TAVNEOS

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Increase in liver function tests occurred in clinical trials. Obtain liver function tests before initiation of therapy and monitor as clinically indicated. ( 5.1 ) Serious Hypersensitivity Reactions: Cases of angioedema occurred in a clinical trial. Observe for signs and symptoms of angioedema and manage accordingly. ( 5.2 ) Hepatitis B Virus (HBV) Reactivation: Cases of HBV reactivation occurred in a clinical trial. Withhold TAVNEOS and institute appropriate anti-infective therapy. ( 5.3 ) Serious Infections: Avoid use of TAVNEOS in patients with active, serious infection, including localized infections. ( 5.4 ) 5.1 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking TAVNEOS. During controlled trials, the TAVNEOS treatment group had a higher incidence of transaminase elevations and hepatobiliary events, including serious and life-threatening events [see Adverse Reactions (6.1) ] . In the postmarketing setting, vanishing bile duct syndrome (VBDS) as a consequence of liver injury, including cases with a fatal outcome, has been reported. These events occurred predominantly in Japan in patients aged 65 years and older, but VBDS may affect patients of any age or ethnicity who are receiving TAVNEOS [see Adverse Reactions (6.2) ] . Obtain liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin) before initiating TAVNEOS, every 4 weeks after start of therapy for the first 6 months of treatment and as clinically indicated thereafter. For patients of Japanese descent, consider more frequent laboratory testing: every 2 weeks after the start of therapy for the first 3 months, followed by laboratory testing every 4 weeks for the next 3 months of treatment, and as clinically indicated thereafter. If a patient receiving treatment with TAVNEOS presents with an elevation in ALT or AST to >3 times the upper limit of normal, evaluate promptly and consider pausing treatment as clinically indicated. If AST or ALT is > 5 times the upper limit of normal (ULN), or ALT or AST > 3 times the ULN with total bilirubin > 2 times the ULN, or ALP ≥ 2 times the ULN, or if the patient has clinical symptoms such as jaundice or pruritus, discontinue TAVNEOS until TAVNEOS-induced liver injury is ruled out [see Adverse Reactions (6.1) ] . Immediately and permanently discontinue TAVNEOS if VBDS is suspected. TAVNEOS is not recommended for patients with active, untreated and/or uncontrolled chronic liver disease (e.g., chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis. Consider the risk and benefit before administering TAVNEOS to a patient with liver disease. Monitor patients closely for hepatic adverse reactions [see Use in Specific Populations (8.7) ] . 5.2 Hypersensitivity Reactions TAVNEOS may cause angioedema [see Adverse Reactions (6.1) ] . In clinical trials, two cases of angioedema occurred, including one serious event requiring hospitalization. If angioedema occurs, discontinue TAVNEOS immediately, provide appropriate therapy, and monitor for airway compromise. TAVNEOS must not be re-administered unless another cause has been established. Educate patients on recognizing the signs and symptoms of a hypersensitivity reaction and to seek immediate medical care should they develop. 5.3 Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation, including life-threatening hepatitis B, was observed in the clinical program. HBV reactivation is defined as an abrupt increase in HBV replication, manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg, in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases, increase in bilirubin levels, liver failure, and death can occur. Screen patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TAVNEOS. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TAVNEOS treatment. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis, or HBV reactivation during and for six months following TAVNEOS therapy. In patients who develop reactivation of HBV while on TAVNEOS, immediately discontinue TAVNEOS and any concomitant therapy associated with HBV reactivation, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TAVNEOS treatment in patients who develop HBV reactivation. Resumption of TAVNEOS treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV. 5.4 Serious Infections Serious infections, including fatal infections, have been reported in patients receiving TAVNEOS. The most common serious infections reported in the TAVNEOS group were pneumonia and urinary tract infections. Avoid use of TAVNEOS in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating TAVNEOS in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TAVNEOS. Interrupt TAVNEOS if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with TAVNEOS should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and TAVNEOS should be interrupted if the patient is not responding to antimicrobial therapy. TAVNEOS may be resumed once the infection is controlled.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Hepatitis B Virus (HBV) Reactivation [see Warnings and Precautions (5.3) ] Serious Infections [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥ 5%) are: nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increased, and paresthesia. 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 Trials Experience Because the clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The identification of potential adverse drug reactions was based on safety data from the phase 3 clinical trial in which 330 patients with ANCA-associated vasculitis were randomized 1:1 to either TAVNEOS or prednisone [see Clinical Studies (14) ] . The mean age of patients was 60.9 years (range of 13 to 88 years), with a predominance of men (56.4%) and Caucasians (84.2%). The cumulative exposure to TAVNEOS was 138.7 patient-years. Additionally, two phase 2 trials were conducted in ANCA-associated vasculitis. The cumulative clinical trial exposure from the phase 2 and 3 trials equals 212.3 patient-years. The most frequent serious adverse reactions reported more frequently in patients treated with TAVNEOS than with prednisone were pneumonia (4.8% TAVNEOS vs. 3.7% prednisone), GPA (3.0% TAVNEOS vs. 0.6% prednisone), acute kidney injury (1.8% TAVNEOS vs. 0.6% prednisone), and urinary tract infection (1.8% TAVNEOS vs. 1.2% prednisone). Within 52 weeks, 4 patients in the prednisone treatment group (2.4%) and 2 patients in the TAVNEOS group (1.2%) died. There were no deaths in the phase 2 trials. In the phase 3 trial, seven patients (4.2%) in the TAVNEOS treatment group and 2 patients (1.2%) in the prednisone treatment group discontinued treatment due to hepatic-related adverse reactions, including hepatobiliary adverse reactions and liver enzymes abnormalities. The most frequent adverse reaction that led to drug discontinuation reported by > 1 patient and more frequently reported in patients treated with TAVNEOS was hepatic function abnormal (1.8%). The most common adverse reactions that occurred in ≥ 5% of patients and higher in the TAVNEOS group as compared with the prednisone group are listed in Table 1. Table 1. Adverse Reactions Reported in ≥ 5% of Patients and Higher in TAVNEOS Group vs. Prednisone Group in Phase 3 Trial Adverse Reaction Prednisone (N = 164) n (%) TAVNEOS (N = 166) n (%) N = number of patients randomized to treatment group in the Safety Population; n = number of patients in specified category. Nausea 34 (20.7) 39 (23.5) Headache 23 (14.0) 34 (20.5) Hypertension 29 (17.7) 30 (18.1) Diarrhea 24 (14.6) 25 (15.1) Vomiting 21 (12.8) 25 (15.1) Rash 13 (7.9) 19 (11.4) Fatigue 15 (9.1) 17 (10.2) Upper abdominal pain 10 (6.1) 11 (6.6) Dizziness 10 (6.1) 11 (6.6) Blood creatinine increased 8 (4.9) 10 (6.0) Paresthesia 7 (4.3) 9 (5.4) Hepatotoxicity and Elevated Liver Function Tests In the phase 3 trial, a total of 19 patients (11.6%) in the prednisone group and 22 patients (13.3%) in the TAVNEOS group had hepatic-related adverse reactions, including hepatobiliary adverse reactions and liver enzyme abnormalities. Study medication was paused or discontinued permanently due to hepatic-related adverse reactions in 5 patients (3.0%) in the prednisone group and 9 patients (5.4%) in the TAVNEOS group. Serious hepatic-related adverse reactions were reported in 6 patients (3.7%) in the prednisone group and 9 patients (5.4%) in the TAVNEOS group. A serious hepatic-related adverse reaction was reported in 1 patient in the TAVNEOS group in the phase 2 studies. Angioedema In the phase 3 trial, 2 patients (1.2%) in the TAVNEOS group had angioedema; one event was a serious adverse reaction requiring hospitalization. Elevated Creatine Phosphokinase In the phase 3 trial, 1 patient (0.6%) in the prednisone group and 6 patients (3.6%) in the TAVNEOS group had increased creatine phosphokinase. One TAVNEOS-treated patient discontinued treatment due to increased creatine phosphokinase. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of TAVNEOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or definitively establish a causal relationship to drug exposure. Hepatobiliary disorders: vanishing bile duct syndrome [ see Warnings and Precautions (5.1) ]

<table width="100%"><caption>Table 1. Adverse Reactions Reported in &#x2265; 5% of Patients and Higher in TAVNEOS Group vs. Prednisone Group in Phase 3 Trial</caption><col width="60%" align="left" valign="top"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" align="left">Adverse Reaction</th><th styleCode="Rrule" valign="bottom">Prednisone (N = 164) n (%)</th><th styleCode="Rrule" valign="bottom">TAVNEOS (N = 166) n (%)</th></tr></thead><tfoot><tr><td align="left" colspan="3">N = number of patients randomized to treatment group in the Safety Population; n = number of patients in specified category.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">34 (20.7)</td><td styleCode="Rrule">39 (23.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">23 (14.0)</td><td styleCode="Rrule">34 (20.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">29 (17.7)</td><td styleCode="Rrule">30 (18.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">24 (14.6)</td><td styleCode="Rrule">25 (15.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">21 (12.8)</td><td styleCode="Rrule">25 (15.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">13 (7.9)</td><td styleCode="Rrule">19 (11.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">15 (9.1)</td><td styleCode="Rrule">17 (10.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper abdominal pain</td><td styleCode="Rrule">10 (6.1)</td><td styleCode="Rrule">11 (6.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">10 (6.1)</td><td styleCode="Rrule">11 (6.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood creatinine increased</td><td styleCode="Rrule">8 (4.9)</td><td styleCode="Rrule">10 (6.0)</td></tr><tr><td styleCode="Lrule Rrule">Paresthesia</td><td styleCode="Rrule">7 (4.3)</td><td styleCode="Rrule">9 (5.4)</td></tr></tbody></table>