IMAAVY

1 INDICATIONS AND USAGE IMAAVY is a neonatal Fc receptor blocker indicated for the treatment of: generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. ( 1.1 ) warm autoimmune hemolytic anemia (wAIHA) in adult and pediatric patients 12 years of age and older currently or previously treated with corticosteroids. ( 1.2 ) 1.1 Generalized Myasthenia Gravis (gMG) IMAAVY is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. 1.2 Warm Autoimmune Hemolytic Anemia (wAIHA) IMAAVY is indicated for the treatment of warm autoimmune hemolytic anemia (wAIHA) in adult and pediatric patients 12 years of age and older currently or previously treated with corticosteroids.

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on dosage, preparation, and administration. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of IMAAVY. ( 2.1 ) Administer via intravenous infusion only. ( 2.2 , 2.3 ) gMG: The recommended initial dosage is 30 mg/kg once via intravenous infusion over at least 30 minutes. Two weeks after the initial dosage, administer a maintenance dosage of 15 mg/kg via intravenous infusion over at least 15 minutes, and continue every two weeks thereafter. ( 2.2 ) wAIHA: The recommended initial dosage is 30 mg/kg once via intravenous infusion over at least 30 minutes. Four weeks after the initial dosage, administer a subsequent dosage of 30 mg/kg via intravenous infusion over at least 15 minutes, and continue every four weeks thereafter. ( 2.3 ) Must be diluted with 0.9% Sodium Chloride Injection prior to administration. ( 2.5 ) Administer as an intravenous infusion via a 0.2 micron in-line or add-on filter. ( 2.5 ) 2.1 Recommended Vaccination Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of IMAAVY. Because IMAAVY causes transient reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with IMAAVY [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage for gMG Dilute IMAAVY prior to administration. Administer via intravenous infusion only [see Dosage and Administration (2.5) ] . Table 1: gMG Recommended Dose Regimen Initial dosage Maintenance dosage 30 mg/kg administered once via intravenous infusion over at least 30 minutes. Two weeks after the initial dose administer a maintenance dose of 15 mg/kg via intravenous infusion over at least 15 minutes. Continue the maintenance dose every two weeks thereafter. 2.3 Recommended Dosage for wAIHA Dilute IMAAVY prior to administration. Administer via intravenous infusion only [see Dosage and Administration (2.5) ] . Table 2: wAIHA Recommended Dose Regimen Initial dosage Subsequent dosage 30 mg/kg administered once via intravenous infusion over at least 30 minutes. Four weeks after the initial dose administer a subsequent dose of 30 mg/kg via intravenous infusion over at least 15 minutes. Continue the subsequent dose every four weeks thereafter. 2.4 Missed Doses If a scheduled infusion is missed, administer the dose of IMAAVY as soon as possible. Resume dosing, maintaining the treatment interval. 2.5 Preparation and Administration Instructions Prior to administration, dilute IMAAVY single-dose vials with only 0.9% Sodium Chloride Injection using the instructions below. For patients who weigh 40 kg or more, the total volume to be administered is 250 mL; for patients who are 12 years or older and weigh less than 40 kg, the total volume to be administered is 100 mL (see Preparation ) . Preparation Prepare the solution for infusion using aseptic technique as follows: Calculate the dosage (mg), total drug volume (mL) of IMAAVY solution required, and the number of IMAAVY vials needed, based on the patient's current weight [see Dosage and Administration (2.2 , 2.3) ] . Each single-dose vial of IMAAVY is at a concentration of 185 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the solution in each vial is colorless to slightly brownish, clear to slightly opalescent, and free of visible particles. Do not use if visible particles are present or if the solution is discolored (other than colorless to slightly brownish). Gently withdraw the calculated volume of IMAAVY from the vial(s). Discard any unused portion of the vials. Dilute total volume withdrawn of IMAAVY by adding to an infusion container containing 0.9% Sodium Chloride Injection to a final volume of: 250 mL for patients who weigh 40 kg or more, or 100 mL for patients who weigh less than 40 kg. Only use infusion containers made of polyolefin, polypropylene, or polyvinylchloride. Gently invert the infusion container at least 10 times to mix the solution. Do not shake. Verify that a uniform solution has been achieved by visual inspection. Do not use if particulate matter or discoloration is present. Storage Conditions of the Diluted Solution Administer the diluted IMAAVY solution immediately after preparation. If the diluted IMAAVY solution is not used immediately: Protect from light. Store refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours. Do not freeze. After preparation or removal from the refrigerator, use or discard the IMAAVY diluted solution within 12 hours, including infusion time. During these 12 hours, store under ambient light at 15 °C to 30 °C (59 °F to 86 °F). Administration If the diluted solution is refrigerated prior to administration, allow to warm to room temperature. Do not use external heat sources to warm IMAAVY. Administer the diluted solution by intravenous infusion only using an infusion set with an in-line or add-on, sterile, non-pyrogenic, low protein-binding filter made of polyethersulfone or polysulfone (pore size 0.2 micrometer or less). Administration sets must be made of either polybutadiene, polyethylene, polyurethane, polypropylene, or polyvinylchloride. Do not infuse IMAAVY concomitantly in the same intravenous line with other agents. Administer IMAAVY infusion intravenously over at least 30 minutes for the initial dose and at least 15 minutes for subsequent doses [see Dosage and Administration (2.2 , 2.3) ] . If an adverse reaction occurs during administration of IMAAVY, the infusion may be slowed or stopped at the discretion of the healthcare professional. Monitor the patient for 30 minutes after each infusion for signs or symptoms of an infusion-related or hypersensitivity reaction [see Warnings and Precautions (5.2 , 5.3) ].

4 CONTRAINDICATIONS IMAAVY is contraindicated in patients with a history of serious hypersensitivity reaction to nipocalimab-aahu or any of the excipients in IMAAVY. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.2) ] . IMAAVY is contraindicated in patients with a history of serious hypersensitivity reaction to nipocalimab-aahu or to any of the excipients in IMAAVY. ( 4 )

5 WARNINGS AND PRECAUTIONS Infections: Delay administration of IMAAVY to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with IMAAVY. If serious infection occurs, administer appropriate treatment and consider withholding IMAAVY until the infection has resolved. ( 5.1 ) Hypersensitivity Reactions: Angioedema, anaphylaxis, rash, urticaria, and eczema have occurred in patients treated with IMAAVY. If a hypersensitivity reaction occurs, discontinue the infusion and institute appropriate therapy. ( 5.2 ) Infusion-Related Reactions: If a severe infusion-related reaction occurs, discontinue the infusion and initiate appropriate therapy; consider the risks and benefits of readministering. If a mild to moderate infusion-related reaction occurs, may rechallenge with close clinical observation, slower infusion rates, and pre-medication. ( 5.3 ) 5.1 Infections IMAAVY may increase the risk of infection [see Adverse Reactions (6.1) ] . In gMG Study 1 [see Clinical Studies (14.1) ] , 42 (43%) out of 98 patients treated with IMAAVY reported 71 events of infection. Across gMG Study 1 (double-blind period) and its extension study (open label-period), out of 186 patients treated with IMAAVY, 132 (71%) patients reported 360 events of infection and serious infections were reported in 7% of patients treated with IMAAVY. In the wAIHA Study (double-blind period), 35 (45%) out of 78 patients treated with IMAAVY reported 52 events of infection [see Clinical Studies (14.2) ] . Across the wAIHA Study (double-blind period) and its extension study (open label-period), out of 113 patients treated with IMAAVY, 80 (71%) patients reported 184 events of infection and serious infections were reported in 12% of patients treated with IMAAVY. Delay IMAAVY administration in patients with an active infection until the infection is resolved. During treatment with IMAAVY, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding IMAAVY until the infection has resolved. Latent Viral Infections Patients treated with IMAAVY may be at an increased risk of activation of latent viral infections, such as herpes zoster [see Adverse Reactions (6.1) ] . In the extension period of gMG Study 1, there were 2 patients with serious adverse reactions related to Epstein-Barr virus (EBV) infection, and 1 of these patients had fatal complications. Patients who screened positive for hepatitis were excluded from gMG Study 1. Follow standard vaccination guidelines [see Dosage and Administration (2.1) ]. Immunization The safety of immunization with live vaccines and the immune response to vaccination during treatment with IMAAVY are unknown. Because IMAAVY causes a reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with IMAAVY. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of treatment with IMAAVY. 5.2 Hypersensitivity Reactions In clinical trials, hypersensitivity reactions, including angioedema, anaphylaxis, rash, urticaria, and eczema were observed in patients treated with IMAAVY. In gMG Study 1 and the wAIHA Study, hypersensitivity reactions were mild or moderate. In gMG Study 1, all hypersensitivity reactions occurred within one hour to 2 weeks of administration. In the wAIHA Study, 76% of hypersensitivity reactions occurred within 2 weeks of administration [see Adverse Reactions (6.1) ] . In gMG Study 1, one patient experienced a hypersensitivity reaction (urticaria) that led to treatment discontinuation. Management of hypersensitivity reactions depends on the type and severity of the reaction. Monitor the patient during treatment with IMAAVY and for 30 minutes after the administration is complete for clinical signs and symptoms of hypersensitivity reactions [see Dosage and Administration (2.5) ] . If a hypersensitivity reaction occurs during administration, discontinue IMAAVY infusion and institute appropriate supportive measures if needed. IMAAVY is contraindicated in patients with a history of serious hypersensitivity to nipocalimab-aahu or any of the excipients of IMAAVY [see Contraindications (4) ] . 5.3 Infusion-Related Reactions In clinical trials, infusion-related reactions, including headache, influenza-like illness, rash, nausea, fatigue, dizziness, chills, and erythema were observed in patients treated with IMAAVY. In gMG Study 1 and the wAIHA Study, infusion-related reactions were mild to moderate in severity. In gMG Study 1, all infusion-related reactions occurred within one hour to 2 days of administration. In the wAIHA Study, 89% of infusion-related reactions occurred within 2 days of administration [see Adverse Reactions (6.1) ] . Monitor patients during treatment with IMAAVY and for 30 minutes after each infusion [see Dosage and Administration (2.5) ] . If a severe infusion-related reaction occurs, discontinue IMAAVY infusion and initiate appropriate therapy. Consider the risks and benefits of readministering IMAAVY following a severe infusion-related reaction. If a mild to moderate infusion-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medication.

7 DRUG INTERACTIONS Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing IMAAVY and using alternative therapies. ( 7.1 ) 7.1 Effect of IMAAVY on Other Drugs Concomitant use of IMAAVY with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivates containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is essential for patient care, consider discontinuing IMAAVY, and using alternative therapies [see Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling Infections [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Infusion-related Reactions [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥10%) in patients with gMG treated with IMAAVY were respiratory tract infections, peripheral edema, and muscle spasms. ( 6.1 ) The most common adverse reactions (≥10%) in patients with wAIHA treated with IMAAVY were peripheral edema, diarrhea and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults with gMG In gMG Study 1 and its extension study, the safety of IMAAVY was evaluated in 186 patients with gMG who received at least one dose of IMAAVY. Of those patients, 168 patients were exposed to IMAAVY every 2 weeks for at least 6 months, and 140 patients were exposed for at least 12 months. In gMG Study 1, 98 adult patients with gMG received IMAAVY 15 mg/kg every two weeks (after 30 mg/kg initial dose) [see Clinical Studies (14.1) ]. Of these 98 patients, approximately 67% were female, 67% were White, 29% were Asian, and 10% were of Hispanic or Latino ethnicity. The mean age at study entry was 53 years (range 20 to 81). Adverse reactions reported in gMG Study 1 in at least 5% of patients treated with IMAAVY and more frequently than placebo, are summarized in Table 3. The most common adverse reactions (reported in at least 10% of patients treated with IMAAVY) were respiratory tract infection, peripheral edema, and muscle spasms. Table 3: Adverse Reactions (≥ 5%) of Patients Treated with IMAAVY and More Frequently than in Placebo in gMG Study 1 Adverse Reaction IMAAVY N=98 % Placebo N=98 % Includes the following reported in patients treated with IMAAVY: Infection Respiratory tract infection COVID-19 (and other related terms), pneumonia, bronchitis, pneumonia bacteria 18 13 Urinary tract infection other related terms 6 3 Herpes zoster and Herpes simplex 6 2 Oral infection glossitis, oral candidiasis, pericoronitis, pulpitis dental, tooth abscess, tooth infection 5 3 Peripheral edema 12 2 Muscle spasm 12 3 Hypersensitivity reaction angioedema, dermatitis atopic, eczema, gingival swelling, rash (and other related terms), urticaria 8 7 Abdominal pain 8 3 Back pain 8 5 Pyrexia 7 1 Diarrhea 7 3 Cough 7 3 Anemia 6 4 Dizziness 5 1 Nausea 5 2 Hypertension 5 2 Insomnia 5 2 Infections In gMG Study 1 and its extension study, infections that occurred in patients treated with IMAAVY (n=186) included upper respiratory tract infection (46%), respiratory tract infection (28%; including pneumonia, bronchitis, COVID-19), urinary tract infection (15%), herpes (8%; including herpes simplex, herpes zoster, herpes zoster oticus), influenza (8%), oral infection (8%; including candidiasis and dental infections), and skin infection (7%; including cellulitis). Two (1%) cases of infections (cellulitis and urinary tract infection) led to discontinuation of IMAAVY [see Warnings and Precautions (5.1) ] . Hypersensitivity Reactions In gMG Study 1 and its extension study, out of 186 patients treated with IMAAVY, 30 (16%) patients experienced hypersensitivity reactions, which occurred within one hour to two weeks of administration. One patient experienced hypersensitivity reaction (urticaria) that required discontinuation of IMAAVY [see Warnings and Precautions (5.2) ] . Infusion-Related Reactions In gMG Study 1 and its extension study, out of 186 patients treated with IMAAVY, 20 (11%) patients experienced infusion-related reactions, which occurred within one hour to 2 days of administration. No patients experienced infusion-related reaction that required discontinuation of IMAAVY [see Warnings and Precautions (5.3) ] . Laboratory Findings Lipids In gMG Study 1 (N=98), patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol ( ≥ 240 mg/dL) and LDL cholesterol ( ≥ 160 mg/dL) (24% and 11% of patients, respectively). In gMG Study 1, these changes from baseline peaked at Week 4, then decreased and plateaued by Week 24 to mean increases of 14 mg/dL and 7 mg/dL, respectively. Five percent of patients treated with IMAAVY had decreases from normal to low of fasting HDL cholesterol (<40 mg/dL). Pediatric Patients 12 Years of Age and Older with gMG In a 24-week, single arm study (gMG Study 2), evaluating the safety of IMAAVY in 7 pediatric patients age 12 to 16 years with gMG who were AChR positive, adverse reactions were consistent with those observed in adult patients with gMG [see Use in Specific Populations (8.4) ] . Adults with wAIHA The safety of IMAAVY in patients with wAIHA was evaluated in 113 adult patients with wAIHA who received at least one dose of IMAAVY. Of these patients, 84 patients received IMAAVY for at least 6 months, and 49 patients received IMAAVY for at least 12 months. The median duration of treatment was 44 weeks. In the double-blind phase of the wAIHA Study, 78 patients received IMAAVY across the dose regimens evaluated in the study [see Clinical Studies (14.2) ]. Adverse reactions that occurred in the wAIHA Study in at least 5% of patients treated with IMAAVY are summarized in Table 4. The most common adverse reactions (reported in at least 10% of patients treated with IMAAVY) were peripheral edema, diarrhea, and pyrexia. Table 4: Adverse Reactions (≥ 5%) of Patients Treated with IMAAVY and More Frequently than in Placebo in the wAIHA Study Adverse Reaction IMAAVY N=78 % Placebo N=39 % Peripheral edema Includes Edema peripheral, Edema and Generalized edema. 12 2.6 Diarrhea 12 8 Pyrexia 10 2.6 Dizziness 9 8 Infection Urinary tract infection Includes Urinary tract infection, Pyelonephritis and Urinary tract infection bacterial. 9 5 Headache 6 5 Additional Clinically Relevant Adverse Reactions occurring in ≤5% of patients Pneumonia (5% with IMAAVY; 5% with placebo) Nausea (3.8% with IMAAVY; 2.6% with placebo) Insomnia (1.3% with IMAAVY; 0% with placebo) Infections In the wAIHA Study and its extension study, infections that occurred in patients treated with IMAAVY (n=113) included upper respiratory tract infection (34%), respiratory tract infection (33%), urinary tract infection (12%), gastroenteritis (5%). Three (2.7%) cases of infections (pneumonia, salmonella sepsis and spontaneous bacterial peritonitis) led to discontinuation of IMAAVY [see Warnings and Precautions (5.1) ] . Hypersensitivity Reactions In the wAIHA Study and its extension study, out of 113 patients treated with IMAAVY, 9 (8%) patients experienced hypersensitivity reactions [see Warnings and Precautions (5.2) ] . Infusion-Related Reactions In the wAIHA Study and its extension study, out of 113 patients treated with IMAAVY, 12 (11%) patients experienced infusion-related reactions. One patient in the wAIHA Study discontinued IMAAVY due to an infusion-related reaction (back pain) [see Warnings and Precautions (5.3) ] . Laboratory Findings Lipids In the double-blind phase of the wAIHA Study (N=78), 2.3% of patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol ( ≥ 240 mg/dL) and LDL cholesterol remained <160 mg/dL for all patients at Week 24. These changes from baseline peaked between Week 4 and Week 12, then decreased and plateaued by Week 24 to mean increases in fasting total cholesterol of 6 mg/dL and fasting LDL of 4.2 mg/dL. Of the patients treated with IMAAVY, 12% had fasting HDL cholesterol of <40 mg/dL.

8.1 Pregnancy Risk Summary There are limited data on the use of IMAAVY in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There was no evidence of direct adverse effects on fetal development following administration of nipocalimab-aahu to pregnant monkeys; however, adverse effects on the placenta were associated with fetal loss at both doses tested (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for IMAAVY. If IMAAVY is administered during pregnancy, or if a patient becomes pregnant while receiving IMAAVY, healthcare providers should report IMAAVY exposure by contacting Janssen at 1-800-526-7736 or www.IMAAVY.com 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. Because IMAAVY reduces maternal serum IgG concentration and impedes placental IgG transfer to the fetus, passive immunity in the infant may be reduced for 6 months or more; therefore: Monitor for the development of serious infection. Effectiveness of vaccines may be reduced. Consider the risks and benefits prior to administering live vaccines to infants exposed to IMAAVY in utero . Data Animal Data Intravenous administration of nipocalimab-aahu (0, 100, or 300 mg/kg) to pregnant monkeys weekly from the end of organogenesis (gestation day 45) through parturition resulted in placental ischemia, associated with fetal loss and decreased levels of immunoglobulin (IgG) in the offspring at both doses tested. IgG levels in offspring returned to normal levels and no adverse effects on immune function were evident by 6 months after birth. Mean systemic exposures achieved at the doses tested were 5- and 24-times the population PK model simulated mean steady state exposure at the recommended human maintenance dose for gMG (15 mg/kg) and 5.5- and 28-times the population PK model simulated mean steady state exposure at the recommended human maintenance dose for wAIHA (30 mg/kg) on an AUC basis.