Efgartigimod Alfa and Hyaluronidase (human Recombinant)

INDICATIONS AND USAGE VYVGART HYTRULO is indicated for the treatment of adult patients with: generalized myasthenia gravis (gMG) chronic inflammatory demyelinating polyneuropathy (CIDP) VYVGART HYTRULO is a combination of efgartigimod alfa, a neonatal Fc receptor blocker, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with: generalized myasthenia gravis (gMG) ( 1 ) chronic inflammatory demyelinating polyneuropathy (CIDP) ( 1 )

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 a new treatment cycle with VYVGART HYTRULO. ( 2.1 ) Important Administration Information VYVGART HYTRULO is for subcutaneous use only. ( 2.2 ) Prefilled syringe can be administered by patients and/or caregivers. ( 2.2 ) Vial to be administered with a winged infusion set by a healthcare professional only. ( 2.2 ) gMG: recommended dose and dose schedule Administer in cycles of once weekly injections for 4 weeks. ( 2.3 ) Prefilled syringe: 1,000 mg efgartigimod alfa and 10,000 units hyaluronidase administered over 20 to 30 seconds. ( 2.3 ) Vial: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase over 30 to 90 seconds. ( 2.3 ) Administer subsequent treatment cycles based on clinical evaluation. ( 2.3 ) CIDP: recommended dose and dose schedule Administer as once weekly injections. ( 2.4 ) Prefilled syringe: 1,000 mg efgartigimod alfa and 10,000 units hyaluronidase administered over approximately 20 to 30 seconds. ( 2.4 ) Vial: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase over 30 to 90 seconds. ( 2.4 ) 2.1 Recommended Vaccination Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART HYTRULO. Because VYVGART HYTRULO causes transient reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with VYVGART HYTRULO [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . 2.2 Important Dosage and Administration Instructions VYVGART HYTRULO is for subcutaneous use only. Do not administer intravenously. Do not dilute VYVGART HYTRULO. Single-Dose Prefilled Syringe VYVGART HYTRULO prefilled syringe may be administered by patients and/or caregivers after proper instruction in subcutaneous injection technique [see Instructions for Use ] . Single-Dose Vial VYVGART HYTRULO vial is to be administered with a winged infusion set by a healthcare professional only [see Dosage and Administration (2.4) ]. 2.3 Recommended Dosage for gMG Single-Dose Prefilled Syringe The recommended dosage of VYVGART HYTRULO prefilled syringe is 1,000 mg / 10,000 units (1,000 mg efgartigimod alfa and 10,000 units hyaluronidase) administered subcutaneously over approximately 20 seconds to 30 seconds in cycles of once weekly injections for 4 weeks. Single-Dose Vial The recommended dosage of VYVGART HYTRULO vial is 1,008 mg / 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 seconds to 90 seconds in cycles of once weekly injections for 4 weeks. General Dosage Considerations Administer subsequent treatment cycles according to clinical evaluation. If a scheduled dose is missed, VYVGART HYTRULO may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed. 2.4 Recommended Dosage for CIDP Single-Dose Prefilled Syringe The recommended dosage of VYVGART HYTRULO prefilled syringe is 1,000 mg / 10,000 units (1,000 mg efgartigimod alfa and 10,000 units hyaluronidase) administered subcutaneously over approximately 20 to 30 seconds as once weekly injections. Single-Dose Vial The recommended dosage of VYVGART HYTRULO vial is 1,008 mg / 11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 seconds to 90 seconds as once weekly injections. General Dosage Considerations If a scheduled injection is missed, VYVGART HYTRULO may be administered up to 3 days after the scheduled time point. Thereafter, resume the original dosing schedule. Not all patients respond to VYVGART HYTRULO . Consider the appropriateness of continuing treatment in patients who experience worsening of neurological symptoms after starting VYVGART HYTRULO [see Adverse Reactions (6.2) and Clinical Studies (14.2) ]. 2.5 Preparation and Administration Instructions Single-Dose Prefilled Syringe Take the VYVGART HYTRULO prefilled syringe out of the refrigerator at least 30 minutes before injecting to allow it to reach room temperature [see How Supplied/Storage and Handling (16) ] . Do not use external heat sources to bring the syringe to room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect that the prefilled syringe solution is yellowish, clear to opalescent and devoid of particulate matter. Do not use if visible particles are present. Each prefilled syringe is for one-time use only. To administer VYVGART HYTRULO prefilled syringe, use a safety needle that is 25G, 5/8 inches in length, and thin wall type. The safety needle is not included in the carton. Choose an injection site on the abdomen (at least 2 inches away from the navel). Do not inject into areas where the skin is irritated, red, bruised, infected, tender, hard, or into areas where there are moles or scars. Rotate injection sites for subsequent administrations. Inject VYVGART HYTRULO prefilled syringe subcutaneously into a pinched skin area at an angle of 45 to 90 degrees for approximately 20 seconds to 30 seconds. Discard any unused portions of medicine remaining in the syringe. Localized injection site reactions may occur after VYVGART HYTRULO is administered [see Adverse Reactions (6.1) ]. Monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration. If a hypersensitivity reaction occurs, the patient should seek medical attention and the healthcare professional should institute appropriate measures, if needed [see Warnings and Precautions (5.2) ] . For detailed instructions on the preparation and administration of VYVGART HYTRULO prefilled syringe see INSTRUCTIONS FOR USE . Single-Dose Vial Use aseptic technique when preparing and administering VYVGART HYTRULO vial. Do not shake the vial. Each vial is for one-time use only. Avoid exposure to direct sunlight. 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 a 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 vial does not contain preservatives. Administer immediately after preparation. Administration To administer VYVGART HYTRULO vial use a 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 2 inches to 3 inches away from the navel). Do not inject in 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 vial subcutaneously into a pi

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: Anaphylaxis, hypotension leading to syncope, angioedema, dyspnea, rash, and urticaria have occurred in patients treated with VYVGART HYTRULO or intravenous efgartigimod alfa-fcab product. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. ( 4 , 5.2 ) Infusion/injection-Related Reactions: If a severe infusion/injection-related reaction occurs, initiate appropriate therapy; consider the risks and benefits of readministering. If a mild to moderate infusion/injection-related reaction occurs, consider rechallenging with close clinical observation, slower infusion/injection rates, and pre-medications. ( 5.3 ) 5.1 Infections VYVGART HYTRULO may increase the risk of infection. The most common infections observed in Study 1 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) ] . A 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. Immunization Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART HYTRULO. The safety of immunization with live vaccines and the immune response to vaccination during treatment with VYVGART HYTRULO are unknown. Because VYVGART HYTRULO causes a reduction in IgG levels, vaccination with live vaccines is not recommended during treatment with VYVGART HYTRULO. 5.2 Hypersensitivity Reactions In clinical trials, hypersensitivity reactions, including rash, angioedema, and dyspnea were observed in patients treated with VYVGART HYTRULO or intravenous efgartigimod alfa-fcab. Urticaria was also observed in patients treated with VYVGART HYTRULO. Hypersensitivity reactions were mild or moderate, occurred within one hour to three weeks of administration. Anaphylaxis and hypotension leading to syncope have been reported in postmarketing experience with intravenous efgartigimod alfa-fcab. Anaphylaxis and hypotension occurred during or within an hour of administration and led to infusion discontinuation and in some cases to permanent treatment discontinuation. Monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration [see Dosage and Administration (2.4) ] . If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. VYVGART HYTRULO is contraindicated in patients with a history of serious hypersensitivity to efgartigimod alfa products, to hyaluronidase, or to any of the excipients of VYVGART HYTRULO [see Contraindications (4) ] . 5.3 Infusion/Injection-Related Reactions Infusion-related reactions have been reported with intravenous efgartigimod alfa-fcab in postmarketing experience. The most frequent symptoms and signs were hypertension, chills, shivering, and thoracic, abdominal, and back pain. Infusion-related reactions occurred during or within an hour of administration and led to infusion discontinuation. If a severe infusion/injection-related reaction occurs, initiate appropriate therapy. Consider the risks and benefits of readministering VYVGART HYTRULO following a severe infusion/injection-related reaction. If a mild to moderate infusion/injection-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion/injection rates, and pre-medications.

CONTRAINDICATIONS VYVGART HYTRULO is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products, to hyaluronidase, or to any of the excipients of VYVGART HYTRULO. Reactions have included anaphylaxis and hypotension leading to syncope [see Warnings and Precautions (5.2) ]. VYVGART HYTRULO is contraindicated in patients with serious hypersensitivity to efgartigimod alfa products, to hyaluronidase, or to any of the excipients of VYVGART HYTRULO. ( 4 )

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 VYVGART HYTRULO and using alternative therapies. ( 7 ) 7.1 Effect of VYVGART HYTRULO on Other Drugs Concomitant use of VYVGART HYTRULO 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 VYVGART HYTRULO and using alternative therapies.

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/Injection-Related Reactions [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥ 10%) in patients with gMG treated with efgartigimod alfa-fcab were respiratory tract infections, headache, and urinary tract infection. Injection site reactions were common (≥ 15%) in patients with gMG and CIDP who were treated with VYVGART HYTRULO ( 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Experience in Patients with gMG The safety of efgartigimod alfa in adult patients with gMG was established in a 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 3) and its open-label extension [see Clinical Studies (14.1) ]. Adverse Reactions with Efgartigimod Alfa-fcab Intravenous in Adult Patients with gMG In clinical studies, the safety of efgartigimod alfa-fcab administered intravenously in adult patients with gMG has been evaluated in 364 patients who received at least one dose of efgartigimod alfa-fcab. In Study 1, 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 a subsequent cycle, specified by study protocol, was 28 days from the last administration of the previous treatment cycle. On average, efgartigimod alfa-fcab-treated patients received 2 cycles in Study 1. The mean and median times to the second treatment cycle were 54 days and 50 days from the last administration 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 with gMG Treated with Efgartigimod Alfa-fcab Intravenously (EFG IV) and More Frequently than in Placebo-Treated Patients in Study 1 (Safety Population) Adverse reaction EFG IV (N=84) % Placebo (N=83) % Respiratory tract infection 33 29 Headache Headache includes migraine and procedural headache. 32 29 Urinary tract infection 10 5 Paraesthesia Paresthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia. 7 5 Myalgia 6 1 In a placebo-controlled study in patients with gMG who are anti-acetylcholine receptor (AChR) antibody negative (Study 2), 119 patients received one cycle of once-weekly administrations for 4 weeks of either efgartigimod alfa-fcab 10 mg/kg (n=58) or placebo (n=61). The overall safety profile in Study 2 was consistent with the known safety profile of efgartigimod alfa-fcab in patients with gMG except for nausea, which occurred in 7% of anti-AChR antibody negative patients who received efgartigimod alfa-fcab compared to 5% of patients who received placebo. The safety of initiating subsequent cycles between 7 and 28 days from the last administration of the previous treatment cycle was assessed in another study in 60 patients (78% anti-AChR antibody positive and 22% anti-AChR antibody negative). Of these patients, 63% were exposed to treatment for over a year when cycles were initiated less than 4 weeks after the last administration. Safety in these patients was similar to that seen in Study 1. Adverse Reactions with VYVGART HYTRULO in Patients with gMG In an active-controlled study in patients with gMG (Study 3), 110 patients were randomized and received one cycle of once weekly administrations for 4 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 3 included 128 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 3, injection site reactions occurred in 38% of patients receiving VYVGART HYTRULO. These were injection site rash, erythema, pruritus, bruising, pain, and urticaria. In Study 3 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 Experience in Patients with CIDP Adverse Reactions with VYVGART HYTRULO in Patients with CIDP In a placebo-controlled study in patients with CIDP (Study 4, stage B), 221 patients were randomized to receive once-weekly administration of either VYVGART HYTRULO 1,008 mg /11, 200 units subcutaneously (n=111) or placebo (n=110) [see Clinical Studies (14.2) ]. The mean duration of treatment with VYVGART HYTRULO in stage B was 25 weeks. The overall safety profile observed in patients with CIDP treated with VYVGART HYTRULO was consistent with the known safety profile of VYVGART HYTRULO and of efgartigimod alfa-fcab administered intravenously. In Study 4, injection site reactions occurred in 15% of patients treated with VYVGART HYTRULO compared to 6% of patients who received placebo. The most common of these injection site reactions were injection site bruising and injection site erythema. All injection site reactions were mild to moderate in severity. Most injection site reactions occurred during the first 3 months of treatment. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of efgartigimod alfa products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Hypersensitivity reactions including anaphylaxis and hypotension, and infusion/injection-related reactions [see Warnings and Precautions (5.2 , 5.3) ]. Neurological: There have been reports of worsening of symptoms and signs of CIDP when transitioning from intravenous immunoglobulin treatments to VYVGART HYTRULO [see Drug Interactions (7.1) ].

Mechanism of Action VYVGART HYTRULO is a coformulation of efgartigimod alfa and hyaluronidase. Efgartigimod alfa is a 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.