IMAAVY Concentrate for solution for infusion Ref.[116055] Active ingredients: Nipocalimab

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 nipocalimab 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 nipocalimab, and their potential interactions, should be considered (see section 4.5).

Infusion-related and hypersensitivity reactions

Administration of nipocalimab may result in infusion-related and hypersensitivity reactions. The most commonly reported infusion-related reactions were headache, rash, nausea, fatigue, dizziness, chills, and erythema. The most commonly reported hypersensitivity reactions were rash, urticaria and eczema. Most infusion-related and hypersensitivity reactions were non-serious, mild or moderate and did not lead to treatment discontinuation. A case of anaphylaxis has been reported that led to the discontinuation of treatment.

The patient should be monitored for 30 minutes after each infusion for clinical signs and symptoms of infusion-related or hypersensitivity reactions. If a serious infusion-related or hypersensitivity reaction occurs during administration, the infusion should be discontinued and appropriate supportive measures should be instituted, if needed. Once resolved, administration may be resumed (see section 4.2).

Increased plasma lipid levels

Increased plasma lipid levels are very common during treatment with Imaavy, both in adolescent and adult patients of all ages (see section 4.8). Plasma lipid levels should therefore be measured approximately 12 weeks following treatment initiation. In adolescents (12 to <18 years) and in patients with high body weight/BMI (e.g. ≥125 kg or BMI >35 kg/m²), consider closer periodic monitoring thereafter. The evaluation whether to continue treatment with Imaavy should consider the potential negative impact on long-term cardiovascular risk, considering also other risk factors, and weigh this against the expected gMG treatment benefit. Continued monitoring of plasma lipid levels and alternative treatment options should be considered.

Infections

As nipocalimab causes reduction in IgG levels, the risk of infections, including the activation of latent viral infections such as herpes zoster, may increase (see section 4.8). Initiation of treatment administration should be delayed in patients with an active infection until the infection is resolved. During treatment, patients should be monitored for clinical signs and symptoms of infection. In patients with a clinically important active infection, appropriate treatment should be administered and nipocalimab treatment should be withheld until the infection has resolved.

Immunisations

The safety of immunisation with live or live-attenuated vaccines and the response to immunisation with these vaccines during treatment are unknown.

For patients that are being treated with nipocalimab, vaccination with live or live-attenuated vaccines is 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 nipocalimab.

Non-live vaccines may be administered as needed at any time during treatment (see sections 4.5 and 5.1). All vaccines should be administered according to immunisation guidelines.

Excipient with known effect

This medicinal product contains 0.97 mg (300 mg vial) or 3.9 mg (1200 mg vial) of polysorbate 80 in each single-use vial which is equivalent to 0.60 mg/mL. Polysorbates may cause allergic reactions.

Effects of nipocalimab on other medicinal products

Concomitant use of nipocalimab is likely to reduce systemic exposure of medicinal products that bind to the immunoglobulin G (IgG) binding site of the human neonatal Fc receptor (FcRn) (e.g., IgG products, IgG-based monoclonal antibodies, antibody derivates containing the human Fc domain of the IgG subclass, or Fc fusion proteins).

In a dedicated clinical interaction study in healthy participants, nipocalimab (single dose 30 mg/kg intravenously) reduced the systemic C_max and AUC of fremanezumab (a full IgG-based monoclonal antibody), co-administered on the same day, by 42% and 66%, respectively. When, in this study, the same dose of nipocalimab was administered 14 days after the fremanezumab dose, C_max of fremanezumab was not altered while its AUC was reduced by 53%.

In another dedicated clinical interaction study in healthy participants, concomitant dosing of nipocalimab (15 mg/kg intravenously every 2 weeks) and etanercept, an Fc-fusion protein, reduced etanercept systemic exposure (C_max by ~9% and AUC by ~28%).

If patients on nipocalimab need treatment with medicinal products that bind to the IgG binding site of FcRn, it is recommended these medicinal products are started 2 weeks after the previous dose of nipocalimab.

When concomitant long-term use of such medicinal products is essential for patient care, closely monitor for reduced effectiveness of such medicinal products and consider discontinuing nipocalimab or using alternative therapies.

Effects of other medicinal products on nipocalimab

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

Vaccines

The impact of nipocalimab on a T-cell dependent (Tdap) or a T-cell independent (PPSV23) vaccine response was assessed in healthy volunteers (n=16). Participants were able to mount a specific IgG response to these vaccines, but vaccine-specific IgG antibody levels were reduced during nipocalimab treatment with recovery to levels similar to the control group after treatment cessation (see sections 4.4 and 5.1).

For patients that are being treated with nipocalimab, vaccination with live or live-attenuated vaccines is 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 nipocalimab (see section 4.4).

Paediatric population

Paediatric patients 12 years and older with gMG

The same interactions as observed in the adult population may occur in adolescent patients aged 12 years and older.

Pregnancy

There are limited amount of data from the use of nipocalimab in pregnant women. There is no available data with nipocalimab use in pregnant women with gMG, and limited data from an open-label Phase 2 clinical study in 13 pregnant women at high-risk for Haemolytic Disease of the Foetus and Newborn, in which nipocalimab was studied in the second and third trimesters of pregnancy. In this study, maternal administration of nipocalimab did not result in pharmacologically active concentrations in neonates or infants, due to nipocalimab's high affinity at neutral (extracellular) pH (see section 5.1).

In an animal study where pregnant cynomolgus monkeys were dosed with nipocalimab during the late first, second and third trimesters of pregnancy, large, central placental infarctions and thrombosis of maternal spiral arteries were observed. In some cases, the findings were associated with foetal loss. However, this study does not indicate maternal toxicity or direct or indirect harmful effects on pre- or postnatal development. Reversible nipocalimab-induced reductions in infant monkey IgG levels were demonstrated (see section 5.3).

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

As nipocalimab is expected to reduce maternal IgG antibody levels, reduction in passive protection to the newborn is anticipated. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to nipocalimab in utero.

Breast-feeding

There are limited data showing that nipocalimab administered during pregnancy is excreted in colostrum and human milk at low levels for up to 8 days post-partum.

Maternal IgG is known to be present in breastmilk during the first days after birth, which decreases to low levels soon thereafter: consequently, a risk to breast-fed infants cannot be excluded during this short period. Afterwards, treatment of breast-feeding women with Imaavy could be considered if the clinical benefit outweighs the risks.

Fertility

There are no data on the effects of nipocalimab on fertility in humans. Animal studies do not indicate harmful effects with respect to fertility (see section 5.3).

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

Summary of the safety profile

The most commonly reported adverse reactions were muscle spasms (12%) and peripheral oedema (12%).

Tabulated list of adverse reactions

A total of 250 adult gMG patients were treated with nipocalimab in Phase 2 and Phase 3 studies. Of these, 205 patients were treated in the Phase 3 study, including 98 in the double-blind phase. In total, 178 were exposed to the recommended maintenance dose (15 mg/kg every 2 weeks, see section 4.2) for at least 6 months, and 132 were exposed for at least 12 months.

Adverse reactions are listed in Table 2 below, classified by MedDRA System Organ Class (SOC). Within each SOC, the adverse reactions are ranked by frequency, with the most frequent reactions first.

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 2. Adverse reactions:

^* See paragraph Description of selected adverse reactions
¹ Includes Herpes zoster and Herpes zoster oticus; evaluation and frequency based on completed placebo-controlled Phase 2 and Phase 3 studies across several indications under study
² Includes pneumonia and bronchitis
³ Includes hypercholesterolaemia, low density lipoproteins increased, blood cholesterol increased and hyperlipidaemia.
⁴ Includes abdominal pain and abdominal pain upper
⁵ Includes peripheral oedema, oedema, and peripheral swelling

Description of selected adverse reactions

Infections

In the Phase 3 double-blind placebo-controlled clinical study in gMG, the overall rate of infections was the same between patients in the nipocalimab group and patients in the placebo group (42 [42.9%] in each group). Most cases were mild to moderate in severity and did not lead to discontinuation of nipocalimab treatment. Urinary tract infection was reported in 5 patients (5.1%) in the nipocalimab group compared to 0 patients (0%) in the placebo group. The events of urinary tract infection were mild (3 [3.1%]) and moderate (2 [2.0%]) in severity. Pneumonia or bronchitis was reported in 5 patients (5.1%) in the nipocalimab group compared to 2 patients (2.0%) in the placebo group.

Lipids increased

In adult and adolescent patients with gMG who received nipocalimab, increases in lipids were observed in most patients. In adults, 30% had treatment-emergent markedly abnormal total cholesterol (≥6.2 mmol/L), compared to 4% in the placebo group. The mean change from baseline for fasting total cholesterol, HDL, and LDL peaked at Week 4, then decreased and plateaued by Week 24 to a mean increase of 0.37 mmol/L, 0.12 mmol/L, and 0.19 mmol/L, respectively. Of the patients with LDL values <4.1 mmol/L prior to starting treatment, 11.3% of patients treated with nipocalimab had LDL values ≥4.1 mmol/L at Week 24 relative to 4.6% of patients on placebo. See section 4.4.

Decreased serum albumin levels

In the Phase 3 double-blind placebo-controlled clinical study in gMG, the mean (SD) percent change from baseline in serum albumin levels during the double-blind phase was -8.4% (5.27%) at Week 2 and -7.2% (5.37%) at Week 24 in patients treated with nipocalimab relative to -0.5% (6.29%) at Week 2 and -2.1% (7.08%) at Week 24 in patients on placebo. No patients had serum albumin levels below the laboratory lower limit of normal (LLN=33 g/L) in the double-blind phase or markedly low serum albumin levels (≤20 g/L) in the double-blind or open-label phase.

Paediatric population

The safety of nipocalimab was assessed in an open-label study including adolescent gMG patients aged 12 years and older (n=8) for up to 24 weeks (see section 5.1). No major differences in the safety profile were identified between adult and adolescent patients. Increased lipid levels in adolescents followed a similar trend to that observed in adults.

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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.