UPLIZNA

5 WARNINGS AND PRECAUTIONS Infusion reactions: Administer premedications prior to infusion. ( 2.2 ) Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue UPLIZNA if a life-threatening or disabling infusion reaction occurs. ( 5.1 ) Infections: Serious, including life-threatening and fatal infections, have occurred in patients treated with B-cell depleting therapies, including UPLIZNA. Delay UPLIZNA administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion. ( 5.2 ) Immunoglobulin levels: Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion. Consider discontinuing UPLIZNA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise. ( 5.3 ) Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA. ( 5.4 , 8.1 ) 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. 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) ]. 5.3 Reduction in Immunoglobulins There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment [see Adverse Reactions (6.1) ]. Monitor the levels of quantitative serum immunoglobulins during treatment with UPLIZNA, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy. Consider discontinuing UPLIZNA therapy if a patient with low immunoglobulin G or M develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins. 5.4 Fetal Risk Based on animal data, UPLIZNA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to UPLIZNA even after B-cell repletion. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving UPLIZNA and for at least 6 months after the last dose [see Use in Specific Populations (8.1) ] .

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 randomized controlled period, comprised of 52 weeks for the anti-AChR antibody positive population and 26 weeks for the anti-MuSK antibody positive population UPLIZNA N = 119 % Placebo N = 119 % Headache 15 7 Infusion-related reaction Infusion-related reaction was defined as any sign or symptom experienced by patients during the infusion of study drug, or any adverse event occurring within 24 hours of study drug administration for which an alternative explanation was not evident. 10 6 Nasopharyngitis 7 3 Cough 7 3 Urinary tract infection 7 3 Laboratory Abnormalities Decreased Immunoglobulins NMOSD At the end of the 6.5-month randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 8% from baseline for patients treated with UPLIZNA as compared to an increase of 6% in patients treated with placebo. The mean decreases from baseline in immunoglobulin G (IgG) and immunoglobulin M (IgM) were approximately 4% and 32%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 6% and IgM was increased by approximately 13% in placebo-treated patients. The proportion of patients treated with UPLIZNA who had IgG levels below the lower limit of normal at year 1 was 7% and at year 2 was 13%. The proportion of patients treated with UPLIZNA who had IgM levels below the lower limit of normal at year 1 was 31% and at year 2 was 42%. IgG4-RD At the end of the 12-month randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 12% from baseline for patients treated with UPLIZNA as compared to an increase of 21% in patients treated with placebo. The mean decreases from baseline in IgG and IgM were approximately 9% and 32%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 26% and IgM was increased by approximately 3% in placebo-treated patients. gMG At the end of the 26-week randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 13% from baseline for patients treated with UPLIZNA as compared to an increase of 15% in patients treated with placebo. The mean decreases from baseline in IgG and IgM were approximately 8% and 30%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 18% and IgM was increased by approximately 5% in placebo-treated patients. The proportion of patients treated with UPLIZNA who had IgG and IgM levels below the lower limit of normal at the end of the 26-week randomized, controlled period was 29% and 16%, respectively, compared to 8% and 4%, respectively, in the placebo group. Decreased Neutrophil Counts NMOSD Neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 7% of UPLIZNA-treated patients versus 2% of patients who received placebo. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 2% of patients treated with UPLIZNA compared to no patients who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a neutrophil count below the limit of normal was 12% for patients treated with UPLIZNA compared to 4% for patients who received placebo. IgG4-RD During the 12-month randomized, controlled period, neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 8% of UPLIZNA-treated patients versus 3% of patients who received placebo. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 2% of patients treated with placebo compared to no patients who received UPLIZNA. gMG During the 26-week randomized, controlled period, neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 3% of patients who received placebo compared to no patients who received UPLIZNA. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 1% of patients treated with UPLIZNA compared to no patients who received placebo. Decreased Lymphocyte Counts NMOSD A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 5% for patients treated with UPLIZNA compared to 4% for patients who received placebo. IgG4-RD A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. During the 12-month randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 42% for patients treated with UPLIZNA compared to 36% for patients who received placebo. gMG A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. During the 26-week randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 35% for patients treated with UPLIZNA compared to 31% for patients who received placebo.

<table width="75%"><caption>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 </caption><col width="40%" align="left" valign="middle"/><col width="32%" align="center" valign="middle"/><col width="28%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" valign="bottom">Adverse Reactions</th><th styleCode="Rrule">UPLIZNA N = 161 %</th><th styleCode="Rrule">Placebo N = 52 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">11</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">8</td><td styleCode="Rrule">8</td></tr><tr><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4</td></tr></tbody></table>

<table width="75%"><caption>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</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" valign="bottom">Adverse Reactions</th><th styleCode="Rrule">UPLIZNA N = 68 %</th><th styleCode="Rrule">Placebo N = 67 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphopenia</td><td styleCode="Rrule">19<footnote>Lymphopenia includes both lymphopenia and lymphocyte count decreased.</footnote></td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">12</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">9</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">6</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="75%"><caption>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</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" valign="bottom">Adverse Reactions<footnote>Based on the overall randomized controlled period, comprised of 52 weeks for the anti-AChR antibody positive population and 26 weeks for the anti-MuSK antibody positive population</footnote></th><th styleCode="Rrule">UPLIZNA N = 119 %</th><th styleCode="Rrule">Placebo N = 119 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">15</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infusion-related reaction<footnote>Infusion-related reaction was defined as any sign or symptom experienced by patients during the infusion of study drug, or any adverse event occurring within 24 hours of study drug administration for which an alternative explanation was not evident.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr></tbody></table>