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 a new treatment cycle 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 to be administered by a healthcare professional only.

VYVGART HYTRULO is for subcutaneous use only and administered with a 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 4 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 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 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.

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.

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, and did not lead to treatment discontinuation.

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.

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 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-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-related reaction occurs, initiate appropriate therapy. Consider the risks and benefits of readministering VYVGART HYTRULO 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-medications.

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.

The safety of efgartigimod alfa in 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 2) and its open-label extension.

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-related reactions [see Warnings and Precautions (5.2 5.3)].

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

8.2 Lactation

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)].

12.1 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.

12.2 Pharmacodynamics

In Study 1 [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 a reduction in total IgG levels relative to baseline. Decrease in AChR autoantibody levels followed a similar pattern. A decrease in AChR-Ab was associated with a 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 a 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 a 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 0 to 4 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).

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VYVGART HYTRULO for subcutaneous injection contains efgartigimod alfa and hyaluronidase [see Description (11)].

Study 1 (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 a 26-week, multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT03669588).

Study 1 enrolled patients who met the following criteria at screening:

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Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV

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MG-Activities of Daily Living (MG-ADL) total score of ≥ 5

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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

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IgG levels of at least 6 g/L

A total of 167 patients were enrolled in Study 1 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 a median age of 46 years at screening (range: 19 to 81 years) and a median time since diagnosis of 7 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 4 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 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. In this study, an MG-ADL responder was defined as a patient with a 2-point or greater reduction in the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 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. A 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 a 13-item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total possible score ranges from 0 to 39, where higher scores indicate more severe impairment. In this study, a QMG responder was defined as a patient who had a 3-point or greater reduction in the total QMG score compared to the treatment cycle baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 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. A 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.

Figure 1 shows the mean change from baseline on the MG-ADL during cycle 1.

Figure 1: Mean Change in Total MG-ADL From Cycle 1 Baseline Over Time in AChR-Ab Positive Patients (mITT Analysis Set)

Figure 2 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 4 Weeks Post Initial Infusion of the First Cycle in AChR-Ab Positive Patients

Store VYVGART HYTRULO vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. Do not shake.

If needed, unopened vials may be stored in the original carton for up to 3 days at room temperature at 20°C to 25°C (68°F to 77°F) for a single period before administration or returned to refrigeration. Do not store the vial at room temperature more than one time. Record the date removed from and the date returned to the refrigerator on the carton.

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VYVGART HYTRULO during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use In Specific Populations (8.1)].

Infections

Instruct patients to communicate any history of infections to the healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection. Advise patients to complete age-appropriate vaccines according to immunization guidelines prior to initiation of a new treatment cycle with VYVGART HYTRULO. Administration of live or live-attenuated vaccines is not recommended during treatment with VYVGART HYTRULO [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with efgartigimod alfa products. Inform patients about the signs and symptoms of these reactions, and advise patients to contact their healthcare provider immediately if these occur [see Warnings and Precautions (5.2)].

Infusion-Related Reactions

Advise patients of the potential risk of infusion-related reactions, which can include hypertension, chills, shivering, and chest, abdominal, and back pain [see Warnings and Precautions (5.3)].