CD4-independent viral isolates.

CD4 Polymorphisms and Ibalizumab-uiyk Activity

CD4 polymorphisms reported in public databases were analyzed to determine if any naturally occurring amino acid substitutions in the CD4 molecule from different human populations would potentially impact the antiviral activity of ibalizumab-uiyk. None of the known CD4 polymorphisms are likely to have an impact on ibalizumab-uiyk binding to CD4.

11. 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. 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.

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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

TROGARZO (ibalizumab-uiyk) injection is a sterile colorless to slightly yellow and clear to slightly opalescent solution with no visible particles for intravenous infusion. 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 available in a carton containing two single-dose vials (NDC 62064-122-02).

Storage and Handling:

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 (3.2)].

Rx only

Rev 03/18