Ibalizumab

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# Overview
Ibalizumab is a CD4-directed post-attachment HIV-1 inhibitor that is FDA approved 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.   Common adverse reactions include diarrhea, dizziness, nausea, and rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Ibalizumab, 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.
- Ibalizumab 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 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 are not required when administered with any other antiretroviral or any other treatments.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ibalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- Immune reconstitution inflammatory syndrome has been reported in one patient treated with Ibalizumab 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.

# Adverse Reactions

## Clinical Trials 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 IV infusion.
Trial TMB-301
- The primary safety assessment of Ibalizumab is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of Ibalizumab 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 followed seven days later by the initiation of an optimized background regimen (OBR) including at least one agent to which the subjects virus was susceptible. Two weeks after the Ibalizumab loading dose, 800 mg of Ibalizumab was administered IV. The IV administration of Ibalizumab 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.
- 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 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.

## Postmarketing Experience
There is limited information regarding Ibalizumab Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Ibalizumab Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Ibalizumab during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 18002584263.
Risk Summary
- No adequate human data are available to establish whether or not Ibalizumab 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibalizumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ibalizumab during labor and delivery.

### Nursing Mothers
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 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.

### Pediatric Use
- The safety and effectiveness of Ibalizumab in pediatric patients have not been established.

### Geriatic Use
- No studies have been conducted with Ibalizumab in geriatric patients.

### Gender
There is no FDA guidance on the use of Ibalizumab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ibalizumab with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ibalizumab in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ibalizumab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ibalizumab in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ibalizumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Diluted Ibalizumab solution should be administered by a trained medical professional.
- Administer Ibalizumab as an IV infusion 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. Do not administer Ibalizumab 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 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 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.

### Monitoring
- Viral load: At baseline and with modification of antiretroviral (ARV) treatment, at 2 to 8 weeks until values are below the limit of detection (less than 200 copies/mL), then every 3 to 4 months; monitoring may be extended to every 6 months for patients who are immunologically stable, adherent, and with suppressed viral loads for more than 2 years.
- CD4 cells counts: At baseline and with modification of ARV treatment, then every 3 to 6 months during at least the first 2 years of treatment and if the CD4 counts are less than 33 cell/mm(3) or viremia develops; after 2 years monitoring may be extended to every 12 months for patients who are clinically stable with suppressed viral loads.
- Hepatitis B screening: Baseline and with modification of ARV treatment; may repeat screening every 12 months if hepatitis B surface antigen or antibody are negative at baseline.
- Hepatitis C antibody testing: Prior to initiation or modification of ARV treatment; may repeat screening every 12 months in high-risk patients if results are negative at baseline.
- ALT, AST, and total bilirubin: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- Basic chemistry including serum, sodium, potassium, bicarbonate, chloride, BUN, creatinine, and creatinine-based estimated glomerular filtration rate: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- CBC with a differential: At baseline and with modification of ARV treatment, 6 months thereafter or every 3 to 6 months if CD4 testing is done.
- Fasting blood glucose or HbA1c: At baseline and with modification of ARV treatment, then every 3 to 6 months in patients with abnormal values or every 12 months in patients with normal values.
- Fasting lipid profile: At baseline and with modification of ARV treatment, then every 6 months in patients with abnormal values or annually in patients with normal values.
- Urinalysis: At baseline or modification of therapy, then every 6 months.
- Pregnancy Test: In women of reproductive potential; prior to therapy initiation.
- Infusion-related reaction: 1 hour after completion of first infusion. If no reaction is observed, the post-infusion observation time can be reduced to 15 minutes thereafter.

# IV Compatibility
There is limited information regarding the compatibility of Ibalizumab and IV administrations.

# Overdosage
There is limited information regarding Ibalizumab overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Ibalizumab-uiyk is an HIV-1 antiretroviral drug.

## Structure
There is limited information regarding Ibalizumab Structure in the drug label.

## 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.

## 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.
- 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-uiyks mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.

## Nonclinical Toxicology
- Carcinogenesis, mutagenesis, and reproductive toxicology studies with Ibalizumab-uiyk have not been conducted.

# Clinical Studies
- 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 Ibalizumab on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of Ibalizumab. This period was to establish the virologic activity of Ibalizumab.
- 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 Ibalizumab was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of Ibalizumab 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/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.

# How Supplied
- Ibalizumab (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.
- Ibalizumab 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 Ibalizumab solution should be administered immediately.

## Storage
There is limited information regarding Ibalizumab Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Immune Reconstitution Syndrome
- Immune Reconstitution Inflammatory Syndrome: Advise patients that immune reconstitution syndrome has been reported in a patient receiving Ibalizumab and to inform their health care provider immediately of any symptoms of infection.
Important Administration Information
- Advise the patient it is important to receive Ibalizumab injections every two weeks as recommended by their healthcare professional and not to change the dosing schedule of Ibalizumab or any antiretroviral medication without consulting their healthcare provider. Advise the patient to contact their healthcare provider immediately if they stop taking Ibalizumab or any other drug in their antiretroviral regimen.
Pregnancy Exposure Registry
- Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to Ibalizumab.
Lactation
- Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

# Precautions with Alcohol
Alcohol-Ibalizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Trogarzo

# Look-Alike Drug Names
There is limited information regarding Ibalizumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price