Inebilizumab

12.1 Mechanism of Action The mechanism by which inebilizumab-cdon exerts its therapeutic effects in NMOSD, IgG4-RD, and gMG is presumed to involve binding to CD19, a cell surface antigen presents on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.

1 INDICATIONS AND USAGE 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 ) Immunoglobulin G4-related disease (IgG4-RD) in adult patients. ( 1.2 ) Generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive. ( 1.2 ) 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. 1.2 Immunoglobulin G4-Related Disease (IgG4-RD) UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients. 1.3 Generalized Myasthenia Gravis (gMG) UPLIZNA is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive.

2 DOSAGE AND ADMINISTRATION Hepatitis B virus, quantitative serum immunoglobulins, and tuberculosis screening is required before the first dose. ( 2.1 ) Prior to every infusion: Determine if there is an active infection ( 2.2 , 5.2 ) Premedicate with a corticosteroid, an antihistamine, and an antipyretic ( 2.2 , 5.1 ) UPLIZNA must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP prior to administration. ( 2.3 , 2.4 ) 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 ) Monitor patients closely during the infusion and for at least one hour after completion of the infusion. ( 2.3 ) 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) ]. 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 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 us

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Reduction in Immunoglobulins [see Warnings and Precautions (5.3) ] The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were NMOSD: urinary tract infection and arthralgia. ( 6.1 ) IgG4-RD: urinary tract infections and lymphopenia. ( 6.1 ) gMG: headache and infusion-related reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Adverse Reactions NMOSD The safety of UPLIZNA was evaluated in Study 1, in which 161 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 52 patients received placebo [see Dosage and Administration (2.1) and Clinical Studies (14) ] . Subsequently, 198 patients were exposed to UPLIZNA during an open-label treatment period. Two-hundred and eight patients in the randomized and open-label treatment periods had a total of 324 person-years of exposure to UPLIZNA, including 165 patients with exposure for at least 6 months and 128 with exposure for one year or more. Table 3 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 1. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and arthralgia. Table 3. Adverse Reactions in Patients with NMOSD with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 1 Adverse Reactions UPLIZNA N = 161 % Placebo N = 52 % Urinary tract infection 11 10 Arthralgia 10 4 Headache 8 8 Back pain 7 4 Across both the randomized and open-label treatment in Study 1, the most common adverse reactions (greater than 10%) were urinary tract infection (20%), nasopharyngitis (13%), infusion reaction (12%), arthralgia (11%), and headache (10%). IgG4-RD The safety of UPLIZNA was evaluated in Study 2, in which 68 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 67 patients received placebo [see Dosage and Administration (2.1) and Clinical Studies (14) ] . Table 4 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 2. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and lymphopenia. Table 4. Adverse Reactions in Patients with IgG4-RD with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 2 Adverse Reactions UPLIZNA N = 68 % Placebo N = 67 % Lymphopenia 19 Lymphopenia includes both lymphopenia and lymphocyte count decreased. 9 Urinary tract infection 12 6 Pyrexia 9 5 Neutropenia 6 5 Myalgia 6 0 Additional adverse reactions during the randomized controlled period in Study 2 were infusion related reactions, influenza, and pneumonia. gMG The safety of UPLIZNA was evaluated in Study 3, in which 119 patients were exposed to UPLIZNA at the recommended dosage regimen and 119 patients received placebo during the randomized, placebo-controlled treatment period. The randomized controlled treatment period was 52 weeks for patients who were anti-AChR antibody positive (n=95 each group) and 26 weeks for patients who were anti-MuSK antibody positive (n=24 each group) [see Dosage and Administration (2.1) and Clinical Studies (14) ] . References to adverse reaction frequency in the overall population in the randomized controlled period of Study 3 are reflective of 52-week data for the anti-AChR antibody positive population, and 26-week data for the anti-MuSK antibody positive population that were available at the time of the primary analysis. Table 5 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 3. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were headache and infusion-related reaction. Table 5. Adverse Reactions in Patients with gMG with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 3 Adverse Reactions Based on the overall rand

7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies Concomitant usage of UPLIZNA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with UPLIZNA.