DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Injection: 120 mg/mL clear, and colorless to slightly yellow solution in single-dose prefilled syringe.. Injection: 120 mg/mL in single-dose prefilled syringe (3).

GERIATRIC USE SECTION.


8.5 Geriatric Use. Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge [see Clinical Pharmacology (12.3)]. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. ENSPRYNG (satralizumab-mwge) injection is available as sterile, preservative-free, clear, colorless to slightly yellow solution in single-dose prefilled syringe (PFS) with needle safety device.ENSPRYNG PFS is not made with natural rubber latex. Each ENSPRYNG carton contains one single-dose 120 mg/mL prefilled syringe (NDC 50242-007-01).. 16.2Storage and Handling. Refrigerate at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake. Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed days at temperature that does not exceed 30C (86F).. Refrigerate at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.. Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed days at temperature that does not exceed 30C (86F).

ADVERSE REACTIONS SECTION.


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)] 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 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 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study [see Clinical Studies (14)]. In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately years in Study and approximately years in Study 2. The median exposure time on placebo treatment was approximately year in both Study and Study 2.Adverse reactions that occurred in Study and Study in more than 5% of patients treated with ENSPRYNG, and at greater incidence than in patients who received placebo, are shown in Table 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 Adverse Reactions Occurring in or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 1Adverse ReactionENSPRYNG(N 41)%PLACEBO(N 23)%Rash170Arthralgia170Pain in extremity159Fatigue154Nausea159Nasopharyngitis124Pruritus100Depression100Cellulitis100Neutropenia104Blood creatine phosphokinase increased104Fall104Table Adverse Reactions Occurring in or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 2Adverse ReactionENSPRYNG IST(N 26)%PLACEBO IST(N 26)%Nasopharyngitis3115Headache2712Upper respiratory tract infection1912Gastritis150Arthralgia120Pharyngitis128. Injection-Related ReactionsIn Study 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.. InfectionsIn 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 patients/100 patient-years (95% CI: 1, 14) in patients treated with ENSPRYNG compared with 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 patients with serious infections was patients/100 patient-years (95% CI: 1, 15) in patients treated with ENSPRYNG compared with 10 patients/100 patient-years (95% CI: 2, 28) in patients receiving placebo.. Laboratory Abnormalities. Decreased Neutrophil CountOf the patients treated with ENSPRYNG, 10% had neutrophils below x 109/L compared to 9% in placebo in Study 1. In Study 2, 15% patients had neutrophils below x 109/L compared to 4% in placebo. There was one patient in Study treated with ENSPRYNG with neutrophil counts 0.5 109/L, and one patient in Study discontinued ENSPRYNG because of neutropenia.. Decreased Platelet CountIn Study 1, shift in platelet count decreases from normal at baseline to below the lower limit of normal (LLN) occurred in 26% of patients treated with ENSPRYNG compared to 5% of patients receiving placebo. In Study 2, decreases in platelet counts from normal at baseline to below the LLN occurred in 35% of patients treated with ENSPRYNG and in 17% of patients receiving placebo. None of the patients had decrease in platelet count to less than 50 109/L.. Elevated Liver EnzymesIn Study 1, increases from normal at baseline to above ULN in ALT or AST occurred in 43% and 25% of patients treated with ENSPRYNG, respectively, compared to 13% and 9% of patients receiving placebo. In Study 2, increases from normal at baseline to above the ULN in ALT or AST occurred in 8% and 8% of patients treated with ENSPRYNG, respectively, compared to 12% and 19% of patients receiving placebo.In Study and Study combined, elevations of ALT or AST greater than times the ULN occurred in 3% of patients treated with ENSPRYNG, compared to no patients treated with placebo. These elevations were not associated with increases in total bilirubin. One patient receiving ENSPRYNG in Study had an elevation of ALT above times the ULN, which was observed weeks after initiation of therapy, normalizing 78 days after discontinuation of ENSPRYNG.. Lipid AbnormalitiesIn Study and Study 2, elevations in total cholesterol above 7.75 mmol/L (300 mg/dl) occurred in 12% and 15% of patients treated with ENSPRYNG, respectively, compared to no patients receiving placebo.Elevations in triglycerides above 3.42 mmol/L (300 mg/dl) occurred in 27% and 12% of patients treated with ENSPRYNG in Study and Study 2, respectively, compared to 13% and 8% of patients receiving placebo.. Fibrinogen LevelsIn Study 1, the median percent reduction in fibrinogen was 38% in patients treated with ENSPRYNG compared to 5% in patients receiving placebo. In Study 2, the median percent reduction in fibrinogen level was 33% in patients treated with ENSPRYNG compared to 0% in patients receiving placebo.. Complement LevelsIn Study 1, the median percent reduction in the C3 and C4 components of complement was 23% and 50% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% patients receiving placebo. In Study 2, the median percent reduction in the C3 and C4 components of complement was 20% and 53% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% in patients receiving placebo.. Body WeightIn the pool of Studies and 2, body weight increases of at least 7% from baseline occurred in 28% of patients treated with ENSPRYNG compared to 8% of patients receiving placebo.Body weight increases of at least 15% from baseline occurred in 4% of patients treated with ENSPRYNG compared to 4% of patients receiving placebo.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-satralizumab-mwge antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In Study and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown. Patients with higher body weight and lower exposure were more likely to develop ADAs (irrespective of treatment with IST). Exposure was lower in ADA positive patients. Although anti-satralizumab-mwge antibody development was not found to affect the efficacy of ENSPRYNG in these patients, the available data are too limited to make definitive conclusions. Immunogenicity does not have clinically-relevant impact on safety. Based on the available information, neither dose interruption nor modification is warranted in those patients who develop ADAs.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies of satralizumab-mwge were not conducted.. MutagenesisGenetic toxicology studies of satralizumab-mwge were not conducted. As an antibody, satralizumab-mwge is not expected to interact directly with DNA.. Impairment of FertilityIn monkeys administered satralizumab-mwge (0, 2, 10, or 50 mg/kg) weekly by subcutaneous injection for 26 weeks, no effects on sperm, estrus cycle, or male and female reproductive organs were observed. At the high dose, plasma exposures (Cave) were approximately 100 times that in humans at the recommended monthly maintenance dose of 120 mg.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. The precise mechanism by which satralizumab-mwge exerts therapeutic effects in NMOSD is unknown but is presumed to involve inhibition of IL-6-mediated signaling through binding to soluble and membrane-bound IL-6 receptors.. 12.2 Pharmacodynamics. The relationship between any of the pharmacodynamic effects of ENSPRYNG and clinical outcomes in NMOSD is unknown.. 12.3 Pharmacokinetics. The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on database of 154 patients.The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and for clearance and volume parameters, respectively). Body weight was shown to be significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to patient weighing 60 kg.Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (+-SD)]: Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day.. AbsorptionThe bioavailability of satralizumab-mwge was 85%.. DistributionSatralizumab-mwge undergoes biphasic distribution. The central volume of distribution was 3.46 and the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 0.336 L/day.. EliminationThe total clearance of satralizumab-mwge is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMOSD patients) is estimated to be 0.0601 L/day. The associated terminal t1/2 is approximately 30 days (range 22 37 days) based on data pooled from Study and Study 2.. MetabolismThe metabolism of satralizumab-mwge has not been directly studied, as antibodies are cleared principally by catabolism.. ExcretionMonoclonal antibodies, including satralizumab-mwge, are not eliminated via renal or hepatic pathways.. Specific PopulationsPopulation pharmacokinetic analyses in patients with NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab-mwge.. Patients with Renal or Hepatic ImpairmentNo formal studies of the effect of renal impairment or hepatic impairment on the pharmacokinetics of satralizumab-mwge were conducted.. Drug Interaction StudiesNo formal drug-drug interaction studies have been performed with ENSPRYNG.Based on population pharmacokinetic analyses of the available data, the impact of commonly used small molecule drugs on the pharmacokinetics of satralizumab-mwge remains inconclusive.Suppression of IL-6 signaling by treatment with ENSPRYNG, from the low baseline levels seen in Study and Study 2, is expected to have minor impact on exposure of concomitant medications metabolized by CYP450 enzymes. The clinical significance of this is unknown.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The efficacy of ENSPRYNG for the treatment of NMOSD in adult patients was established in two studies. Study was randomized (2:1), placebo-controlled trial in 95 patients without concurrent IST (Study 1, NCT02073279) in which 64 patients were anti-AQP4 antibody positive and 31 patients were anti-AQP4 antibody negative.Study was randomized (1:1), placebo-controlled trial in 76 adult patients with concurrent IST (Study 2, NCT02028884). Of these, 52 adult patients were anti-AQP4 antibody positive and 24 adult patients were anti-AQP4 antibody negative.Patients met the following eligibility criteria:Study 1: Clinical evidence of relapse in the previous 12 monthsStudy 2: Clinical evidence of at least relapses in the previous years, at least one of which must have occurred in the previous yearEDSS score of to 6.5 (both studies)Study 1: Patients were excluded if previously treated with IST within an interval specified for each such therapyStudy 2: One of the following baseline treatments at stable dose as monotherapy for weeks prior to baseline: azathioprine, mycophenolate mofetil, oral corticosteroidsIn Study 1, 41 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 23 received placebo. Females accounted for 76% of the ENSPRYNG group and 96% of the placebo group. The remaining baseline demographic characteristics were balanced between the treatment groups. The mean age was 44 years. Fifty percent were White, 22% were Black or African-American, and 20% were Asian. The mean EDSS score was 3.8.In Study 2, 26 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 26 received placebo. All patients were receiving either concurrent azathioprine (42%), oral corticosteroids (52%), or mycophenolate mofetil (6%) during the trial. The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 100% of the study population. Forty-six percent of patients were White and 52% were Asian. The mean age was 46 years. The mean EDSS score was 4.0.All potential relapses were adjudicated by blinded Clinical Endpoint Committee (CEC). The primary efficacy endpoint for both studies was the time to the first CEC-confirmed relapse.In Study 1, the time to the first CEC-confirmed relapse was significantly longer in ENSPRYNG-treated patients compared to patients who received placebo (risk reduction 55%; hazard ratio 0.45; = 0.0184). In the anti-AQP4 antibody positive population, there was 74% risk reduction; hazard ratio 0.26; = 0.0014 (Table 5; Figure 1). There was no evidence of benefit in the anti-AQP4 antibody negative patients.In Study 2, the time to the first CEC-confirmed relapse was significantly longer in patients treated with ENSPRYNG compared to patients who received placebo (risk reduction 62%; hazard ratio 0.38; = 0.0184). In the anti-AQP4 antibody positive population, there was 78% risk reduction; hazard ratio 0.22; = 0.0143 (Table 5; Figure 2). There was no evidence of benefit in the anti-AQP4 antibody negative patients.Table Efficacy Results from Study and Study in anti-AQP4 Antibody Positive NMOSD PatientsStudy 1Study 2ENSPRYNGN=41PlaceboN=23ENSPRYNG ISTIST immunosuppressant therapy N= 26Placebo ISTN=26Time to Clinical Endpoint Committee (CEC)-Determined Relapse (Primary Efficacy Endpoint)Number (%) of Patients with Relapse9 (22)13 (56.5)3 (11.5)11 (42.3)Hazard Ratio (95% CI)0.26(0.11, 0.63)0.22(0.06, 0.82)p-value0.00140.0143Risk Reduction74%78%Proportion of Protocol Defined Relapse-Free Patients at 96 Weeks76.5%41.1%91.1%56.8%Figure Study 1: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive PatientsFigure Study 2: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive Patients. Study 1: Clinical evidence of relapse in the previous 12 months. Study 2: Clinical evidence of at least relapses in the previous years, at least one of which must have occurred in the previous year. EDSS score of to 6.5 (both studies). Study 1: Patients were excluded if previously treated with IST within an interval specified for each such therapy. Study 2: One of the following baseline treatments at stable dose as monotherapy for weeks prior to baseline: azathioprine, mycophenolate mofetil, oral corticosteroids. Figure 1. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.


6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of 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 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study [see Clinical Studies (14)]. In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately years in Study and approximately years in Study 2. The median exposure time on placebo treatment was approximately year in both Study and Study 2.Adverse reactions that occurred in Study and Study in more than 5% of patients treated with ENSPRYNG, and at greater incidence than in patients who received placebo, are shown in Table 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 Adverse Reactions Occurring in or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 1Adverse ReactionENSPRYNG(N 41)%PLACEBO(N 23)%Rash170Arthralgia170Pain in extremity159Fatigue154Nausea159Nasopharyngitis124Pruritus100Depression100Cellulitis100Neutropenia104Blood creatine phosphokinase increased104Fall104Table Adverse Reactions Occurring in or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 2Adverse ReactionENSPRYNG IST(N 26)%PLACEBO IST(N 26)%Nasopharyngitis3115Headache2712Upper respiratory tract infection1912Gastritis150Arthralgia120Pharyngitis128. Injection-Related ReactionsIn Study 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.. InfectionsIn 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 patients/100 patient-years (95% CI: 1, 14) in patients treated with ENSPRYNG compared with 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 patients with serious infections was patients/100 patient-years (95% CI: 1, 15) in patients treated with ENSPRYNG compared with 10 patients/100 patient-years (95% CI: 2, 28) in patients receiving placebo.. Laboratory Abnormalities. Decreased Neutrophil CountOf the patients treated with ENSPRYNG, 10% had neutrophils below x 109/L compared to 9% in placebo in Study 1. In Study 2, 15% patients had neutrophils below x 109/L compared to 4% in placebo. There was one patient in Study treated with ENSPRYNG with neutrophil counts 0.5 109/L, and one patient in Study discontinued ENSPRYNG because of neutropenia.. Decreased Platelet CountIn Study 1, shift in platelet count decreases from normal at baseline to below the lower limit of normal (LLN) occurred in 26% of patients treated with ENSPRYNG compared to 5% of patients receiving placebo. In Study 2, decreases in platelet counts from normal at baseline to below the LLN occurred in 35% of patients treated with ENSPRYNG and in 17% of patients receiving placebo. None of the patients had decrease in platelet count to less than 50 109/L.. Elevated Liver EnzymesIn Study 1, increases from normal at baseline to above ULN in ALT or AST occurred in 43% and 25% of patients treated with ENSPRYNG, respectively, compared to 13% and 9% of patients receiving placebo. In Study 2, increases from normal at baseline to above the ULN in ALT or AST occurred in 8% and 8% of patients treated with ENSPRYNG, respectively, compared to 12% and 19% of patients receiving placebo.In Study and Study combined, elevations of ALT or AST greater than times the ULN occurred in 3% of patients treated with ENSPRYNG, compared to no patients treated with placebo. These elevations were not associated with increases in total bilirubin. One patient receiving ENSPRYNG in Study had an elevation of ALT above times the ULN, which was observed weeks after initiation of therapy, normalizing 78 days after discontinuation of ENSPRYNG.. Lipid AbnormalitiesIn Study and Study 2, elevations in total cholesterol above 7.75 mmol/L (300 mg/dl) occurred in 12% and 15% of patients treated with ENSPRYNG, respectively, compared to no patients receiving placebo.Elevations in triglycerides above 3.42 mmol/L (300 mg/dl) occurred in 27% and 12% of patients treated with ENSPRYNG in Study and Study 2, respectively, compared to 13% and 8% of patients receiving placebo.. Fibrinogen LevelsIn Study 1, the median percent reduction in fibrinogen was 38% in patients treated with ENSPRYNG compared to 5% in patients receiving placebo. In Study 2, the median percent reduction in fibrinogen level was 33% in patients treated with ENSPRYNG compared to 0% in patients receiving placebo.. Complement LevelsIn Study 1, the median percent reduction in the C3 and C4 components of complement was 23% and 50% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% patients receiving placebo. In Study 2, the median percent reduction in the C3 and C4 components of complement was 20% and 53% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% in patients receiving placebo.. Body WeightIn the pool of Studies and 2, body weight increases of at least 7% from baseline occurred in 28% of patients treated with ENSPRYNG compared to 8% of patients receiving placebo.Body weight increases of at least 15% from baseline occurred in 4% of patients treated with ENSPRYNG compared to 4% of patients receiving placebo.

CONTRAINDICATIONS SECTION.


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 infection [see Warnings and Precautions (5.1)] Active or untreated latent tuberculosis [see Warnings and Precautions (5.1)] A known hypersensitivity to satralizumab or any of the inactive ingredients [see Warnings and Precautions (5.4)] Active Hepatitis 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 infection (4) Active or untreated latent tuberculosis (4). Known hypersensitivity to satralizumab or any of the inactive ingredients (4). Active Hepatitis infection (4). Active or untreated latent tuberculosis (4).

DESCRIPTION SECTION.


11 DESCRIPTION. Satralizumab-mwge is recombinant humanized anti-human interleukin (IL-6) receptor monoclonal antibody based on human IgG2 framework. Each light chain and heavy chain consists of 214 and 443 amino acids, respectively. Satralizumab-mwge is glycoprotein with an approximate molecular weight of 143 kDa and is produced by recombinant DNA technology in Chinese hamster ovary cells. The binding of satralizumab-mwge to the IL-6 receptor is pH-sensitive.ENSPRYNG (satralizumab-mwge) injection for subcutaneous administration is supplied as sterile, clear, colorless to slightly yellow solution with no preservative with an approximate pH of 6. ENSPRYNG is supplied in single-dose prefilled syringe. Each syringe delivers mL of solution containing 120 mg of satralizumab-mwge, L-arginine (26.1 mg), L-histidine (3.1 mg), poloxamer 188 (0.5 mg), L-aspartic acid (pH adjustment), and Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Hepatitis 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 maintenance dosage of 120 mg every weeks. (2.2) See Full Prescribing Information for important preparation and administration instructions. (2.3). Hepatitis 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 maintenance dosage of 120 mg every 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 Virus ScreeningPrior to initiating ENSPRYNG, perform Hepatitis 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 ScreeningPrior to initiating ENSPRYNG, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without history of appropriate treatment, consult infectious disease experts before initiating treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1)].. Liver Transaminase ScreeningLiver 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).. VaccinationsBecause vaccination with live-attenuated or live vaccines is not recommended during treatment with ENSPRYNG, administer all immunizations according to immunization guidelines at least weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 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 maintenance dosage of 120 mg every weeks.. Missed DoseIf 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 Recommended Dosage for Delayed or Missed DosesLast Dose AdministeredRecommended Dosage for Delayed or Missed DosesLess than weeks during the maintenance period or missed loading doseAdminister 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 weeks. Loading period If the second loading dose is delayed or missed, administer as soon as possible and administer the 3rd and final loading dose weeks later.If the third loading dose is delayed or missed, administer as soon as possible and administer the 1st maintenance dose weeks later.8 weeks to less than 12 weeks120 mg by subcutaneous injection at 00 weeks refers to time of the first administration after the missed dose. and weeks, followed by 120 mg every weeks.12 weeks or longer120 mg by subcutaneous injection at 0, 2, and weeks followed by 120 mg every weeks.. 2.3 Important Administration Instructions. ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of health care professional (HCP). After proper training in subcutaneous injection technique, patient may self-inject ENSPRYNG or the patients caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG Instructions for Use (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG. Patients or caregivers should seek immediate medical attention if the patient develops symptoms of serious allergic reaction and should not administer further doses until evaluated by HCP [see Contraindications (4) and Warning and Precautions (5.4)]. Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way. Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged. Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU. Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.. ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of health care professional (HCP). After proper training in subcutaneous injection technique, patient may self-inject ENSPRYNG or the patients caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG Instructions for Use (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG.. Patients or caregivers should seek immediate medical attention if the patient develops symptoms of serious allergic reaction and should not administer further doses until evaluated by HCP [see Contraindications (4) and Warning and Precautions (5.4)].. Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.. Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged.. Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU.. Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.. 2.4 Safety Monitoring During Treatment. Liver TransaminasesMonitor ALT and AST levels every weeks for the first months of treatment with ENSPRYNG, followed by every months for one year, and thereafter as clinically necessary [see Warnings and Precautions (5.2)]. If an ALT or AST elevation of greater than times the ULN occurs, discontinue ENSPRYNG as follows:If associated with any bilirubin elevation, discontinue ENSPRYNG, and reinitiation is not recommended. If not associated with any bilirubin elevation above the ULN, when the ALT or AST level has returned to the normal range and following benefit-risk assessment of the patient, treatment with ENSPRYNG can be restarted per the schedule in Table 2. Table 2Recommended Dosage for Restart of Treatment After Liver Transaminase ElevationLast Dose AdministeredRecommended Dosage for Restart of TreatmentLess than 12 weeksRestart at dosage of 120 mg by subcutaneous injection every weeks.12 weeks or longerRestart at dose of 120 mg by subcutaneous injection at Weeks 00 weeks refers to time of the first administration after the missed dose., 2, and 4, followed by dosage of 120 mg every weeks.If treatment is restarted, the liver parameters must be closely monitored, and if any subsequent increase in ALT/AST and/or bilirubin above the ULN is observed, ENSPRYNG should be discontinued, and another reinitiation is not recommended. If associated with any bilirubin elevation, discontinue ENSPRYNG, and reinitiation is not recommended. If not associated with any bilirubin elevation above the ULN, when the ALT or AST level has returned to the normal range and following benefit-risk assessment of the patient, treatment with ENSPRYNG can be restarted per the schedule in Table 2. Table 2Recommended Dosage for Restart of Treatment After Liver Transaminase ElevationLast Dose AdministeredRecommended Dosage for Restart of TreatmentLess than 12 weeksRestart at dosage of 120 mg by subcutaneous injection every weeks.12 weeks or longerRestart at dose of 120 mg by subcutaneous injection at Weeks 00 weeks refers to time of the first administration after the missed dose., 2, and 4, followed by dosage of 120 mg every weeks.If treatment is restarted, the liver parameters must be closely monitored, and if any subsequent increase in ALT/AST and/or bilirubin above the ULN is observed, ENSPRYNG should be discontinued, and another reinitiation is not recommended. Neutrophil CountsMonitor neutrophils to weeks after initiation of therapy and thereafter at regular clinically determined intervals. If the neutrophil count is below 1.0 109/L and confirmed by repeat testing, ENSPRYNG should be interrupted until the neutrophil count is 1.0 109/L [see Warnings and Precautions (5.3)].

IMMUNOGENICITY.


6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-satralizumab-mwge antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In Study and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown. Patients with higher body weight and lower exposure were more likely to develop ADAs (irrespective of treatment with IST). Exposure was lower in ADA positive patients. Although anti-satralizumab-mwge antibody development was not found to affect the efficacy of ENSPRYNG in these patients, the available data are too limited to make definitive conclusions. Immunogenicity does not have clinically-relevant impact on safety. Based on the available information, neither dose interruption nor modification is warranted in those patients who develop ADAs.

INDICATIONS & USAGE SECTION.


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).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).. InfectionsInform patients that an increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG. Instruct patients to contact their healthcare provider immediately when symptoms suggesting infection (e.g., fever, chills, constant cough, or sore throat) appear during treatment [see Warning and Precautions (5.1)].. VaccinationsAdvise patients to complete any required vaccinations at least weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of ENSPRYNG for non-live vaccines [see Warnings and Precautions 5.1]. Elevated Liver EnzymesInform patients on the importance of liver enzyme testing [see Warnings and Precautions (5.2)]. Decreased Neutrophil CountsInform patients on the importance of neutrophil count testing [see Warnings and Precautions (5.3)]. Hypersensitivity ReactionsInform patients about the signs and symptoms of hypersensitivity reactions and anaphylaxis and advise them to contact their healthcare provider immediately if these symptoms occur [see Warnings and Precautions (5.4)].. Instruction on Injection TechniqueInstruct patients and caregivers to read the Instructions for Use before the patient starts using ENSPRYNG, and each time the patient gets refill as there may be new information they need to know.Perform the first injection under the guidance of qualified healthcare professional. If patient or caregiver is to administer subcutaneous ENSPRYNG, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous ENSPRYNG and the suitability for home use [see Dosage and Administration (2.3) and Instructions for Use]. Instruct patients to remove the prefilled syringe from the refrigerator prior to use and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.Advise patients to consult their healthcare provider if the full dose is not received.A puncture-resistant container for disposal of syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper prefilled syringe disposal, and caution against reuse of these texts.

INSTRUCTIONS FOR USE SECTION.


Instructions for Use ENSPRYNG(R) (en-spryng) (satralizumab-mwge) Injection. Read this Instructions for Use before you start using your prefilled syringe and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider will decide if you or caregiver can give you injections of ENSPRYNG at home. They will also show you or caregiver the correct and safe way to use the syringe before you use it for the first time.Talk to your healthcare provider if you have any questions.Important InformationEach syringe is prefilled with medicine called ENSPRYNG.Each carton of ENSPRYNG contains only prefilled syringe.Each prefilled syringe can be used only time.Do not share your ENSPRYNG syringe with other people. You may give them serious infection or get serious infection from them.Do not:take the needle cap off until you are ready to inject ENSPRYNG.use the syringe if it has been dropped or damaged.try to take the syringe apart at any time.leave the syringe unattended.re-use the same syringe.How should store the ENSPRYNG prefilled syringeKeep the unused syringe in the refrigerator between 36F to 46F (2C to 8C) until ready to use.Before giving an injection, if the ENSPRYNG is not opened, it can be removed from and placed back in the refrigerator if needed. The total combined time out of the refrigerator should not be more than days at temperature that does not go above 86F (30C).Keep the syringe in its original carton away from direct sunlight.Always keep the syringe dry.Keep the ENSPRYNG syringe and all medicines out of the reach of children.Do not:freeze the syringe.use the syringe if it has been frozen.shake.Supplies needed to give your injectionEach ENSPRYNG carton contains:1 prefilled syringe for 1-time use only.Not included in the carton:1 alcohol pad1 sterile cotton ball or gauze1 small bandage1 FDA-cleared puncture-resistant sharps container for safe disposal of the needle cap and used syringe. See Step 21 Disposing of ENSPRYNG at the end of this Instructions for Use.ENSPRYNG prefilled syringe(See Figure and Figure B)Before use:Figure AAfter use:Figure BThe syringe has needle-shield that automatically covers the needle when the injection is complete.Prepare to use ENSPRYNG1.Take the carton containing the syringe out of the refrigerator and place it on clean, flat work surface (like table).2.Check the expiration (EXP) date on the back of the carton (See Figure C). Do not use if the carton has expired.3.Check the front of the carton to make sure it is sealed (Figure C). Do not use if the seal has been broken.If the expiration date has passed or the seal is broken, do not use. Then go to Step 21 Disposing of ENSPRYNG and contact your healthcare provider.Figure C4.Open the sealed carton (See Figure D).Figure D5.Carefully lift the syringe out of the carton by holding the barrel (See Figure E).Do not:turn the carton upside down to remove the syringe.touch the activation guards because this may damage the syringe.hold the plunger or needle cap.Figure ECheck the syringe(See Figure F)6.Check the expiration date on the syringe. Do not use the syringe if it has expired.7.Check the syringe for any damage. Do not use if it is cracked or broken.8.Check that the liquid through the viewing window is clear and colorless to slightly yellow. Do not inject the medicine if the liquid is cloudy, discolored, or has particles in it.There may be some small air bubbles in the syringe. This is normal and you should not try to remove them. Figure FIf the expiration (EXP) date has passed, the syringe is damaged or the liquid is cloudy, discolored or has particles in it, do not use. Then go to Step 21 Disposing of ENSPRYNG and contact your healthcare provider.Let your syringe warm up9.After you have checked the syringe, place it on clean, flat work surface (like table) for 30 minutes. This will allow it to reach room temperature. (See Figure G). It is important to let the syringe gently warm up as injecting cold medicine may feel uncomfortable and make it harder to push. Do not: speed up the warming process in any way, such as using microwave or placing the syringe in warm water.remove the needle cover while the syringe is reaching room temperature. Figure GWash your hands10.Wash your hands with soap and water. (See Figure H).Figure HChoose the injection site11.Choose your injection site in either:the lower part of your stomach (abdomen) orthe front and middle of your thighs. (See Figure I). Figure Do not inject into the 2-inch (5 cm) area around your belly button.Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.Choose different injection site for each new injection. Choose different place to inject which is at least inch (2.5 cm) away from the place where you last injected. Clean the injection site12.Wipe the injection site with an alcohol pad and let it air dry.Do not:fan or blow on the area which you have cleaned.touch the injection site again before you give the injection.Figure JInject ENSPRYNG13.Hold the barrel of the syringe between your thumb and index finger. With your other hand, pull the needle cap straight off. You may see drop of liquid at the end of the needle. This is normal and will not affect your dose (See Figure K).Use the syringe within minutes of removing the cap or the needle may clog. Do not:take the needle cap off until you are ready to inject ENSPRYNG.put the needle cap back on after it has been removed as this may damage the needle.touch the needle or let it touch any surfaces after removing the needle cap.Figure K14.Throw away the needle cap in puncture-resistant sharps container immediately. See Step 21 Disposing of ENSPRYNG.15.Hold the barrel of the syringe using your thumb and index finger. With your other hand, pinch the area of skin you have cleaned (See Figure L).16.Use quick, dart-like motion to insert the needle at an angle between 45 to 90(See Figure L).Do not: insert the needle through clothing.change the angle of the injection.insert the needle again. Figure L17.After the needle is inserted, let go of the pinched skin.18.Slowly inject all of the medicine by gently pushing the plunger all the way down until it touches the activation guards (See Figure M).Figure 19.Gently release the plunger and allow the needle to come out of the skin at the same angle it was inserted (See Figure N). Figure NThe needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into puncture-resistant sharps container to avoid injury. See Step 21 Disposing of ENSPRYNG.Taking care of the injection site20.There may be little bleeding at the injection site. You can press cotton ball or gauze over the injection site but do not rub it. If needed, you may also cover the area you injected with small bandage. If the medicine gets into contact with your skin, wash the area with water.Disposing of ENSPRYNG21.Put your used syringe in an FDA-cleared sharps disposal container immediately after use (See Figure O). Do not throw away (dispose of) the syringe in your household trash.Figure If you do not have an FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plasticcan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outupright and stable during useleak-resistantproperly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in trash unless your community guidelines permit this.Do not recycle your used sharps disposal container. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: Genentech, Inc. Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990U.S. License No.: 1048Approved: 8/2020ENSPRYNG(R) is registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan(C) 2020 Genentech, Inc. All rights reserved.. Each syringe is prefilled with medicine called ENSPRYNG.. Each carton of ENSPRYNG contains only prefilled syringe.. Each prefilled syringe can be used only time.. take the needle cap off until you are ready to inject ENSPRYNG.. use the syringe if it has been dropped or damaged.. try to take the syringe apart at any time.. leave the syringe unattended.. re-use the same syringe.. Keep the unused syringe in the refrigerator between 36F to 46F (2C to 8C) until ready to use.. Before giving an injection, if the ENSPRYNG is not opened, it can be removed from and placed back in the refrigerator if needed. The total combined time out of the refrigerator should not be more than days at temperature that does not go above 86F (30C).. Keep the syringe in its original carton away from direct sunlight.. Always keep the syringe dry.. freeze the syringe.. use the syringe if it has been frozen.. shake.. prefilled syringe for 1-time use only.. alcohol pad. sterile cotton ball or gauze. small bandage. FDA-cleared puncture-resistant sharps container for safe disposal of the needle cap and used syringe. See Step 21 Disposing of ENSPRYNG at the end of this Instructions for Use.. 1.Take the carton containing the syringe out of the refrigerator and place it on clean, flat work surface (like table).. 2.Check the expiration (EXP) date on the back of the carton (See Figure C). Do not use if the carton has expired.. 3.Check the front of the carton to make sure it is sealed (Figure C). Do not use if the seal has been broken.. 4.Open the sealed carton (See Figure D).. 5.Carefully lift the syringe out of the carton by holding the barrel (See Figure E).Do not:turn the carton upside down to remove the syringe.touch the activation guards because this may damage the syringe.hold the plunger or needle cap.. turn the carton upside down to remove the syringe.. touch the activation guards because this may damage the syringe.. hold the plunger or needle cap.. 6.Check the expiration date on the syringe. Do not use the syringe if it has expired.. 7.Check the syringe for any damage. Do not use if it is cracked or broken.. 8.Check that the liquid through the viewing window is clear and colorless to slightly yellow. Do not inject the medicine if the liquid is cloudy, discolored, or has particles in it.There may be some small air bubbles in the syringe. This is normal and you should not try to remove them. There may be some small air bubbles in the syringe. This is normal and you should not try to remove them.. 9.After you have checked the syringe, place it on clean, flat work surface (like table) for 30 minutes. This will allow it to reach room temperature. (See Figure G). It is important to let the syringe gently warm up as injecting cold medicine may feel uncomfortable and make it harder to push. Do not: speed up the warming process in any way, such as using microwave or placing the syringe in warm water.remove the needle cover while the syringe is reaching room temperature. speed up the warming process in any way, such as using microwave or placing the syringe in warm water.. remove the needle cover while the syringe is reaching room temperature.. 10.Wash your hands with soap and water. (See Figure H).. 11.Choose your injection site in either:the lower part of your stomach (abdomen) orthe front and middle of your thighs. (See Figure I). Figure Do not inject into the 2-inch (5 cm) area around your belly button.Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.. the lower part of your stomach (abdomen) or. the front and middle of your thighs. (See Figure I). Figure . Do not inject into the 2-inch (5 cm) area around your belly button.. Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.. 12.Wipe the injection site with an alcohol pad and let it air dry.Do not:fan or blow on the area which you have cleaned.touch the injection site again before you give the injection.. fan or blow on the area which you have cleaned.. touch the injection site again before you give the injection.. 13.Hold the barrel of the syringe between your thumb and index finger. With your other hand, pull the needle cap straight off. You may see drop of liquid at the end of the needle. This is normal and will not affect your dose (See Figure K).Use the syringe within minutes of removing the cap or the needle may clog. Do not:take the needle cap off until you are ready to inject ENSPRYNG.put the needle cap back on after it has been removed as this may damage the needle.touch the needle or let it touch any surfaces after removing the needle cap.. Use the syringe within minutes of removing the cap or the needle may clog. Do not:. take the needle cap off until you are ready to inject ENSPRYNG.. put the needle cap back on after it has been removed as this may damage the needle.. touch the needle or let it touch any surfaces after removing the needle cap.. 14.Throw away the needle cap in puncture-resistant sharps container immediately. See Step 21 Disposing of ENSPRYNG.. 15.Hold the barrel of the syringe using your thumb and index finger. With your other hand, pinch the area of skin you have cleaned (See Figure L).. 16.Use quick, dart-like motion to insert the needle at an angle between 45 to 90(See Figure L).Do not: insert the needle through clothing.change the angle of the injection.insert the needle again. insert the needle through clothing.. change the angle of the injection.. insert the needle again.. 17.After the needle is inserted, let go of the pinched skin.. 18.Slowly inject all of the medicine by gently pushing the plunger all the way down until it touches the activation guards (See Figure M).Figure . 19.Gently release the plunger and allow the needle to come out of the skin at the same angle it was inserted (See Figure N). Figure NThe needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into puncture-resistant sharps container to avoid injury. See Step 21 Disposing of ENSPRYNG.. The needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into puncture-resistant sharps container to avoid injury. See Step 21 Disposing of ENSPRYNG.. 20.There may be little bleeding at the injection site. You can press cotton ball or gauze over the injection site but do not rub it. If needed, you may also cover the area you injected with small bandage. If the medicine gets into contact with your skin, wash the area with water.. 21.Put your used syringe in an FDA-cleared sharps disposal container immediately after use (See Figure O). Do not throw away (dispose of) the syringe in your household trash.Figure If you do not have an FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plasticcan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outupright and stable during useleak-resistantproperly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in trash unless your community guidelines permit this.Do not recycle your used sharps disposal container. If you do not have an FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plasticcan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outupright and stable during useleak-resistantproperly labeled to warn of hazardous waste inside the container made of heavy-duty plastic. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out. upright and stable during use. leak-resistant. properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your used sharps disposal container in trash unless your community guidelines permit this.. Do not recycle your used sharps disposal container.. Image. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. Figure O.

LACTATION SECTION.


8.2 Lactation. Risk SummaryNo information is available on the presence of satralizumab-mwge in human milk, the effects of the satralizumab-mwge on the breastfed infant, or the effects of the satralizumab-mwge on milk production. Satralizumab-mwge was excreted in the milk of lactating monkeys administered satralizumab-mwge throughout pregnancy. Human IgG is excreted in human milk and the potential for absorption in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ENSPRYNG and any potential adverse effects on the breastfed infant from ENSPRYNG or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. The precise mechanism by which satralizumab-mwge exerts therapeutic effects in NMOSD is unknown but is presumed to involve inhibition of IL-6-mediated signaling through binding to soluble and membrane-bound IL-6 receptors.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies of satralizumab-mwge were not conducted.. MutagenesisGenetic toxicology studies of satralizumab-mwge were not conducted. As an antibody, satralizumab-mwge is not expected to interact directly with DNA.. Impairment of FertilityIn monkeys administered satralizumab-mwge (0, 2, 10, or 50 mg/kg) weekly by subcutaneous injection for 26 weeks, no effects on sperm, estrus cycle, or male and female reproductive organs were observed. At the high dose, plasma exposures (Cave) were approximately 100 times that in humans at the recommended monthly maintenance dose of 120 mg.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 120 mg/mL Syringe Carton. NDC 50242-007-01Rx onlyEnspryng(R) (satralizumab-mwge)Injection120 mg/mL For Subcutaneous Use.Single-Dose Prefilled Syringe. Refrigerate at 2C to 8C (36F to 46F) in original carton to protect from light.Do not freeze. Do not shake. ATTENTION PHARMACIST: Each patient is required to receive the enclosedMedication Guide. prefilled syringeGenentech10240933. PRINCIPAL DISPLAY PANEL 120 mg/mL Syringe Carton.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. The relationship between any of the pharmacodynamic effects of ENSPRYNG and clinical outcomes in NMOSD is unknown.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on database of 154 patients.The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and for clearance and volume parameters, respectively). Body weight was shown to be significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to patient weighing 60 kg.Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (+-SD)]: Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day.. AbsorptionThe bioavailability of satralizumab-mwge was 85%.. DistributionSatralizumab-mwge undergoes biphasic distribution. The central volume of distribution was 3.46 and the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 0.336 L/day.. EliminationThe total clearance of satralizumab-mwge is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMOSD patients) is estimated to be 0.0601 L/day. The associated terminal t1/2 is approximately 30 days (range 22 37 days) based on data pooled from Study and Study 2.. MetabolismThe metabolism of satralizumab-mwge has not been directly studied, as antibodies are cleared principally by catabolism.. ExcretionMonoclonal antibodies, including satralizumab-mwge, are not eliminated via renal or hepatic pathways.. Specific PopulationsPopulation pharmacokinetic analyses in patients with NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab-mwge.. Patients with Renal or Hepatic ImpairmentNo formal studies of the effect of renal impairment or hepatic impairment on the pharmacokinetics of satralizumab-mwge were conducted.. Drug Interaction StudiesNo formal drug-drug interaction studies have been performed with ENSPRYNG.Based on population pharmacokinetic analyses of the available data, the impact of commonly used small molecule drugs on the pharmacokinetics of satralizumab-mwge remains inconclusive.Suppression of IL-6 signaling by treatment with ENSPRYNG, from the low baseline levels seen in Study and Study 2, is expected to have minor impact on exposure of concomitant medications metabolized by CYP450 enzymes. The clinical significance of this is unknown.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryThere 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 - 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 reactionsMonoclonal 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 DataWeekly 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 (Cave) in dams at the low and high doses were approximately and 100 times, respectively, that in humans at the recommended monthly maintenance dose of 120 mg.

SPL MEDGUIDE SECTION.


This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued: 8/2020MEDICATION GUIDEENSPRYNG(R) (en-spryng)(satralizumab-mwge)injection, for subcutaneous useWhat is the most important information should know about ENSPRYNGENSPRYNG may cause serious side effects including:1.Infections. ENSPRYNG can increase your risk of serious infections some of which can be life-threatening. Talk to your healthcare provider if you are being treated for an infection or call them right away if you think you have signs of an infection, with or without fever, such as:chills, feeling tired, muscle aches, cough that will not go away or sore throatskin redness, swelling, tenderness, pain or sores on your bodydiarrhea, belly pain, or feeling sickburning when you urinate or urinating more often than usualYour healthcare provider will check if you have an infection and treat it if needed before you start or continue to take ENSPRYNG. Your healthcare provider should test you for hepatitis and tuberculosis (TB) before you start taking ENSPRYNG.All required vaccinations should be completed before starting ENSPRYNG. People using ENSPRYNG should not be given live or live-attenuated vaccines. Live or live-attenuated vaccines should be given at least weeks before you start ENSPRYNG. Your healthcare provider may recommend that you get non-live (inactivated) vaccine, such as some of the seasonal flu vaccines. If you plan to get non-live (inactivated) vaccine, it should be given, whenever possible, at least weeks before you start ENSPRYNG.2.Increased liver enzymes.Your healthcare provider should order blood tests to check your liver enzymes before and while you are taking ENSPRYNG. Your healthcare provider will tell you how often you will need to have these blood tests. Make sure you get all of your follow-up blood tests as ordered by your healthcare provider. Your healthcare provider will tell you if you need to wait to start ENSPRYNG if your liver enzymes are increased.3.Low neutrophil count.ENSPRYNG can cause decrease in your neutrophil counts in your blood. Neutrophils are white blood cells that help the body fight off bacterial infections. Your healthcare provider should order blood tests to check your neutrophil count while you are taking ENSPRYNG.See What are the possible side effects with ENSPRYNGWhat is ENSPRYNGENSPRYNG is prescription medicine used to treat neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 (AQP4) antibody positive.It is not known if ENSPRYNG is safe and effective in children.Do not take ENSPRYNG if you:are allergic to satralizumab-mwge or any of the ingredients in ENSPRYNG. See What are the ingredients in ENSPRYNG at the end of this Medication Guide for complete list of ingredients in ENSPRYNG.have an active hepatitis infection.have active or untreated inactive (latent) TB. Before you take ENSPRYNG, tell your healthcare provider about all of your medical conditions, including if you:have or think you have an infection. See What is the most important information should know about ENSPRYNG have liver problems.have ever had hepatitis or are carrier of the hepatitis virus.have had or have been in contact with someone with tuberculosis.have had recent vaccination or are scheduled to receive any vaccination.are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if ENSPRYNG will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if ENSPRYNG passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take ENSPRYNG.Tell your healthcare provider about all the medicines you are taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take ENSPRYNGENSPRYNG is provided as solution in single-dose, prefilled syringe of 120 mg/mL of satralizumab-mwge.See the Instructions for Use inside the carton for complete instructions for the right way to prepare and inject ENSPRYNG.ENSPRYNG is given by an injection under the skin (subcutaneously). If your healthcare provider decides that you or your caregiver can give your injections of ENSPRYNG, you or your caregiver should receive training on the right way to prepare and inject ENSPRYNG.Always inject all of the medicine in the syringe.The first injections (loading period) of ENSPRYNG are taken time every weeks.After this, injection of ENSPRYNG is taken every weeks (maintenance period). Keep taking ENSPRYNG time every weeks for as long as your healthcare provider tells you to.If you miss dose of ENSPRYNG, talk to your health care provider about restarting dosing.What are the possible side effects of ENSPRYNGENSPRYNG may cause serious side effects, including:See What is the most important information should know about ENSPRYNG Serious allergic reactions. Serious allergic reactions that may be life-threatening have happened with other medicines like ENSPRYNG. Tell your healthcare provider before taking your next dose if you had hives, rash, or flushing after your injection. Seek medical attention right away if you have any symptoms of serious allergic reaction, such as:shortness of breath or trouble breathing dizziness or feeling faintswelling of your lips, face, or tonguemoderate or severe stomach (abdominal) pain or vomitingchest painThe most common side effects of ENSPRYNG include:sore throat, runny nose (nasopharyngitis)rashfatigueextremity painheadacheupper respiratory tract infectionnauseainflammation of the stomach lining (gastritis)joint painThese are not all the possible side effects of ENSPRYNG.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.How should store ENSPRYNGStore ENSPRYNG in the refrigerator between 36F to 46F (2C to 8C) in the original carton.Protect from light.Do not freeze or use the syringe if it has been frozen.Do not shake.ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if needed. The total combined time out of the refrigerator should not be more than days at temperature that does not go above 86F (30C).General information about the safe and effective use of ENSPRYNG.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ENSPRYNG for condition for which it was not prescribed. Do not give ENSPRYNG to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ENSPRYNG that is written for health professionals.What are the ingredients in ENSPRYNGActive ingredient: satralizumab-mwge Inactive ingredients: L-arginine, L-histidine, poloxamer 188, L-aspartic acid, and Water for Injection.Manufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990ENSPRYNG(R) is registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, JapanU.S. License No.: 1048For more information, go to www.ENSPRYNG.com or call 1-844-NSPRYNG.. 1.Infections. ENSPRYNG can increase your risk of serious infections some of which can be life-threatening. Talk to your healthcare provider if you are being treated for an infection or call them right away if you think you have signs of an infection, with or without fever, such as:chills, feeling tired, muscle aches, cough that will not go away or sore throatskin redness, swelling, tenderness, pain or sores on your bodydiarrhea, belly pain, or feeling sickburning when you urinate or urinating more often than usualYour healthcare provider will check if you have an infection and treat it if needed before you start or continue to take ENSPRYNG. chills, feeling tired, muscle aches, cough that will not go away or sore throat. skin redness, swelling, tenderness, pain or sores on your body. diarrhea, belly pain, or feeling sick. burning when you urinate or urinating more often than usual. Your healthcare provider should test you for hepatitis and tuberculosis (TB) before you start taking ENSPRYNG.. All required vaccinations should be completed before starting ENSPRYNG. People using ENSPRYNG should not be given live or live-attenuated vaccines. Live or live-attenuated vaccines should be given at least weeks before you start ENSPRYNG. Your healthcare provider may recommend that you get non-live (inactivated) vaccine, such as some of the seasonal flu vaccines. If you plan to get non-live (inactivated) vaccine, it should be given, whenever possible, at least weeks before you start ENSPRYNG.. 2.Increased liver enzymes.Your healthcare provider should order blood tests to check your liver enzymes before and while you are taking ENSPRYNG. Your healthcare provider will tell you how often you will need to have these blood tests. Make sure you get all of your follow-up blood tests as ordered by your healthcare provider. Your healthcare provider will tell you if you need to wait to start ENSPRYNG if your liver enzymes are increased.. 3.Low neutrophil count.ENSPRYNG can cause decrease in your neutrophil counts in your blood. Neutrophils are white blood cells that help the body fight off bacterial infections. Your healthcare provider should order blood tests to check your neutrophil count while you are taking ENSPRYNG.. are allergic to satralizumab-mwge or any of the ingredients in ENSPRYNG. See What are the ingredients in ENSPRYNG at the end of this Medication Guide for complete list of ingredients in ENSPRYNG.. have an active hepatitis infection.. have active or untreated inactive (latent) TB. have or think you have an infection. See What is the most important information should know about ENSPRYNG have liver problems.. have ever had hepatitis or are carrier of the hepatitis virus.. have had or have been in contact with someone with tuberculosis.. have had recent vaccination or are scheduled to receive any vaccination.. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if ENSPRYNG will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if ENSPRYNG passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take ENSPRYNG.. ENSPRYNG is provided as solution in single-dose, prefilled syringe of 120 mg/mL of satralizumab-mwge.. See the Instructions for Use inside the carton for complete instructions for the right way to prepare and inject ENSPRYNG.. ENSPRYNG is given by an injection under the skin (subcutaneously). If your healthcare provider decides that you or your caregiver can give your injections of ENSPRYNG, you or your caregiver should receive training on the right way to prepare and inject ENSPRYNG.. Always inject all of the medicine in the syringe.. The first injections (loading period) of ENSPRYNG are taken time every weeks.. After this, injection of ENSPRYNG is taken every weeks (maintenance period). Keep taking ENSPRYNG time every weeks for as long as your healthcare provider tells you to.. If you miss dose of ENSPRYNG, talk to your health care provider about restarting dosing.. See What is the most important information should know about ENSPRYNG Serious allergic reactions. Serious allergic reactions that may be life-threatening have happened with other medicines like ENSPRYNG. Tell your healthcare provider before taking your next dose if you had hives, rash, or flushing after your injection. Seek medical attention right away if you have any symptoms of serious allergic reaction, such as:. shortness of breath or trouble breathing dizziness or feeling faint. swelling of your lips, face, or tongue. moderate or severe stomach (abdominal) pain or vomiting. chest pain. The most common side effects of ENSPRYNG include:. sore throat, runny nose (nasopharyngitis). rash. fatigue. extremity pain. headache. upper respiratory tract infection. nausea. inflammation of the stomach lining (gastritis). joint pain. Store ENSPRYNG in the refrigerator between 36F to 46F (2C to 8C) in the original carton.. Protect from light.. Do not freeze or use the syringe if it has been frozen.. Do not shake.. ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if needed. The total combined time out of the refrigerator should not be more than days at temperature that does not go above 86F (30C).

SPL UNCLASSIFIED SECTION.


2.1 Assessments Prior to the First Dose of ENSPRYNG. Hepatitis Virus ScreeningPrior to initiating ENSPRYNG, perform Hepatitis 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 ScreeningPrior to initiating ENSPRYNG, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without history of appropriate treatment, consult infectious disease experts before initiating treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1)].. Liver Transaminase ScreeningLiver 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).. VaccinationsBecause vaccination with live-attenuated or live vaccines is not recommended during treatment with ENSPRYNG, administer all immunizations according to immunization guidelines at least weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of ENSPRYNG for non-live vaccines [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.


16.2Storage and Handling. Refrigerate at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake. Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed days at temperature that does not exceed 30C (86F).. Refrigerate at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.. Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed days at temperature that does not exceed 30C (86F).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere 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 - 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 reactionsMonoclonal 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 DataWeekly 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 (Cave) in dams at the low and high doses were approximately and 100 times, respectively, that in humans at the recommended monthly maintenance dose of 120 mg.. 8.2 Lactation. Risk SummaryNo information is available on the presence of satralizumab-mwge in human milk, the effects of the satralizumab-mwge on the breastfed infant, or the effects of the satralizumab-mwge on milk production. Satralizumab-mwge was excreted in the milk of lactating monkeys administered satralizumab-mwge throughout pregnancy. Human IgG is excreted in human milk and the potential for absorption in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ENSPRYNG and any potential adverse effects on the breastfed infant from ENSPRYNG or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge [see Clinical Pharmacology (12.3)]. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

WARNINGS AND PRECAUTIONS SECTION.


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). 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 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 Virus (HBV) ReactivationRisk 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.. TuberculosisTuberculosis 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 history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with 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.. VaccinationsLive 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 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 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 higher incidence than in patients receiving placebo [see Adverse Reactions (6.1)].ALT and AST levels should be monitored every weeks for the first months of treatment, followed by every 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 higher incidence than placebo [see Adverse Reactions (6.1)]. Neutrophil counts should be monitored to 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.