Efgartigimod Alfa and Hyaluronidase (Human Recombinant)

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 )

Injection: 1,000 mg efgartigimod alfa and 10,000 units hyaluronidase per 5 mL (200 mg/2,000 units per mL) as yellowish, clear to opalescent solution, in a single-dose prefilled syringe. Injection: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000 units per mL) as yellowish, clear to opalescent solution, in a single-dose vial. Injection: 1,000 mg efgartigimod alfa and 10,000 units hyaluronidase per 5 mL (200 mg/2,000 units per mL) in a single-dose prefilled syringe. ( 3 ) Injection: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000 units per mL) in a single-dose vial. ( 3 )

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 )

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.

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) ].

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.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VYVGART HYTRULO during pregnancy. Healthcare providers and patients may call 1-855-272-6524 or go to https://www.Vyvgartpregnancy.com to enroll in or to obtain information about the registry. Risk Summary There 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 Reactions Monoclonal 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 vaccines to infants exposed to VYVGART HYTRULO in utero [see Warnings and Precautions (5.1) ]. Data Animal Data VYVGART 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 8 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 a study in which hyaluronidase (human recombinant) 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 U hyaluronidase), on a U/kg basis. – There were no adverse effects on pre- and postnatal development following subcutaneous administration of hyaluronidase (human recombinant) to mice throughout gestation and lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART HYTRULO, on a U/kg basis.

8.2 Lactation Risk Summary There 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 mother's 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 m 2 ) and severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) on pharmacokinetic parameters of VYVGART HYTRULO [see Clinical Pharmacology (12.3) ].

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.