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)] Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.2)] The most common adverse reactions (>= 10%) in patients with gMG treated with efgartigimod alfa-fcab were respiratory tract infections, headache, and urinary tract infection. Additional common adverse reactions with VYVGART HYTRULO are injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Argenx at 1-833-argx411 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of efgartigimod alfa in patients with gMG was established in double blinded placebo-controlled study with efgartigimod alfa-fcab administered intravenously (Study 1) and its open-label extension, and in an active-controlled study of VYVGART HYTRULO administered subcutaneously (Study 2) and its open-label extension.. Adverse Reactions with Efgartigimod Alfa-fcab IntravenousIn clinical studies, the safety of efgartigimod alfa-fcab administered intravenously has been evaluated in 246 patients who received at least one dose of efgartigimod alfa-fcab, including 57 patients exposed to at least treatment cycles and patients exposed to at least 10 treatment cycles. In placebo-controlled study (Study 1) in patients with gMG, 84 patients received efgartigimod alfa-fcab 10 mg/kg [see Clinical Studies (14)]. Of these 84 patients, approximately 75% were female, 82% were White, 11% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean age at study entry was 46 years (range 19 to 78). The minimum time to initiate subsequent cycle, specified by study protocol, was 50 days from the start of the previous treatment cycle. On average, efgartigimod alfa-fcab-treated patients received cycles in Study 1. The mean and median times to the second treatment cycle were 94 days and 72 days from the initial infusion of the first treatment cycle, respectively, for efgartigimod alfa-fcab-treated patients. Adverse reactions reported in at least 5% of patients treated with efgartigimod alfa-fcab and more frequently than placebo are summarized in Table 1. The most common adverse reactions (reported in at least 10% of efgartigimod alfa-fcab-treated patients) were respiratory tract infection, headache, and urinary tract infection.Table 1: Adverse Reactions in at least 5% of Patients Treated with Efgartigimod Alfa-fcab Intravenously (EFG IV) and More Frequently than in Placebo-Treated Patients in Study (Safety Population)Adverse reactionEFG IV(N=84)%Placebo(N=83)%Respiratory tract infection 3329HeadacheHeadache includes migraine and procedural headache. 3229Urinary tract infection105ParaesthesiaParaesthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia. 75Myalgia61. Adverse Reactions with VYVGART HYTRULOIn an active-controlled study in patients with gMG (Study 2), 110 patients were randomized and received one cycle of once weekly administrations for weeks (4 administrations total), of either VYVGART HYTRULO subcutaneously (n=55) or efgartigimod alfa-fcab intravenously (n=55) at recommended doses [see Dosage and Administration (2.2)]. The open-label extension of Study included some patients who switched from efgartigimod alfa-fcab IV to VYVGART HYTRULO. The most common adverse reactions (reported in at least 10% of VYVGART HYTRULO-treated patients) were injection site reactions and headache.In Study 2, injection site reactions occurred in 38% of patients receiving VYVGART HYTRULO. These were injection site rash, erythema, pruritis, bruising, pain, and urticaria.In the Study and its open-label extension (n 168), all injection site reactions were mild to moderate in severity and did not lead to treatment discontinuation. The majority occurred within 24 hours after administration and resolved spontaneously. Most injection site reactions occurred during the first treatment cycle, and the incidence decreased with each subsequent cycle.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. VYVGART HYTRULO is coformulation of efgartigimod alfa and hyaluronidase.Efgartigimod alfa is human IgG1 antibody fragment that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. This effect is transient and permeability of the subcutaneous tissue is restored within 24 to 48 hours.. 12.2Pharmacodynamics In Study [see Clinical Studies (14)], the pharmacological effect of efgartigimod alfa-fcab was assessed by measuring the decrease in serum IgG levels and AChR autoantibody levels. In patients testing positive for AChR antibodies and who were treated with efgartigimod alfa-fcab intravenous, there was reduction in total IgG levels relative to baseline. Decrease in AChR autoantibody levels followed similar pattern. decrease in AChR-Ab was associated with clinical response in AChR-Ab positive patients, as measured by the change from baseline in MG-ADL total score.In Study 2, the pharmacological effect of VYVGART HYTRULO administered subcutaneously (SC) at 1,008 mg 11,200 Units was compared to efgartigimod alfa-fcab administered intravenously at 10 mg/kg (EFG IV) in gMG patients. The maximum mean reduction in AChR-Ab level was observed at week 4, with mean reduction of 62.2% and 59.7% in the VYVGART HYTRULO SC and efgartigimod alfa-fcab IV arm, respectively. The decrease in total IgG levels followed similar pattern. The 90% confidence intervals for the geometric mean ratios of AChR-Ab reduction at day 29 and AUEC0-4w (area under the effect-time curve from time to weeks post dose) were within the range of 80% to 125%, indicating no clinically significant difference between the two formulations. 12.3 Pharmacokinetics. Efgartigimod alfa exposures were approximately dose-proportional up to the highest subcutaneously tested dose of VYVGART HYTRULO (1750 mg, 1.75 times the recommended dosage).. DistributionThe volume of distribution is 15 to 20L.. Metabolism and EliminationEfgartigimod alfa and hyaluronidase are expected to be degraded by proteolytic enzymes into small peptides and amino acids.The terminal half-life is 80 to 120 hours (3 to days).After single intravenous dose of 10 mg/kg efgartigimod alfa-fcab in healthy subjects, less than 0.1% of the administered dose was recovered in urine. Specific Populations. Age, Sex and RaceA population pharmacokinetics analysis assessing the effects of age, body weight, sex, and race did not suggest any clinically significant impact of these covariates on efgartigimod alfa exposures.. Body WeightA population pharmacokinetics analysis suggests that the influence of body weight on efgartigimod alfa exposure after administration of VYVGART HYTRULO SC 1008 mg was limited and not clinically relevant.. Patients with Renal ImpairmentNo dedicated pharmacokinetic study has been performed in patients with renal impairment. population PK analysis of data from the VYVGART HYTRULO clinical studies indicated that patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2) had 11% increase in exposure relative to the exposure in patients with normal renal function [see Use in Specific Populations (8.6)]. Patients with Hepatic ImpairmentNo dedicated pharmacokinetic study has been performed in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa. Drug Interaction StudiesClinical drug interactions studies have not been performed with efgartigimod alfa.. P450 EnzymesEfgartigimod alfa is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Drug Interactions with Other Drugs or Biological ProductsEfgartigimod alfa may decrease concentrations of compounds that bind to the human FcRn [see Drug Interactions (7.1)]. 12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of VYVGART HYTRULO or of other efgartigimod products.In up to 10 weeks treatment in Study 2, the incidence of anti-efgartigimod alfa antibodies was 35% (19/55) following treatment with VYVGART HYTRULO and 20% (11/55) in patients receiving intravenous efgartigimod alfa-fcab. For both IV and SC arms, neutralizing anti-efgartigimod alfa antibodies were detected in 4% (2/55) of patients. Some neutralizing antibodies may not be detected by the assay. The available data are too limited to make definitive conclusions regarding immunogenicity and the effect on pharmacokinetics, safety, or efficacy of VYVGART HYTRULO.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Study (described below) which established the effectiveness of efgartigimod alfa-fcab for the treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was conducted with efgartigimod alfa-fcab intravenous formulation. In Study 2, VYVGART HYTRULO demonstrated comparable pharmacodynamic effect on AChR antibody reduction as compared to the efgartigimod alfa-fcab intravenous formulation, which established the efficacy of VYVGART HYTRULO [see Clinical Pharmacology (12.2)]. Study (Efgartigimod Alfa-fcab Intravenous)The efficacy of efgartigimod alfa-fcab intravenous (EFG IV) for the treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was established in 26-week, multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT03669588).Study enrolled patients who met the following criteria at screening: -Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV-MG-Activities of Daily Living (MG-ADL) total score of >= 5-On stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone -IgG levels of at least g/LA total of 167 patients were enrolled in Study and were randomized to receive either EFG IV 10mg/kg (1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83). Baseline characteristics were similar between treatment groups. Patients had median age of 46 years at screening (range: 19 to 81 years) and median time since diagnosis of years. Seventy-one percent were female, and 84% were White. Median MG-ADL total score was 9, and median Quantitative Myasthenia Gravis (QMG) total score was 16. The majority of patients (n=65 for EFG IV; n=64 for placebo) were positive for AChR antibodies.At baseline, over 80% of patients in each group received AChE inhibitors, over 70% in each treatment group received steroids, and approximately 60% in each treatment group received NSISTs, at stable doses. Patients were treated with 10 mg/kg EFG IV administered as an intravenous infusion over one hour once weekly for weeks. In patients weighing 120 kg or more, EFG IV was administered as 1200 mg per infusion. Subsequent treatment cycles were administered based on clinical evaluation, but no sooner than 50 days from the start of the previous treatment cycle.The efficacy of EFG IV was measured using the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions of signs or symptoms that are typically affected in gMG. Each text is assessed on 4-point scale where score of represents normal function and score of represents loss of ability to perform that function. total score ranges from to 24, with the higher scores indicating more impairment. In this study, an MG-ADL responder was defined as patient with 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least consecutive weeks, with the first reduction occurring no later than week after the last infusion of the cycle. The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders during the first treatment cycle between treatment groups in the AChR-Ab positive population. statistically significant difference favoring EFG IV was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the EFG IV-treated group vs 29.7% in the placebo-treated group (p <0.0001)].The efficacy of EFG IV was also measured using the Quantitative Myasthenia Gravis (QMG) total score which is 13-text categorical grading system that assesses muscle weakness. Each text is assessed on 4-point scale where score of represents no weakness and score of represents severe weakness. total possible score ranges from to 39, where higher scores indicate more severe impairment. In this study, QMG responder was defined as patient who had 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least consecutive weeks, with the first reduction occurring no later than week after last infusion of the cycle.The secondary endpoint was the comparison of the percentage of QMG responders during the first treatment cycle between both treatment groups in the AChR-Ab positive patients. statistically significant difference favoring EFG IV was observed in the QMG responder rate during the first treatment cycle [63.1% in the EFG IV-treated group vs 14.1% in the placebo-treated group (p <0.0001)].The results are presented in Table 2.Table 2: MG-ADL and QMG Responders During Cycle in AChR-Ab Positive Patients (mITT Analysis Set)EFG IVn=65%Placebon=64%P-valueOdds Ratio (95% CI)EFG IV= Efgartigimod alfa-fcab intravenous; MG-ADL=Myasthenia Gravis Activities of Daily Living; QMG =Quantitative Myasthenia Gravis; mITT=modified intent-to-treat; n=number of patients for whom the observation was reported; CI confidence interval;Logistic regression stratified for AChR-Ab status (if applicable), Japanese/Non-Japanese and standard of care, with baseline MG-ADL as covariate QMG as covariatesTwo-sided exact p-valueMG-ADL Responders67.729.7< 0.00014.951 (2.213, 11.528)QMG Responders63.114.1< 0.000110.842 (4.179, 31.200)Figure shows the mean change from baseline on the MG-ADL during cycle 1.Figure 1: Mean Change in Total MG-ADL From Cycle Baseline Over Time in AChR-Ab Positive Patients (mITT Analysis Set)Figure shows the distribution of response on the MG-ADL and QMG during cycle 1, four weeks after the first infusion with EFG IV.Figure 2: Percentage of Patients with MG-ADL and QMG Total Score Change Weeks Post Initial Infusion of the First Cycle in AChR-Ab Positive Patients. -Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV. -MG-Activities of Daily Living (MG-ADL) total score of >= 5. -On stable dose of MG therapy prior to screening, that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone -IgG levels of at least g/L. Figure 1. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of efgartigimod alfa in patients with gMG was established in double blinded placebo-controlled study with efgartigimod alfa-fcab administered intravenously (Study 1) and its open-label extension, and in an active-controlled study of VYVGART HYTRULO administered subcutaneously (Study 2) and its open-label extension.. Adverse Reactions with Efgartigimod Alfa-fcab IntravenousIn clinical studies, the safety of efgartigimod alfa-fcab administered intravenously has been evaluated in 246 patients who received at least one dose of efgartigimod alfa-fcab, including 57 patients exposed to at least treatment cycles and patients exposed to at least 10 treatment cycles. In placebo-controlled study (Study 1) in patients with gMG, 84 patients received efgartigimod alfa-fcab 10 mg/kg [see Clinical Studies (14)]. Of these 84 patients, approximately 75% were female, 82% were White, 11% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean age at study entry was 46 years (range 19 to 78). The minimum time to initiate subsequent cycle, specified by study protocol, was 50 days from the start of the previous treatment cycle. On average, efgartigimod alfa-fcab-treated patients received cycles in Study 1. The mean and median times to the second treatment cycle were 94 days and 72 days from the initial infusion of the first treatment cycle, respectively, for efgartigimod alfa-fcab-treated patients. Adverse reactions reported in at least 5% of patients treated with efgartigimod alfa-fcab and more frequently than placebo are summarized in Table 1. The most common adverse reactions (reported in at least 10% of efgartigimod alfa-fcab-treated patients) were respiratory tract infection, headache, and urinary tract infection.Table 1: Adverse Reactions in at least 5% of Patients Treated with Efgartigimod Alfa-fcab Intravenously (EFG IV) and More Frequently than in Placebo-Treated Patients in Study (Safety Population)Adverse reactionEFG IV(N=84)%Placebo(N=83)%Respiratory tract infection 3329HeadacheHeadache includes migraine and procedural headache. 3229Urinary tract infection105ParaesthesiaParaesthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia. 75Myalgia61. Adverse Reactions with VYVGART HYTRULOIn an active-controlled study in patients with gMG (Study 2), 110 patients were randomized and received one cycle of once weekly administrations for weeks (4 administrations total), of either VYVGART HYTRULO subcutaneously (n=55) or efgartigimod alfa-fcab intravenously (n=55) at recommended doses [see Dosage and Administration (2.2)]. The open-label extension of Study included some patients who switched from efgartigimod alfa-fcab IV to VYVGART HYTRULO. The most common adverse reactions (reported in at least 10% of VYVGART HYTRULO-treated patients) were injection site reactions and headache.In Study 2, injection site reactions occurred in 38% of patients receiving VYVGART HYTRULO. These were injection site rash, erythema, pruritis, bruising, pain, and urticaria.In the Study and its open-label extension (n 168), all injection site reactions were mild to moderate in severity and did not lead to treatment discontinuation. The majority occurred within 24 hours after administration and resolved spontaneously. Most injection site reactions occurred during the first treatment cycle, and the incidence decreased with each subsequent cycle.

DESCRIPTION SECTION.

11 DESCRIPTION VYVGART HYTRULO is coformulation of efgartigimod alfa and hyaluronidase (human recombinant).Efgartigimod alfa, neonatal Fc receptor blocker, is human immunoglobulin G1 (IgG1) -derived Fc fragment (fragment, crystallized) of the za allotype, produced in Chinese hamster ovary (CHO) cells. The efgartigimod alfa Fc fragment is homodimer consisting of two identical peptide chains each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity for FcRn. The molecular weight of efgartigimod alfa is approximately 54 kDa.Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human recombinant) is glycosylated single-chain protein produced by Chinese hamster ovary cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has molecular weight of approximately 61 kDa.VYVGART HYTRULO (efgartigimod alfa and hyaluronidase-qvfc) injection is sterile, preservative free, yellowish, clear to opalescent solution supplied in single-dose vial for subcutaneous injection.Each 5.6 mL single-dose vial of VYVGART HYTRULO contains 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase (human recombinant). Each mL of solution contains 180 mg of efgartigimod alfa, 2,000 units of hyaluronidase (human recombinant) and histidine (1.4 mg), L-histidine hydrochloride monohydrate (2.2 mg), methionine (1.5 mg), polysorbate 20 (0.4 mg), sodium chloride (5.8 mg), sucrose (20.5 mg), and water for injection, USP, at pH of 6.0.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. See Full Prescribing Information for instructions on dosage, preparation, and administration. (2.1, 2.2, 2.3, 2.4)Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of new treatment cycle with VYVGART HYTRULO. (2.1)Administer by healthcare professional only. (2.2) For subcutaneous use with winged infusion set. (2.2)The recommended dose is 1,008 mg 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for weeks. (2.3)Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established. (2.3). See Full Prescribing Information for instructions on dosage, preparation, and administration. (2.1, 2.2, 2.3, 2.4). Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of new treatment cycle with VYVGART HYTRULO. (2.1). Administer by healthcare professional only. (2.2) For subcutaneous use with winged infusion set. (2.2). The recommended dose is 1,008 mg 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for weeks. (2.3). Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established. (2.3). 2.1 Recommended Vaccination. Because VYVGART HYTRULO causes transient reduction in IgG levels, immunization with live-attenuated or live vaccines is not recommended during treatment with VYVGART HYTRULO. Evaluate the need to administer age-appropriate immunizations according to immunization guidelines before initiation of new treatment cycle with VYVGART HYTRULO [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].. 2.2Important Dosage and Administration Instructions. VYVGART HYTRULO is to be administered by healthcare professional only.VYVGART HYTRULO is for subcutaneous use only and administered with winged infusion set [see Dosage and Administration (2.4)]. Do not administer intravenously.Do not dilute VYVGART HYTRULO.. 2.3 Recommended Dose and Dose Schedules. The recommended dosage of VYVGART HYTRULO is 1,008 mg 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for weeks.Administer subsequent treatment cycles according to clinical evaluation. The safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.If scheduled dose is missed, VYVGART HYTRULO may be administered up to days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.. 2.4 Preparation and Administration Instructions. Use aseptic technique when preparing and administering VYVGART HYTRULO. Do not shake the vial. Each vial is for one time use only. Avoid exposure to direct sunlight. PreparationTake the VYVGART HYTRULO vial out of the refrigerator at least 15 minutes before injecting to allow it to reach room temperature [see How Supplied/Storage and Handling (16)]. Do not use external heat sources.Check that the VYVGART HYTRULO solution is yellowish, clear to opalescent. Parenteral medicine products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Do not use if opaque particles or other foreign particles are present.Withdraw the entire content of VYVGART HYTRULO from the vial using polypropylene syringe and an 18G stainless steel transfer needle.Remove large air bubbles, if present. Each vial contains overfill to compensate for liquid loss during preparation and to compensate for the priming volume of the winged infusion set.VYVGART HYTRULO does not contain preservatives. Administer immediately after preparation.. Take the VYVGART HYTRULO vial out of the refrigerator at least 15 minutes before injecting to allow it to reach room temperature [see How Supplied/Storage and Handling (16)]. Do not use external heat sources.. Check that the VYVGART HYTRULO solution is yellowish, clear to opalescent. Parenteral medicine products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Do not use if opaque particles or other foreign particles are present.. Withdraw the entire content of VYVGART HYTRULO from the vial using polypropylene syringe and an 18G stainless steel transfer needle.. Remove large air bubbles, if present. Each vial contains overfill to compensate for liquid loss during preparation and to compensate for the priming volume of the winged infusion set.. VYVGART HYTRULO does not contain preservatives. Administer immediately after preparation.. AdministrationTo administer VYVGART HYTRULO use winged infusion set made of polyvinyl chloride (PVC), 25G, 12 inches tubing, maximum priming volume of 0.4 mL.Remove the transfer needle from the syringe and connect the syringe to the winged infusion set. Prior to administration, fill the tubing of the winged infusion set by gently pressing the syringe plunger until the plunger is at 5.6 mL. There should be solution at the end of the winged infusion set needle.Choose an injection site on the abdomen (at least to inches away from the navel). Do not inject on areas where the skin is red, bruised, tender, hard, or into areas where there are moles or scars.Rotate injection sites for subsequent administrations. Inject VYVGART HYTRULO subcutaneously into pinched skin area at an angle of about 45 degrees over 30 to 90 seconds.Localized injection site reactions may occur after VYVGART HYTRULO is administered. [see Adverse Reactions (6.1)]. Discard any unused portions of medicine remaining in the vial, the syringe and the winged infusion set.Healthcare professionals should monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration. If hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention [see Warnings and Precautions (5.2)]. To administer VYVGART HYTRULO use winged infusion set made of polyvinyl chloride (PVC), 25G, 12 inches tubing, maximum priming volume of 0.4 mL.. Remove the transfer needle from the syringe and connect the syringe to the winged infusion set. Prior to administration, fill the tubing of the winged infusion set by gently pressing the syringe plunger until the plunger is at 5.6 mL. There should be solution at the end of the winged infusion set needle.. Choose an injection site on the abdomen (at least to inches away from the navel). Do not inject on areas where the skin is red, bruised, tender, hard, or into areas where there are moles or scars.Rotate injection sites for subsequent administrations. Do not inject on areas where the skin is red, bruised, tender, hard, or into areas where there are moles or scars.. Rotate injection sites for subsequent administrations.. Inject VYVGART HYTRULO subcutaneously into pinched skin area at an angle of about 45 degrees over 30 to 90 seconds.. Localized injection site reactions may occur after VYVGART HYTRULO is administered. [see Adverse Reactions (6.1)]. Discard any unused portions of medicine remaining in the vial, the syringe and the winged infusion set.. Healthcare professionals should monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration. If hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention [see Warnings and Precautions (5.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Efgartigimod alfa exposures were approximately dose-proportional up to the highest subcutaneously tested dose of VYVGART HYTRULO (1750 mg, 1.75 times the recommended dosage).. DistributionThe volume of distribution is 15 to 20L.. Metabolism and EliminationEfgartigimod alfa and hyaluronidase are expected to be degraded by proteolytic enzymes into small peptides and amino acids.The terminal half-life is 80 to 120 hours (3 to days).After single intravenous dose of 10 mg/kg efgartigimod alfa-fcab in healthy subjects, less than 0.1% of the administered dose was recovered in urine. Specific Populations. Age, Sex and RaceA population pharmacokinetics analysis assessing the effects of age, body weight, sex, and race did not suggest any clinically significant impact of these covariates on efgartigimod alfa exposures.. Body WeightA population pharmacokinetics analysis suggests that the influence of body weight on efgartigimod alfa exposure after administration of VYVGART HYTRULO SC 1008 mg was limited and not clinically relevant.. Patients with Renal ImpairmentNo dedicated pharmacokinetic study has been performed in patients with renal impairment. population PK analysis of data from the VYVGART HYTRULO clinical studies indicated that patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2) had 11% increase in exposure relative to the exposure in patients with normal renal function [see Use in Specific Populations (8.6)]. Patients with Hepatic ImpairmentNo dedicated pharmacokinetic study has been performed in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa. Drug Interaction StudiesClinical drug interactions studies have not been performed with efgartigimod alfa.. P450 EnzymesEfgartigimod alfa is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Drug Interactions with Other Drugs or Biological ProductsEfgartigimod alfa may decrease concentrations of compounds that bind to the human FcRn [see Drug Interactions (7.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on the use of VYVGART HYTRULO or efgartigimod alfa containing products during pregnancy. There was no evidence of adverse developmental outcomes following the intravenous administration of efgartigimod alfa at up to 100 mg/kg/day in rats and rabbits (see Data). The background rate of major birth defects and miscarriage in the indicated population is unknown. 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.. 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. Therefore, efgartigimod alfa may be transmitted from the mother to the developing fetus.As VYVGART HYTRULO is expected to reduce maternal IgG antibody levels, reduction in passive protection to the newborn is anticipated. Risk and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to VYVGART HYTRULO in utero [see Warnings and Precautions (5.1)]. Data. Animal DataVYVGART HYTRULO for subcutaneous injection contains efgartigimod alfa and hyaluronidase [see Description (11)].Efgartigimod alfa:-Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. Maternal efgartigimod alfa exposures at the highest no-effect doses were approximately and 62 times, respectively, that in humans at the recommended human dose (RHD) of 1008 mg. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. Maternal exposures at the highest no-effect dose were approximately 13 times that in humans at the RHD. Hyaluronidase:-In study in which hyaluronidase (recombinant human) was administered by subcutaneous injection to pregnant mice throughout organogenesis, increased embryofetal mortality and decreased fetal body weights were observed at the highest doses tested. The no-effect dose for adverse effects on embryofetal development in the mouse was approximately 1800 times the dose of hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO (1,008 mg efgartigimod alfa and 11,200 hyaluronidase), on U/kg basis.-There were no adverse effects on pre- and postnatal development following subcutaneous administration of hyaluronidase (recombinant human) to mice throughout gestation and lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART HYTRULO, on U/kg basis.. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. Maternal efgartigimod alfa exposures at the highest no-effect doses were approximately and 62 times, respectively, that in humans at the recommended human dose (RHD) of 1008 mg. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. Maternal exposures at the highest no-effect dose were approximately 13 times that in humans at the RHD. -In study in which hyaluronidase (recombinant human) was administered by subcutaneous injection to pregnant mice throughout organogenesis, increased embryofetal mortality and decreased fetal body weights were observed at the highest doses tested. The no-effect dose for adverse effects on embryofetal development in the mouse was approximately 1800 times the dose of hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO (1,008 mg efgartigimod alfa and 11,200 hyaluronidase), on U/kg basis.. -There were no adverse effects on pre- and postnatal development following subcutaneous administration of hyaluronidase (recombinant human) to mice throughout gestation and lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART HYTRULO, on U/kg basis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on the use of VYVGART HYTRULO or efgartigimod alfa containing products during pregnancy. There was no evidence of adverse developmental outcomes following the intravenous administration of efgartigimod alfa at up to 100 mg/kg/day in rats and rabbits (see Data). The background rate of major birth defects and miscarriage in the indicated population is unknown. 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.. 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. Therefore, efgartigimod alfa may be transmitted from the mother to the developing fetus.As VYVGART HYTRULO is expected to reduce maternal IgG antibody levels, reduction in passive protection to the newborn is anticipated. Risk and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to VYVGART HYTRULO in utero [see Warnings and Precautions (5.1)]. Data. Animal DataVYVGART HYTRULO for subcutaneous injection contains efgartigimod alfa and hyaluronidase [see Description (11)].Efgartigimod alfa:-Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. Maternal efgartigimod alfa exposures at the highest no-effect doses were approximately and 62 times, respectively, that in humans at the recommended human dose (RHD) of 1008 mg. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. Maternal exposures at the highest no-effect dose were approximately 13 times that in humans at the RHD. Hyaluronidase:-In study in which hyaluronidase (recombinant human) was administered by subcutaneous injection to pregnant mice throughout organogenesis, increased embryofetal mortality and decreased fetal body weights were observed at the highest doses tested. The no-effect dose for adverse effects on embryofetal development in the mouse was approximately 1800 times the dose of hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO (1,008 mg efgartigimod alfa and 11,200 hyaluronidase), on U/kg basis.-There were no adverse effects on pre- and postnatal development following subcutaneous administration of hyaluronidase (recombinant human) to mice throughout gestation and lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART HYTRULO, on U/kg basis.. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to pregnant rats and rabbits throughout organogenesis resulted in no adverse effects on embryofetal development in either species. Maternal efgartigimod alfa exposures at the highest no-effect doses were approximately and 62 times, respectively, that in humans at the recommended human dose (RHD) of 1008 mg. -Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to rats throughout gestation and lactation resulted in no adverse effects on pre- or postnatal development. Maternal exposures at the highest no-effect dose were approximately 13 times that in humans at the RHD. -In study in which hyaluronidase (recombinant human) was administered by subcutaneous injection to pregnant mice throughout organogenesis, increased embryofetal mortality and decreased fetal body weights were observed at the highest doses tested. The no-effect dose for adverse effects on embryofetal development in the mouse was approximately 1800 times the dose of hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO (1,008 mg efgartigimod alfa and 11,200 hyaluronidase), on U/kg basis.. -There were no adverse effects on pre- and postnatal development following subcutaneous administration of hyaluronidase (recombinant human) to mice throughout gestation and lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART HYTRULO, on U/kg basis.. 8.2 Lactation Risk SummaryThere is no information regarding the presence of efgartigimod alfa or hyaluronidase, from administration of VYVGART HYTRULO, in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VYVGART HYTRULO and any potential adverse effects on the breastfed infant from VYVGART HYTRULO 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 VYVGART HYTRULO did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger adult patients.. 8.6 Renal Impairment. No dose adjustment of VYVGART HYTRULO is needed for patients with mild renal impairment. There are insufficient data to evaluate the impact of moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) and severe renal impairment (eGFR <30 mL/min/1.73 m2) on pharmacokinetic parameters of VYVGART HYTRULO [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infections: Delay administration of VYVGART HYTRULO to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with VYVGART HYTRULO. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART HYTRULO until the infection has resolved. (5.1)Hypersensitivity reactions: angioedema, dyspnea, and rash have occurred in patients treated with VYVGART HYTRULO. If hypersensitivity reaction occurs, the healthcare professional should institute appropriate supportive measures if needed or the patient should seek medical attention. (5.2). Infections: Delay administration of VYVGART HYTRULO to patients with an active infection. Monitor for signs and symptoms of infection in patients treated with VYVGART HYTRULO. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART HYTRULO until the infection has resolved. (5.1). Hypersensitivity reactions: angioedema, dyspnea, and rash have occurred in patients treated with VYVGART HYTRULO. If hypersensitivity reaction occurs, the healthcare professional should institute appropriate supportive measures if needed or the patient should seek medical attention. (5.2). 5.1 Infections VYVGART HYTRULO may increase the risk of infection. The most common infections observed in Study were urinary tract infection (10% of efgartigimod alfa-fcab-treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of efgartigimod alfa-fcab-treated patients compared to 29% of placebo-treated patients) [see Adverse Reactions (6.1) and Clinical Studies (14)]. higher frequency of patients who received efgartigimod alfa-fcab compared to placebo were observed to have below normal levels for white blood cell counts (12% versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities were mild to moderate in severity. Delay VYVGART HYTRULO administration in patients with an active infection until the infection is resolved. During treatment with VYVGART HYTRULO, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART HYTRULO until the infection has resolved.. ImmunizationImmunization with vaccines during VYVGART HYTRULO treatment has not been studied. The safety of immunization with live or live-attenuated vaccines and the response to immunization with any vaccine are unknown. Because VYVGART HYTRULO causes reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with VYVGART HYTRULO. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of new treatment cycle with VYVGART HYTRULO.. 5.2 Hypersensitivity Reactions. Hypersensitivity reactions, including rash, angioedema, and dyspnea were observed in patients treated with VYVGART HYTRULO and efgartigimod alfa-fcab. Urticaria was also observed in patients treated with VYVGART HYTRULO. In clinical trials, hypersensitivity reactions were mild or moderate, occurred within one hour to three weeks of administration, and did not lead to treatment discontinuation. Healthcare professionals should monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration [see Dosage and Administration (2.4)]. If hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention.