Uplinza

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.
  )
• The treatment of 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.
  )

• 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

    An increased risk of infections has been observed with other B-cell depleting therapies. 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%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

    Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

    UPLIZNA has not been studied in combination with other immunosuppressants. If combining UPLIZNA with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.

    Hepatitis B Virus (HBV) Reactivation

    Risk of HBV reactivation has been observed with other B-cell depleting antibodies. There have been no cases of HBV reactivation in patients treated with UPLIZNA, but patients with 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 hepatitis. For patients who are chronic carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

    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 can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. During the randomized clinical trial period, infusion reactions were observed with the first course of UPLIZNA in 9.3% of NMOSD patients. Infusion reactions of UPLIZNA were observed in 7.4% of IgG4-RD patients during the randomized controlled period. 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 and IgG4-RD

  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 and IgG4-RD

    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 and IgG4-RD

  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) solution in a single-dose vial (
  3 DOSAGE FORMS AND STRENGTHS

  • Injection: 100 mg/10 mL (10 mg/mL) solution in a single-dose vial

  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.