Uplinza (Inebilizumab)

UPLIZNA is a CD19-directed cytolytic antibody indicated for the treatment of:

• Neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. (
  1.1 Neuromyelitis Optica Spectrum Disorder (NMOSD)

  UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
  )
• Immunoglobulin G4-related disease (IgG4-RD) in adult patients. (
  1.2 Immunoglobulin G4-Related Disease (IgG4-RD)

  UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.
  )
• Generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive. (
  1.2 Immunoglobulin G4-Related Disease (IgG4-RD)

  UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.
  )

• Hepatitis B virus, quantitative serum immunoglobulins, and tuberculosis screening is required before the first dose. (
  2.1 Assessments Prior to First Dose of UPLIZNA

  Hepatitis B Virus Screening

  Prior to initiating UPLIZNA, perform Hepatitis B virus (HBV) screening. UPLIZNA is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with UPLIZNA

  [see Contraindications (4)and Warnings and Precautions (5.2)].

  Serum Immunoglobulins

  Prior to initiating UPLIZNA, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with UPLIZNA

  [see Warnings and Precautions (5.3)].

  Tuberculosis Screening

  Prior to initiating UPLIZNA, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, consult infectious disease experts before initiating treatment with UPLIZNA

  [see Contraindications (4)and Warnings and Precautions (5.2)]

  .

  Vaccinations

  Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA for live or live-attenuated vaccines

  [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)].
  )
• Prior to every infusion:
  • Determine if there is an active infection (
    2.2 Assessment and Premedication Before Every Infusion

    Infection Assessment

    Prior to every infusion of UPLIZNA, determine whether there is an active infection. In case of active infection, delay infusion of UPLIZNA until the infection resolves

    [see Warnings and Precautions (5.2)].

    Premedication

    Table 1 shows premedication to administer prior to each infusion of UPLIZNA to reduce the frequency and severity of infusion reactions

    [see Warnings and Precautions (5.1)].

    Table 1. Premedication Prior to Each UPLIZNA Infusion

    Type of Premedication	Route of Administration	Examples (or Equivalent)	Administration Time Prior to UPLIZNA Infusion
    corticosteroid	intravenous	methylprednisolone 80 mg to 125 mg	30 minutes
    antihistamine	oral	diphenhydramine 25 mg to 50 mg	30 to 60 minutes
    antipyretic	oral	acetaminophen 500 mg to 650 mg	30 to 60 minutes
    ,
    5.2 Infections

    Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with B-cell depleting therapies, including UPLIZNA.

    The most common infections reported by UPLIZNA-treated patients in the randomized and open-label clinical trial periods for NMOSD included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). In the IgG4-RD randomized controlled and open-label periods, the most common infections reported by UPLIZNA-treated patients were upper respiratory tract infection (11%), nasopharyngitis (10%), urinary tract infection (9%), and influenza (6%). In the gMG randomized controlled period, the most common infections reported by UPLIZNA-treated patients were urinary tract infection (7%) and nasopharyngitis (7%).

    Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

    Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

    If combining UPLIZNA with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.

    Hepatitis B Virus (HBV) Reactivation

    HBV reactivation has been observed with the use of B-cell depleting therapies, including UPLIZNA. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with B-cell depleting therapies.

    HBV reactivation was observed in a patient treated with UPLIZNA during the gMG clinical trial, and has also been observed in the postmarketing setting. Patients with active or chronic HBV infection were excluded from clinical trials.

    Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer UPLIZNA to patients with active HBV infection confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for HBsAg and positive for HBcAb, or who are carriers of HBV (i.e., HBsAg+), consult liver disease experts before starting and during treatment with UPLIZNA.

    Progressive Multifocal Leukoencephalopathy (PML)

    PML is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no confirmed cases of PML were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell depleting antibodies and other therapies that affect immune competence. In UPLIZNA clinical trials one subject died following the development of new brain lesions for which a definitive diagnosis could not be established, though the differential diagnosis included an atypical NMOSD relapse, PML, or acute disseminated encephalomyelitis. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

    Tuberculosis

    Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Consider anti-tuberculosis therapy prior to initiation of UPLIZNA in patients with a history of latent active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment.

    Vaccinations

    Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA. The safety of immunization with live or live-attenuated vaccines following UPLIZNA therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

    Vaccination of Infants Born to Mothers Treated with UPLIZNA During Pregnancy

    In infants of mothers exposed to UPLIZNA during pregnancy, do not administer live or live-attenuated vaccines before confirming recovery of B-cell counts in the infant. Depletion of B-cells in these exposed infants may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered prior to recovery from B-cell and immunoglobulin level depletion, but consultation with a qualified specialist should be considered to assess whether a protective immune response was mounted

    [see Use in Specific Populations (8.1)].
    )
  • Premedicate with a corticosteroid, an antihistamine, and an antipyretic (
    2.2 Assessment and Premedication Before Every Infusion

    Infection Assessment

    Prior to every infusion of UPLIZNA, determine whether there is an active infection. In case of active infection, delay infusion of UPLIZNA until the infection resolves

    [see Warnings and Precautions (5.2)].

    Premedication

    Table 1 shows premedication to administer prior to each infusion of UPLIZNA to reduce the frequency and severity of infusion reactions

    [see Warnings and Precautions (5.1)].

    Table 1. Premedication Prior to Each UPLIZNA Infusion

    Type of Premedication	Route of Administration	Examples (or Equivalent)	Administration Time Prior to UPLIZNA Infusion
    corticosteroid	intravenous	methylprednisolone 80 mg to 125 mg	30 minutes
    antihistamine	oral	diphenhydramine 25 mg to 50 mg	30 to 60 minutes
    antipyretic	oral	acetaminophen 500 mg to 650 mg	30 to 60 minutes
    ,
    5.1 Infusion Reactions

    UPLIZNA can cause infusion reactions, including anaphylaxis. Symptoms of infusion reactions can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. Infusion reactions were observed in 9.3%, 7.4%, and 10.1% of patients treated with UPLIZNA during the randomized controlled periods of Study 1 in patients with NMOSD, Study 2 in patients with IgG4-RD, and Study 3 in patients with gMG, respectively. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions.

    Reducing the Risk of Infusion Reactions and Managing Infusion Reactions

    Administer pre-medication with a corticosteroid, an antihistamine, and an antipyretic

    [see Dosage and Administration (2.2)].

    Management recommendations for infusion reactions depend on the type and severity of the reaction

    .

    For life-threatening infusion reactions, immediately and permanently stop UPLIZNA and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
    )
• UPLIZNA must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP prior to administration. (
  2.3 Recommended Dosage and Administration

  NMOSD, IgG4-RD, and gMG

  UPLIZNA is administered as an intravenous infusion (see Table 2). The recommended dosage is:

  • Initial dose: 300 mg intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion.
  • Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months.

  Administration

  UPLIZNA must be diluted prior to administration

  [see Dosage and Administration (2.4)].

  Prior to the start of the intravenous infusion, the prepared infusion solution should be at room temperature.

  Administer UPLIZNA under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious infusion reactions

  [see Warnings and Precautions (5.1)].

  Administer the prepared solution intravenously via an infusion pump at an increasing rate to completion, approximately 90 minutes, according to the schedule in Table 2. Administer through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

  Table 2. Recommended Infusion Rate for UPLIZNA Administration When Diluted in a 250 mL Intravenous Bag

  Elapsed Time (minutes)	Infusion Rate (mL/hour)
  0-30	42
  31-60	125
  61 to completion	333

  Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion.
  ,
  2.4 Preparation and Storage of Infusion Solution

  Preparation

  Visually inspect UPLIZNA solution for particulate matter and discoloration

  [see Dosage Forms and Strengths (3)].

  If the solution is cloudy, discolored, or it contains discrete particulate matter, do not use and contact the manufacturer (1-800-772-6436). Do not shake the vial.

  Obtain an intravenous bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. Do not use other diluents to dilute UPLIZNA.

  Withdraw 10 mL of UPLIZNA from each of the 3 vials contained in the carton and transfer a total of 30 mL into the 250 mL intravenous bag. Mix diluted solution by gentle inversion. Do not shake the solution.

  Discard the unused portion remaining in the vials.

  Storage of Infusion Solution

  UPLIZNA does not contain a preservative.

  Administer the prepared infusion solution immediately. If not administered immediately, store the infusion solution for a maximum of 24 hours in the refrigerator between 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature between 20°C to 25°C (68°F to 77°F) prior to the start of the infusion.
  )
• UPLIZNA is administered as an intravenous infusion titrated to completion, approximately 90 minutes. The recommended dose is:
  • Initial dose: 300 mg intravenous infusion followed two weeks later by a second 300 mg intravenous infusion.
  • Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months. (
    2.3 Recommended Dosage and Administration

    NMOSD, IgG4-RD, and gMG

    UPLIZNA is administered as an intravenous infusion (see Table 2). The recommended dosage is:

    • Initial dose: 300 mg intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion.
    • Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months.

    Administration

    UPLIZNA must be diluted prior to administration

    [see Dosage and Administration (2.4)].

    Prior to the start of the intravenous infusion, the prepared infusion solution should be at room temperature.

    Administer UPLIZNA under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious infusion reactions

    [see Warnings and Precautions (5.1)].

    Administer the prepared solution intravenously via an infusion pump at an increasing rate to completion, approximately 90 minutes, according to the schedule in Table 2. Administer through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

    Table 2. Recommended Infusion Rate for UPLIZNA Administration When Diluted in a 250 mL Intravenous Bag

    Elapsed Time (minutes)	Infusion Rate (mL/hour)
    0-30	42
    31-60	125
    61 to completion	333

    Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion.
    )
• Monitor patients closely during the infusion and for at least one hour after completion of the infusion. (
  2.3 Recommended Dosage and Administration

  NMOSD, IgG4-RD, and gMG

  UPLIZNA is administered as an intravenous infusion (see Table 2). The recommended dosage is:

  • Initial dose: 300 mg intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion.
  • Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months.

  Administration

  UPLIZNA must be diluted prior to administration

  [see Dosage and Administration (2.4)].

  Prior to the start of the intravenous infusion, the prepared infusion solution should be at room temperature.

  Administer UPLIZNA under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious infusion reactions

  [see Warnings and Precautions (5.1)].

  Administer the prepared solution intravenously via an infusion pump at an increasing rate to completion, approximately 90 minutes, according to the schedule in Table 2. Administer through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

  Table 2. Recommended Infusion Rate for UPLIZNA Administration When Diluted in a 250 mL Intravenous Bag

  Elapsed Time (minutes)	Infusion Rate (mL/hour)
  0-30	42
  31-60	125
  61 to completion	333

  Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion.
  )

Injection: 100 mg/10 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to UPLIZNA during pregnancy or shortly before conception. Healthcare providers are encouraged to advise their patients to register by contacting the UPLIZNA Pregnancy Registry by calling the coordinating center at 1 (303) 724-4644 or www.upliznapregnancyregistry.com.

UPLIZNA is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. There are no adequate data on the developmental risk associated with the use of UPLIZNA in pregnant women. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. B-cell levels in infants following maternal exposure to UPLIZNA have not been studied in clinical trials. The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg/week) to human CD19 transgenic (huCD19 Tg) male and female mice prior to and during mating and continuing in females through gestation day 15 resulted in no adverse effects on embryofetal development; however, there was a marked reduction in B-cells in fetal blood and liver at both doses tested. These results demonstrate that inebilizumab-cdon crosses the placenta and depletes B-cells in the fetus.

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg) to huCD19 Tg mice every three days throughout organogenesis and lactation resulted in depletion of B-cells and persistent reductions in immune function (even following repletion of B-cells and lasting into adulthood) in offspring at both doses tested. At the end of the lactation period, plasma inebilizumab-cdon levels in offspring were only slightly lower than those in maternal plasma. A no-effect level for immunotoxicity in the offspring was not identified.