4.1. Therapeutic indications

Vyvgart is indicated as an add-on to standard therapy for the treatment of adult patients with generalised Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.

4.2. Posology and method of administration

Efgartigimod alfa must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with neuromuscular disorders.

Posology

The recommended dose is 10 mg/kg as a 1-hour intravenous infusion to be administered in cycles of once weekly infusions for 4 weeks. Subsequent treatment cycles should be administered according to clinical evaluation. The frequency of treatment cycles may vary by patient (see section 5.1).

In the clinical development program, the earliest time to initiate a subsequent treatment cycle was 7 weeks from the initial infusion of the previous cycle. The safety of initiating subsequent cycles sooner than 7 weeks from the start of the previous treatment cycle has not been established.

In patients weighing 120 kg or more, the recommended dose is 1 200 mg (3 vials) per infusion (see section 6.6).

Missed dose

If a scheduled infusion is not possible, treatment may be administered up to 3 days before or after the scheduled time point. Thereafter, the original dosing schedule should be resumed until the treatment cycle is completed. If a dose needs to be delayed for more than 3 days, the dose should not be administered to ensure two consecutive doses are given with an interval of at least 3 days.

Special populations

Elderly

No dose adjustment is required in patients aged 65 years and older (see section 5.2).

Renal impairment

Limited safety and efficacy data in patients with mild renal impairment is available, no dose adjustment is required for patients with mild renal impairment. There is very limited safety and efficacy data in patients with moderate or severe renal impairment (see section 5.2).

Hepatic impairment

No data in patients with hepatic impairment are available. No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of efgartigimod alfa in paediatric population have not yet been established. No data are available.

Method of administration

This medicinal product should only be administered via intravenous infusion. Do not administer as an intravenous push or bolus injection. It should be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration as described in section 6.6.

This medicinal product should be administered over 1 hour. Appropriate treatment for infusion and hypersensitivity-related reactions should be readily available before administration of efgartigimod alfa. In case of infusion reactions, the infusion should be administered at a slower rate, interrupted or can be discontinued (see section 4.4).

Administration

• Inspect the solution visually for particulate matter prior to administration.

• Infuse the total 125 mL of diluted medicinal product over 1 hour using a 0.2 µm filter. Administer the full amount of solution, flushing the entire line with sodium chloride 9 mg/mL (0.9%) solution for injection at the end.

• Vyvgart should be administered immediately after dilution and the infusion of diluted solution should be completed within 4 hours of dilution.

• Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, unless the method of dilution precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Do not freeze. Allow the diluted medicinal product to reach room temperature before administration. Complete the infusion within 4 hours of removal from the refrigerator. The diluted medicinal product should not be heated in any other manner than via ambient air.

• Should infusion reactions occur, the infusion should be administered at a slower rate, interrupted or can be discontinued (see section 4.4).

• Other medicinal products should not be injected into infusion side ports or mixed with Vyvgart.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Myasthenia Gravis Foundation of America (MGFA) Class V patients

Treatment with efgartigimod alfa in patients with MGFA Class V (i.e. myasthenic crisis), defined as intubation with or without mechanical ventilation except in the setting of routine postoperative care, has not been studied. The sequence of therapy initiation between established therapies for MG crisis and efgartigimod alfa, and their potential interactions, should be considered (see section 4.5).

Infections

As efgartigimod alfa causes transient reduction in IgG levels the risk of infections may increase (see sections 4.8 and 5.1). The most common infections observed in clinical trials were upper respiratory tract infections and urinary tract infections (see section 4.8). Patients should be monitored for clinical signs and symptoms of infections during treatment with Vyvgart. In patients with an active infection, the benefit-risk of maintaining or withholding treatment with efgartigimod alfa should be considered until the infection has resolved. If serious infections occur, delaying treatment with efgartigimod alfa should be considered until the infection has resolved.

Infusion reactions and hypersensitivity reactions

Infusion reactions such as rash or pruritus may occur. In the clinical trial, infusion reactions were mild to moderate and did not lead to treatment discontinuation. Patients should be monitored during administration and for 1 hour thereafter for clinical signs and symptoms of infusion reactions. Should a reaction occur and based on severity of the reaction the infusion should be administered at a slower rate, interrupted or discontinued and appropriate supportive measures should be instituted. Once resolved, administration may be cautiously resumed, based on clinical evaluation.

Cases of anaphylactic reaction have been reported in the post marketing setting. If an anaphylactic reaction is suspected, administration of Vyvgart should be immediately discontinued and appropriate medical treatment initiated. Patients should be informed of the signs and symptoms of hypersensitivity and anaphylactic reactions and advised to contact their healthcare provider immediately should they occur.

Immunisations

All vaccines should be administered according to immunisation guidelines.

The safety of immunisation with live or live-attenuated vaccines and the response to immunisation with these vaccines during treatment with efgartigimod alfa are unknown. For patients that are being treated with efgartigimod alfa, vaccination with live or live-attenuated vaccines is generally not recommended. If vaccination with live or live-attenuated vaccines is required, these vaccines should be administered at least 4 weeks before treatment and at least 2 weeks after the last dose of efgartigimod alfa.

Other vaccines may be administered as needed at any time during treatment with efgartigimod alfa.

Immunogenicity

In the double-blind placebo-controlled study, pre-existing antibodies that bind to efgartigimod alfa were detected in 25/165 (15%) patients with gMG. Treatment-induced antibodies to efgartigimod alfa were detected in 17/83 (21%) patients. In 3 of these 17 patients, treatment-induced anti-drug antibodies (ADAs) persisted until the end of the study. Neutralising antibodies were detected in 6/83 (7%) of patients treated with Vyvgart, including the 3 patients with persisting treatment-induced ADAs. Retreatment did not cause an increase in incidence or titres of efgartigimod alfa antibodies.

There was no apparent impact of antibodies to efgartigimod alfa on clinical efficacy or safety, nor on pharmacokinetics and pharmacodynamic parameters.

Immunosuppressant and anticholinesterase therapies

When non-steroidal immunosuppressants, corticosteroids and anticholinesterase therapies are decreased or discontinued, patients should be monitored closely for signs of disease exacerbation.

Sodium content

This medicinal product contains 67.2 mg sodium per vial, equivalent to 3.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This medicinal product will be further prepared for administration with sodium containing solution (see section 6.6) and this should be considered in relation to the total sodium intake to the patient from all sources per day.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Efgartigimod alfa may decrease concentrations of compounds that bind to the human neonatal Fc Receptor (FcRn), i.e., immunoglobulin products, monoclonal antibodies, or antibody derivatives containing the human Fc domain of the IgG subclass. If possible, it is recommended to postpone initiation of treatment with these products to 2 weeks after the last dose of any given treatment cycle of Vyvgart. As a precaution, patients receiving Vyvgart while on treatment with these products should be closely monitored for the intended efficacy response of those products.

Plasma exchange, immunoadsorption, and plasmapheresis may reduce circulating levels of efgartigimod alfa.

All vaccines should be administered according to immunisation guidelines.

The potential interaction with vaccines was studied in a nonclinical model using Keyhole limpet hemocyanin (KLH) as the antigen. The weekly administration of 100 mg/kg to monkeys did not impact the immune response to KLH immunisation. For patients that are being treated with efgartigimod alfa, vaccination with live or live-attenuated vaccines is generally not recommended. If vaccination with live or live-attenuated vaccines is required, these vaccines should be administered at least 4 weeks before treatment and at least 2 weeks after the last dose of efgartigimod alfa (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There is no available data on the use of efgartigimod alfa during pregnancy. Antibodies including therapeutic monoclonal antibodies are known to be actively transported across the placenta (after 30 weeks of gestation) by binding to the FcRn.

Efgartigimod alfa may be transmitted from the mother to the developing foetus. As efgartigimod alfa is expected to reduce maternal antibody levels, and is also expected to inhibit the transfer of maternal antibodies to the foetus, reduction in passive protection to the newborn is anticipated. Therefore, risks and benefits of administering live / live-attenuated vaccines to infants exposed to efgartigimod alfa in utero should be considered (see section 4.4).

Treatment of pregnant women with Vyvgart should only be considered if the clinical benefit outweighs the risks.

Breast-feeding

There is no information regarding the presence of efgartigimod alfa in human milk, the effects on the breastfed child or the effects on milk production. Animal studies on the transfer of efgartigimod alfa into milk have not been conducted, and therefore, excretion into maternal milk cannot be excluded. Maternal IgG is known to be present in human milk. Treatment of lactating women with efgartigimod alfa should only be considered if the clinical benefit outweighs the risks.

Fertility

There is no available data on the effect of efgartigimod alfa on fertility in humans. Animal studies showed no impact of efgartigimod alfa on male and female fertility parameters (see section 5.3).

4.7. Effects on ability to drive and use machines

Vyvgart has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most frequently observed adverse reactions were upper respiratory tract infections and urinary tract infections (10.7% and 9.5%, respectively).

Tabulated list of adverse reactions

The safety of Vyvgart was evaluated in 167 patients with gMG in the Phase 3 double-blind placebo-controlled clinical study.

Adverse reactions are listed in Table 1 by system organ class and preferred term. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100) or rare (≥ 1/10 000 to < 1/1 000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

System organ class

Adverse reaction

Frequency category

Infections and infestations*

Upper respiratory tract infections

Very common

Urinary tract infections

Common

Bronchitis

Common

Immune system disorders

Anaphylactic reactiona

Not known

Gastrointestinal disorders

Nausea a

Common

Musculoskeletal and connective tissue disorders

Myalgia

Common

Injury, poisoning and procedural complications*

Procedural headache

Common

* See paragraph “Description of selected adverse reactions”

a From spontaneous post-marketing reporting

Description of selected adverse reactions

Infections

The most frequently reported adverse reactions were infections, and the most reported infections were upper respiratory tract infections (10.7% [n = 9] of patients treated with efgartigimod alfa and 4.8% [n = 4] of patients treated with placebo) and urinary tract infections (9.5% [n = 8] of patients treated with efgartigimod alfa and 4.8% [n = 4] of patients treated with placebo). These infections were mild to moderate in severity in patients who received efgartigimod alfa (≤ Grade 2 according to the Common Terminology Criteria for Adverse Events). Overall, treatment emergent infections were reported in 46.4% (n = 39) of patients treated with efgartigimod alfa and 37.3% (n = 31) of patients treated with placebo. The median time from treatment initiation to emergence of infections was 6 weeks. Incidence of infections did not increase with subsequent treatment cycles. Treatment discontinuation or temporary interruption of treatment due to an infection occurred in less than 2% of patients.

Procedural headache

Procedural headache was reported in 4.8% of the patients treated with efgartigimod alfa and 1.2% of patients treated with placebo. Procedural headache was reported when a headache was judged to be temporally related to the intravenous infusion of efgartigimod alfa. All were mild or moderate except one event which was reported as severe (Grade 3).

All other adverse reactions were mild or moderate with the exception of one case of myalgia (Grade 3).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MRHA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are no known specific signs and symptoms of overdose with efgartigimod alfa. In the event of an overdose the adverse events that may occur are not expected to be different from those that may be observed at the recommended dose. Patients should be monitored for adverse reactions, and appropriate symptomatic and supportive treatment initiated. There is no specific antidote for overdose with efgartigimod alfa.