Highlights

Indications and usage

Rozanolixizumab-noli is indicated for the treatment of generalized myasthenia gravis in adult patients who are AChR or MuSK antibody positive.

Dosage and administration

Recommended vaccination

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

Recommended dosage

The recommended dosage of rozanolixizumab-noli is based on body weight, as shown in Table 1.

Table 1. Recommended Dose Based on Body Weight

Administer the recommended dosage as a subcutaneous infusion using an infusion pump at a rate of up to 20 mL/hour once weekly for 6 weeks. For detailed preparation and administration instructions, see Preparation and administration instructions.

Administer subsequent treatment cycles based on clinical evaluation. The safety of initiating subsequent cycles sooner than 63 days from the start of the previous treatment cycle has not been established.

If a scheduled dose is missed, rozanolixizumab-noli may be administered up to 4 days after the scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is completed.

Preparation and administration instructions

Rozanolixizumab-noli should only be prepared and infused by a healthcare provider.

Rozanolixizumab-noli is for subcutaneous administration only using an infusion pump. Refer to the infusion pump manufacturer's instructions for full preparation and administration information. It is recommended to use pumps where the administered volume can be pre-set, as each vial contains excess volume for priming the infusion line.

The following criteria are recommended for the administration of rozanolixizumab-noli:

Read the instructions below before preparing and administering rozanolixizumab-noli solution.

Dosage forms and strength

Rozanolixizumab-noli is a clear to slightly opalescent, colorless to pale brownish yellow solution available as:

Contraindications

None.

Warnings and precautions

Infections

Rozanolixizumab-noli may increase the risk of infection. Delay rozanolixizumab-noli administration in patients with an active infection until the infection is resolved. During treatment with rozanolixizumab-noli, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding rozanolixizumab-noli until the infection has resolved.

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

Aseptic meningitis

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

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema and rash, were observed in patients treated with rozanolixizumab-noli. Management of hypersensitivity reactions depends on the type and severity of the reaction. Monitor patients during treatment with rozanolixizumab-noli and for 15 minutes after the administration is complete 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.

Adverse reactions

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

Clinical trial 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 rozanolixizumab-noli has been evaluated in 196 patients who received at least one dose of rozanolixizumab-noli, including 88 patients exposed to at least five treatment cycles and nine patients exposed to at least 10 treatment cycles.

In a placebo-controlled study (Study 1) in patients with generalized myasthenia gravis, 133 patients received rozanolixizumab-noli. 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 rozanolixizumab-noli received one 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 rozanolixizumab-noli on average initiated four cycles in 1 year (range one to seven cycles). The median time between start of treatment cycles was 98 days for patients treated with rozanolixizumab-noli who initiated four cycles.

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

Table 2. Adverse Reactions in at least 5% of Patients Treated with Rozanolixizumab-noli 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 rozanolixizumab-noli, 94 (48%) patients reported infections. Common infections (occurring at a frequency of at least 5%) 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 rozanolixizumab-noli. Three fatal cases of identified pneumonia were caused by COVID-19 infection in two patients and an unknown pathogen in one patient. Six cases of infections led to the discontinuation of rozanolixizumab-noli.

Aseptic meningitis. In clinical trials, one patient with generalized myasthenia gravis and two patients with another neurologic disease experienced a serious adverse reaction of drug-induced aseptic meningitis, which led to hospitalization and discontinuation of rozanolixizumab-noli.

Hypersensitivity reactions and administration site reactions. In clinical trials, hypersensitivity reactions occurred within 1 day to 2 weeks of administration. One patient discontinued rozanolixizumab-noli due to a hypersensitivity reaction.

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

Headache. In Study 1, seven (5.3%) cases of severe headache were reported in patients treated with rozanolixizumab-noli. 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.

Drug interactions

Effect of rozanolixizumab-noli on other drugs

Concomitant use of rozanolixizumab-noli with medications that bind to the human neonatal Fc receptor (FcRn) (eg, immunoglobulin products, monoclonal antibodies, or antibody derivatives containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce the 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 rozanolixizumab-noli and using alternative therapies.

Use in specific populations

Pregnancy

Risk summary. There are limited data on rozanolixizumab-noli 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.

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.

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.

Lactation

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 rozanolixizumab-noli and any potential adverse effects on the breastfed child from rozanolixizumab-noli or from the underlying maternal condition.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

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

Clinical pharmacology

Mechanism of action

Rozanolixizumab-noli is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.

Pharmacodynamics

In Study 1, the pharmacological effect of rozanolixizumab-noli was assessed by measuring the decrease in serum IgG levels and AChR and MuSK autoantibody levels. In patients testing positive for AChR and MuSK autoantibodies who were treated with rozanolixizumab-noli, there was a reduction in total IgG levels relative to baseline. Decreases in AChR autoantibody and MuSK autoantibody levels followed a similar pattern.

Pharmacokinetics

Rozanolixizumab-noli exhibited nonlinear pharmacokinetics. Rozanolixizumab-noli exposure increased in a greater than dose-proportional manner over a dose range from 1 mg/kg to 20 mg/kg (two times the maximum recommended dose) following subcutaneous administration.

Absorption. Following subcutaneous administration of rozanolixizumab-noli, peak plasma levels were achieved after approximately 2 days in healthy subjects.

Distribution. The apparent volume of distribution of rozanolixizumab-noli is 6.6 L.

Elimination.

Metabolism. Rozanolixizumab-noli is expected to be degraded by proteolytic enzymes into small peptides and amino acids.

Excretion. The apparent clearance for the rozanolixizumab-noli is 0.89 L/day.

Specific populations

Age, sex, and race. The pharmacokinetics of rozanolixizumab-noli were not affected by age, sex, or race based on a population pharmacokinetics analysis.

Patients with renal impairment. No dedicated pharmacokinetic study has been conducted in patients with renal impairment. Renal impairment is not expected to affect the pharmacokinetics of rozanolixizumab-noli. Based on a population pharmacokinetic analysis, which included participants with mild to moderate renal impairment, renal function (estimated glomerular filtration rate [eGFR] 38–161 mL/min/1.73 m2) had no clinically significant effect on rozanolixizumab-noli’s apparent clearance. No dose adjustment is required in patients with renal impairment.

Patients with hepatic impairment. No dedicated pharmacokinetic study has been conducted in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of rozanolixizumab-noli.

Drug interaction studies

Clinical drug interaction studies have not been performed with rozanolixizumab-noli.

P450 enzymes. Rozanolixizumab-noli is not metabolized by cytochrome P450 enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

Drug interactions with other drugs or biological products. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.

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 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 the efficacy of rozanolixizumab-noli. The safety profile appears to be similar in ADA-positive and ADA-negative patients.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis and mutagenesis. Studies to assess the carcinogenic potential of rozanolixizumab-noli have not been conducted.

Studies to assess the genotoxic potential of rozanolixizumab-noli have not been conducted.

Impairment of fertility. Subcutaneous administration of rozanolixizumab-noli (0 or 150 mg/kg) every 3 days for 26 weeks to sexually mature cynomolgus monkeys resulted in no adverse effects on sperm parameters (count, motility, or morphology) or estrus cyclicity. The dose tested in monkeys is 30 times the maximum recommended human dose of approximately 10 mg/kg, on a mg/kg/week basis.

Clinical studies

The efficacy of rozanolixizumab-noli for the treatment of generalized myasthenia gravis in adults who are anti-AChR antibody positive or anti-MuSK antibody positive was established in a multicenter, randomized, double-blind, placebo-controlled study (Study 1; NCT03971422). The study included a 4-week screening period and a 6-week treatment period followed by 8 weeks of observation. During the treatment period, rozanolixizumab-noli or placebo was administered subcutaneously once a week for 6 weeks.

Study 1 enrolled patients who met the following criteria:

In Study 1, a total of 200 patients were randomized 1:1:1 to receive weight-tiered doses of rozanolixizumab-noli (n=133), equivalent to approximately 7 mg/kg (n=66) or 10 mg/kg (n=67), or placebo (n=67). Baseline characteristics were similar between treatment groups. Patients had a median age of 52 years at baseline (range: 18 to 89 years) and a median time since diagnosis of 6 years. Sixty-one percent of patients were female, 68% were White, 11% were Asian, 3% were Black or African American, 1% were American Indian or Alaska Native, and 7% were of Hispanic or Latino ethnicity. Median MG-ADL total score was 8, and the median Quantitative Myasthenia Gravis (QMG) total score was 15. Most patients (89.5%, n=179) were positive for AChR antibodies, and 10.5% (n=21) were positive for MuSK antibodies.

At baseline in each group, over 83% of patients received AChE inhibitors, over 56% received steroids, and approximately 50% received NSISTs at stable doses.

Patients were treated with rozanolixizumab-noli via subcutaneous infusion once per week for a period of 6 weeks, followed by an observation period of up to 8 weeks.

The efficacy of rozanolixizumab-noli was measured using the MG-ADL scale, which assesses the impact of generalized myasthenia gravis on daily functions of eight signs or symptoms that are typically affected in generalized myasthenia gravis. 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.

The primary efficacy endpoint was the comparison of the change from baseline between treatment groups in the MG-ADL total score at day 43. A statistically significant difference favoring rozanolixizumab-noli was observed in the MG-ADL total score change from baseline (-3.4 points in rozanolixizumab-noli-treated group at either dose vs -0.8 points in the placebo-treated group [p<0.001]).

The secondary endpoint was the change between treatment groups from baseline to day 43 in the QMG. The QMG 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.

A statistically significant difference favoring rozanolixizumab-noli was observed in the QMG total score change from baseline (-5.4 points and -6.7 points in rozanolixizumab-noli-treated group at approximately 7 mg/kg and 10 mg/kg dose level, respectively, versus -1.9 points in the placebo-treated group [p<0.001]).

For the detailed results, see the Clinical Studies section of the DAILYMED drug label information.

How supplied/storage and handling

How supplied

Rozanolixizumab-noli injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish yellow solution supplied as:

Storage and handling

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

If needed, vials may be stored at room temperature up to 77°F (25°C) for a single period of up to 20 days in the original carton to protect the vial from light. Once a vial has been stored at room temperature, it should not be returned to the refrigerator. The discard date is 20 days after removal of the vial from the refrigerator. Write the discard date in the space provided on the carton. Discard the vial if not used within 20 days or if the expiration date has passed, whichever occurs first.

Patient counseling information

Infections

Instruct patients to report any history of infections to their healthcare provider and to contact their healthcare provider if they develop any symptoms of an infection.

Vaccinations

Advise patients to complete age-appropriate vaccines according to immunization guidelines before initiation of a new treatment cycle with rozanolixizumab-noli. Administration of live or live-attenuated vaccines is not recommended during treatment with rozanolixizumab-noli.

Aseptic meningitis

Inform patients that rozanolixizumab-noli could cause aseptic meningitis. Instruct patients to contact their healthcare provider if symptoms consistent with meningitis develop.

Hypersensitivity reactions

Inform patients about the signs and symptoms of hypersensitivity reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of hypersensitivity reactions.