Enspryng

1 INDICATIONS AND USAGE ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ENSPRYNG is an interleukin-6 (IL-6) receptor antagonist indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ( 1 )

2 DOSAGE AND ADMINISTRATION Hepatitis B virus, tuberculosis, and liver transaminase screening is required before the first dose. ( 2.1 ) Prior to every use, determine if there is an active infection. ( 2.2 ) The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. ( 2.2 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.3 ) 2.1 Assessments Prior to the First Dose of ENSPRYNG Hepatitis B Virus Screening Prior to initiating ENSPRYNG, perform Hepatitis B virus (HBV) screening. ENSPRYNG 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 ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1) ] . Tuberculosis Screening Prior to initiating ENSPRYNG, 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 ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1) ] . Liver Transaminase Screening Liver transaminases and serum bilirubin should be assessed prior to initiation of treatment with ENSPRYNG [see Warnings and Precautions (5.2) ] . Caution should be exercised when considering initiation of ENSPRYNG treatment in patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels are greater than 1.5 times the upper limit of normal (ULN). Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment with ENSPRYNG, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage For subcutaneous use only. Prior to every use of ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections. In case of active infection, delay use of ENSPRYNG until the infection is resolved [see Warnings and Precautions (5.1) ] . The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. Missed Dose If a dose of ENSPRYNG is missed for any reason other than increases in liver enzymes [see Dosage and Administration (2.4) ] , administer as described in Table 1 . Table 1 Recommended Dosage for Delayed or Missed Doses Last Dose Administered Recommended Dosage for Delayed or Missed Doses Less than 8 weeks during the maintenance period or missed a loading dose Administer 120 mg by subcutaneous injection as soon as possible, and do not wait until the next planned dose. Maintenance period After the delayed or missed dose is administered, reset the dose schedule to every 4 weeks. Loading period If the second loading dose is delayed or missed, administer as soon as possible and administer the 3 rd and final loading dose 2 weeks later. If the third loading dose is delayed or missed, administer as soon as possible and administer the 1 st maintenance dose 4 weeks later. 8 weeks to less than 12 weeks 120 mg by subcutaneous injection at 0 "0 weeks" refers to time of the first administration after the missed dose. and 2 weeks, followed by 120 mg every 4 weeks. 12 weeks or longer 120 mg by subcutaneous injection at 0 , 2, and 4 weeks followed by 120 mg every 4 weeks. 2.3 Important Administratio…

5 WARNINGS AND PRECAUTIONS Infections: Delay ENSPRYNG administration in patients with an active infection until the infection is resolved. Vaccination with live or live-attenuated vaccines is not recommended during treatment. ( 5.1 ) Elevated Liver Enzymes: Monitor ALT and AST levels during treatment; interruption of ENSPRYNG may be required. ( 5.2 ) Decreased Neutrophil Counts: Monitor neutrophils during treatment. ( 5.3 ) 5.1 Infections An increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG. The most common infections reported in a randomized clinical trial of patients treated with ENSPRYNG who were not on other chronic immunosuppressant therapies (Study 1), and that occurred more often than in patients receiving placebo, were nasopharyngitis (12%) and cellulitis (10%). The most common infections in patients who were on an additional concurrent immunosuppressant, and that occurred more often than in patients receiving placebo, were nasopharyngitis (31%), upper respiratory infection (19%), and pharyngitis (12%). Delay ENSPRYNG administration in patients with an active infection, including localized infections, until the infection is resolved. Hepatitis B Virus (HBV) Reactivation Risk of HBV reactivation has been observed with other immunosuppressant therapies. Patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment with ENSPRYNG. Do not administer ENSPRYNG to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+] or are negative for HBsAg and positive for HB core antibody [HBcAb+], consult liver disease experts before starting and during treatment with ENSPRYNG. Tuberculosis Tuberculosis has occurred in patients treated with other interleukin-6 receptor antagonists. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating ENSPRYNG. Consider anti-tuberculosis therapy prior to initiation of ENSPRYNG in patients with a history of latent or 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. Patients should be monitored for the development of symptoms and signs of tuberculosis with ENSPRYNG, even if initial tuberculosis testing is negative. Vaccinations Live or live-attenuated vaccines should not be given concurrently with ENSPRYNG because clinical safety has not been established. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines. 5.2 Elevated Liver Enzymes Mild and moderate elevations of liver enzymes have been observed in patients treated with ENSPRYNG at a higher incidence than in patients receiving placebo [see Adverse Reactions (6.1) ] . ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, and thereafter, as clinically indicated [see Dosage and Administration (2.4) ]. 5.3 Decreased Neutrophil Counts Decreases in neutrophil counts were observed in patients treated with ENSPRYNG at a higher incidence than placebo [see Adverse Reactions (6.1) ]. Neutrophil counts should be monitored 4 to 8 weeks after initiation of therapy, and thereafter at regular clinically determined intervals [see Dosage and Administration (2.4) ]. 5.4 Hypersensitivity Reactions Hypersensitivity reactions, including rash, urticaria, and fatal anaphylaxis, have occurred with other interleukin-6 receptor antagonists.

4 CONTRAINDICATIONS ENSPRYNG is contraindicated in patients with: A known hypersensitivity to satralizumab or any of the inactive ingredients [see Warnings and Precautions (5.4) ] Active Hepatitis B infection [see Warnings and Precautions (5.1) ] Active or untreated latent tuberculosis [see Warnings and Precautions (5.1) ] Known hypersensitivity to satralizumab or any of the inactive ingredients ( 4 ) Active Hepatitis B infection ( 4 ) Active or untreated latent tuberculosis ( 4 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENSPRYNG during pregnancy. Healthcare providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-277-9338. Risk Summary There are no adequate data on the developmental risk associated with the use of ENSPRYNG in pregnant women. In an animal reproduction study, no adverse effects on maternal animals or fetal development were observed in pregnant monkeys and their offspring, with administration of satralizumab-mwge at doses up to 50 mg/kg/week (see Data ) . In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Fetal/neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ENSPRYNG in utero [see Warnings and Precautions (5.1) ] . Data Animal Data Weekly subcutaneous administration of satralizumab-mwge (0, 2, or 50 mg/kg) to monkeys throughout pregnancy resulted in no adverse effects on postnatal development of the offspring; however, immune function was impaired in offspring at both doses. Plasma exposures (C ave ) in dams at the low and high doses were approximately 3 and 100 times, respectively, that in humans at the recommended monthly maintenance dose of 120 mg.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Elevated Liver Enzymes [see Warnings and Precautions (5.2) ] Decreased Neutrophil Counts [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] The most common adverse reactions (incidence at least 15%) are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of ENSPRYNG was evaluated in two randomized, placebo-controlled clinical trials [Study 1 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study 2 evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 1 and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 2 [see Clinical Studies (14) ] . In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately 2 years in Study 1 and approximately 3 years in Study 2. The median exposure time on placebo treatment was approximately 1 year in both Study 1 and Study 2. Adverse reactions that occurred in Study 1 and Study 2 in more than 5% of patients treated with ENSPRYNG, and at a greater incidence than in patients who received placebo, are shown in Table 3 and Table 4 , respectively. The most common adverse reactions (15% or greater with ENSPRYNG in either) were nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Table 3 Adverse Reactions Occurring in 4 or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 1 Adverse Reaction ENSPRYNG (N = 41) % PLACEBO (N = 23) % Rash 17 0 Arthralgia 17 0 Pain in extremity 15 9 Fatigue 15 4 Nausea 15 9 Nasopharyngitis 12 4 Pruritus 10 0 Depression 10 0 Cellulitis 10 0 Neutropenia 10 4 Blood creatine phosphokinase increased 10 4 Fall 10 4 Table 4 Adverse Reactions Occurring in 3 or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 2 Adverse Reaction ENSPRYNG + IST (N = 26) % PLACEBO + IST (N = 26) % Nasopharyngitis 31 15 Headache 27 12 Upper respiratory tract infection 19 12 Gastritis 15 0 Arthralgia 12 0 Pharyngitis 12 8 Injection-Related Reactions In Study 1 and Study 2, injection-related reactions were reported in 9% of patients treated with ENSPRYNG compared with 8% in patients receiving placebo. These reactions in the ENSPRYNG-treated patients were predominantly mild to moderate in severity, and most occurred within 24 hours after the injection. The most commonly reported systemic symptom was diarrhea. The reported local injection site reactions were pruritus, injection site reaction, and skin mass. Infections In Study 1, the rate of patients with infections was 51 patients/100 patient-years (95% CI: 32, 78) in patients treated with ENSPRYNG compared with 108 patients/100 patient-years (95% CI: 52, 199) in patients receiving placebo. The rate of patients with serious infections was 5 patients/100 patient-years (95% CI: 1, 14) in patients treated with ENSPRYNG compared with 4 patients/100 patient-years (95% CI: 0, 21) in patients receiving placebo. In Study 2, the rate of patients with infections was 168 patients/100 patient-years (95% CI: 100, 265) in patients treated with ENSPRYNG compared with 143 patients/100 patient-years (95% CI: 83, 229) in patients treated with placebo. The rate of pati…