Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 Infections
VYVGART may increase the risk of infection. The most common infections observed in Study 1 were urinary tract infection (10% of VYVGART-treated patients compared to 5% of placebo-treated patients) and respiratory tract infections (33% of VYVGART-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 VYVGART 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 administration in patients with an active infection until the infection is resolved. During treatment with VYVGART, monitor for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate treatment and consider withholding VYVGART until the infection has resolved.

Immunization

Immunization with vaccines during VYVGART 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 causes a reduction in IgG levels, vaccination with live-attenuated or live vaccines is not recommended during treatment with VYVGART. Evaluate the need to administer age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with VYVGART.

5.2 Hypersensitivity Reactions

In clinical trials, hypersensitivity reactions, including rash, angioedema, and dyspnea were observed in VYVGART-treated patients. 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 VYVGART. 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 patients during administration and for 1 hour thereafter for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention. VYVGART is contraindicated in patients with a history of serious hypersensitivity to efgartigimod alfa products or to any of the excipients of VYVGART [see Contraindications (4)].

5.3 Infusion-Related Reactions

Infusion-related reactions have been reported with VYVGART 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 during administration, discontinue VYVGART infusion and initiate appropriate therapy. Consider the risks and benefits of readministering VYVGART 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.

5.4 Effects on ability to drive and use machines

VYVGART has no or negligible influence on the ability to drive and use machines.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: 
•   Infections [see Warnings and Precautions (5.1)]
•   Hypersensitivity Reactions [see Warnings and Precautions (5.2)] •   Infusion-Related Reactions [see Warnings and Precautions (5.3)] 
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.

In clinical studies, the safety of VYVGART has been evaluated in 246 patients who received at least one dose of VYVGART, including 57 patients exposed to at least 7 treatment cycles and 8 patients exposed to at least 10 treatment cycles.

In a placebo-controlled study (Study 1) in patients with gMG, 84 patients received VYVGART 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 between treatment cycles, specified by study protocol, was 50 days. On average, VYVGART-treated patients received 2 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 VYVGART-treated patients.

Adverse reactions reported in at least 5% of patients treated with VYVGART and more frequently than placebo are summarized in Error! Reference source not found.. The most common adverse reactions (reported in at least 10% of VYVGART-treated patients) were respiratory tract infection, headache, and urinary tract infection.

Table 1: Adverse Reactions in ≥ 5% of Patients Treated with VYVGART and More Frequently than in Placebo-Treated Patients in Study 1 (Safety Population)
Adverse reaction                             VYVGART       Placebo
(N=84)     (N=83)
%           %
Respiratory tract infection                                               33          29 *
Headache                                                                  32          29 
Urinary tract infection                                                       10                       5 Paraesthesia†                                                                  7                       5 Myalgia                                                                        6                       1 *
Headache includes migraine and procedural headache.
†Paraesthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia.


6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of VYVGART. 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)].

6.3 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VYVGART in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In up to 26 weeks of treatment in Study 1, 20% (17/83) of patients developed antibodies to VYVGART. Seven percent (6/83) of patients developed neutralizing antibodies.

Because few patients tested positive for anti-efgartigimod alfa antibodies and neutralizing antibodies, the available data are too limited to make definitive conclusions regarding immunogenicity and the effect on pharmacokinetics, safety, or efficacy of VYVGART.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il

Effects on Driving