RYSTIGGO Solution for injection Ref.[107277] Active ingredients: Rozanolixizumab

5.1 Infections

RYSTIGGO may increase the risk of infection [see Adverse Reactions (6.1)]. Delay RYSTIGGO administration in patients with an active infection until the infection is resolved. During treatment with RYSTIGGO, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding RYSTIGGO until the infection has resolved.

Immunization

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

5.2 Aseptic Meningitis

Serious adverse reactions of aseptic meningitis (also called drug-induced aseptic meningitis) have been reported in patients treated with RYSTIGGO [see Adverse Reactions (6.1)]. If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and rash, were observed in patients treated with RYSTIGGO [see Adverse Reactions (6.1)]. Management of hypersensitivity reactions depend on the type and severity of the reaction. Monitor patients during treatment with RYSTIGGO and for 15 minutes after the administration is complete for clinical signs and symptoms of hypersensitivity reactions [see Dosage and Administration (2.3)]. If a hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures if needed or the patient should seek medical attention.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Infections [see Warnings and Precautions (5.1)]
• Aseptic Meningitis [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]

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 RYSTIGGO has been evaluated in 196 patients who received at least one dose of RYSTIGGO, including 88 patients exposed to at least 5 treatment cycles and 9 patients exposed to at least 10 treatment cycles.

In a placebo-controlled study (Study 1) in patients with gMG, 133 patients received RYSTIGGO [see Clinical Studies (14)]. Of these 133 patients, approximately 56% were female, 68% were White, 12% were Asian, and 6% were of Hispanic or Latino ethnicity. The mean age at study entry was 52.5 years (range 19 to 89 years).

Patients treated with RYSTIGGO received 1 treatment cycle in Study 1. In an extension study, the minimum time for initiating subsequent treatment cycles, specified by study protocol, was 63 days from the start of the previous treatment cycle. Patients treated with RYSTIGGO on average initiated 4 cycles in one year (range 1 to 7 cycles). The median time between start of treatment cycles was 98 days for patients treated with RYSTIGGO who initiated 4 cycles.

Adverse reactions reported in at least 5% of patients treated with RYSTIGGO and more frequently than placebo are summarized in Table 2. The most common adverse reactions (reported in at least 10% of patients treated with RYSTIGGO) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea.

Table 2. Adverse Reactions in at least 5% of Patients Treated with RYSTIGGO and More Frequently than in Patients who Received Placebo in Study 1 (Safety Population):

Infections

In Study 1 and the extension studies, out of 196 patients treated with RYSTIGGO, 94 (48%) patients reported infections. Common infections (at least 5% frequency) were upper respiratory tract infections (17%), COVID-19 (14%), urinary tract infections (9%), and herpes simplex (6%). Serious infections were reported in 4% of patients treated with RYSTIGGO. Three fatal cases of pneumonia were identified caused by COVID-19 infection in two patients and an unknown pathogen in one patient. Six cases of infections led to discontinuation of RYSTIGGO [see Warnings and Precautions (5.1)].

Aseptic Meningitis

In clinical trials, one patient with gMG and two patients with another neurological disease experienced a serious adverse reaction of drug-induced aseptic meningitis, which led to hospitalization and discontinuation of RYSTIGGO [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions and Administration Site Reactions

In clinical trials, hypersensitivity reactions occurred within 1 day to 2 weeks of administration. One patient discontinued RYSTIGGO due to a hypersensitivity reaction [see Warnings and Precautions (5.3)].

Local reactions at the administration site occurred within 1 to 3 days after the most recent RYSTIGGO infusion.

Headache

In Study 1, seven (5.3%) cases of severe headache were reported in patients treated with RYSTIGGO. None of the patients who received placebo reported severe headache. One patient was hospitalized due to severe headache and one patient discontinued treatment due to severe headache associated with fever, photophobia, phonophobia, nausea, and vertigo.

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 rozanolixizumab-noli or of other rozanolixizumab products.

The anti-drug antibody (ADA) incidence from Study 1 (MG0003) was 37% (49/133) at the end of the observation period after one treatment cycle of 6-week dosing. The incidence of neutralizing antibodies was 21% (28/133). For patients who developed ADA, there was up to 60% decrease in trough concentrations compared with those in ADA negative patients. However, these observations need to be interpreted with caution because of the limitations with PK analytical assay sensitivity. There appears to be no clinically meaningful impact of ADA (including neutralizing antibodies) on efficacy of rozanolixizumab-noli. The safety profile appears to be similar in ADA positive and ADA negative patients.

7.1 Effect of RYSTIGGO on Other Drugs

Concomitant use of RYSTIGGO with medications that bind to the human neonatal Fc receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivatives 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 RYSTIGGO and using alternative therapies.

Risk Summary

There are limited data on RYSTIGGO use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Following administration of rozanolixizumab-noli to pregnant monkeys at doses greater than those used clinically, increases in embryonic death, reduced body weight, and impaired immune function were observed in the absence of maternal toxicity (see Data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Subcutaneous administration of rozanolixizumab-noli (0, 50, or 150 mg/kg) to pregnant monkeys every 3 days throughout pregnancy (gestation day 20 to parturition) resulted in an increase in embryonic death and reduced body weight and impaired immune function in offspring at both doses. A no-effect dose for adverse developmental effects was not identified; the doses tested in monkeys are 10 and 30 times the maximum recommended human dose of approximately 10 mg/kg, on a mg/kg/week basis.

Risk Summary

There are no data on the presence of rozanolixizumab-noli 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 RYSTIGGO and any potential adverse effects on the breastfed child from RYSTIGGO or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of RYSTIGGO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients.