ENSPRYNG 120mg injection solution in pre-filled syringe medication leaflet

Enspryng 120 mg solution for injection in pre-filled syringe

Each pre-filled syringe (PFS) contains 120 mg of satralizumab in 1 mL.

Satralizumab is produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Colourless to slightly yellow liquid. The solution has a pH of approximately 6.0 and an osmolality ofapproximately 310 mOsm/kg.

Enspryng is indicated as a monotherapy or in combination with immunosuppressive therapy (IST) forthe treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult and adolescent patientsfrom 12 years of age who are anti-aquaporin-4 IgG (AQP4-IgG) seropositive (see section 5.1).

Treatment should be initiated under the supervision of a physician experienced in the treatment ofneuromyelitis optica (NMO) or NMOSD.

Enspryng can be used as a monotherapy or in combination with oral corticosteroids (OCs),azathioprine (AZA) or mycophenolate mofetil (MMF) (see section 5.1). The posology in adolescentpatients ≥12 years of age with body weight ≥ 40 kg and adult patients is the same.

Loading doses

The recommended loading dose is 120 mg subcutaneous (SC) injection every two weeks for the firstthree administrations (first dose at week 0, second dose at week 2 and third dose at week 4).

Maintenance doses

The recommended maintenance dose is 120 mg SC injection every four weeks.

Enspryng is intended for long-term treatment.

If an injection is missed, for any reason other than increases in liver enzymes, it should beadministered as described in table 1.

Table 1: Recommended dosage for delayed or missed doses

Last dose administered Recommended dosage for delayed or missed doses

Missed a loading dose or less The recommended dose should be administered as soon asthan 8 weeks during the possible without waiting until the next planned dose.maintenance period

Loading period

If the second loading dose is delayed or missed, this dose shouldbe administered as soon as possible and the third and finalloading dose 2 weeks later.

If the third loading dose is delayed or missed, this dose should beadministered as soon as possible and the first maintenance dose 4weeks later.

Maintenance period

After the delayed or missed dose is administered, the dosingschedule should be reset to every 4 weeks.

8 weeks to less than 12 weeks The recommended dose should be administered at 0*, 2 weeksand every 4 weeks thereafter.

12 weeks or longer The recommended dose should be administered at 0*, 2, 4 weeksand every 4 weeks thereafter.

* “0 weeks” refers to time of the first administration after the missed dose.

Dose modification advice for liver enzyme abnormalities

If the alanine aminotransferase (ALT) or aspartate transaminase (AST) elevation is >5 x upper limit ofnormal (ULN) and associated with any bilirubin elevation, treatment must be discontinued, andreinitiation is not recommended.

If the ALT or AST elevation is >5 x ULN and not associated with any bilirubin elevation, treatmentshould be discontinued. Treatment can be restarted at a dose of 120 mg SC injection every four weekswhen the ALT and AST levels have returned to the normal range and based on assessment of benefit-risk of treatment in the patient. If the decision is taken to restart treatment, liver parameters must beclosely monitored, and if any subsequent increase in ALT/AST and/or bilirubin is observed, treatmentmust be discontinued, and reinitiation is not recommended (see sections 4.4 and 4.8).

Table 2: Recommended dose for restart of treatment after liver transaminase elevation

Last dose administered Recommended dose for restart of treatment

Less than 12 weeks Treatment should be restarted using the recommended dose, given every4 weeks.

12 weeks or longer Treatment should be restarted using the recommended dose, given atweeks 0*, 2, 4 and every 4 weeks thereafter.

* “0 weeks” refers to time of the first administration after the restart of treatment.

Dose modification advice for neutropenia

If the neutrophil count is below 1.0 x 109/L and confirmed by repeat testing, treatment should beinterrupted until the neutrophil count is >1.0 x 109/L.

Dose modification advice for low platelet count

If the platelet count is below 75 x 109/L and confirmed by repeat testing, treatment should beinterrupted until the platelet count is ≥75 x 109/L.

The posology in adolescent patients ≥12 years of age with body weight ≥ 40 kg and adult patients isthe same (see sections 5.1 and 5.2). The safety and efficacy of satralizumab in children with bodyweight < 40 kg have not yet been established. No data are available.

No dose adjustment is required in patients ≥65 years of age (see section 5.2).

The safety and efficacy of satralizumab have not been formally studied in patients with renalimpairment. No dose adjustment is recommended for patients with mild renal impairment (see section5.2).

The safety and efficacy of satralizumab have not been studied in patients with hepatic impairment. Nodata are available (see section 5.2).

Elevations of liver enzymes have been observed during treatment with satralizumab (see sections 4.4and 4.8). For dose adjustment, see above section Dose modification advice for liver enzymeabnormalities.

Satralizumab 120 mg is administered by SC injection using a single-dose PFS. The total content(1 mL) of the PFS should be administered.

The recommended injection sites are the abdomen and thigh. Injection sites should be rotated andinjections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard,or not intact.

Comprehensive instructions for the administration of satralizumab are given at the end of the packageleaflet.

Administration by the patient and/or caregiver

The first injection must be performed under the supervision of a qualified Healthcare Professional(HCP).

After adequate training on how to prepare and perform the injection, an adult patient/caregiver mayadminister all other doses at home if the treating physician determines that it is appropriate and theadult patient/caregiver can perform the injection technique.

Patients/caregivers should seek immediate medical attention if the patient develops symptoms ofserious allergic reactions and should check with their HCP to confirm whether treatment can becontinued or not.

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

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

Administration of satralizumab should be delayed in patients with an active infection until theinfection is controlled (see section 4.2).

Vigilance for the timely detection and diagnosis of infection is recommended for patients receivingtreatment with satralizumab. Treatment should be delayed in case the patient develops any serious oropportunistic infection and appropriate therapy should be initiated under further monitoring. Patientsshould be instructed on seeking early medical attention in case of signs and symptoms of infections tofacilitate timely diagnosis of infections. Patients should be provided with a patient alert card.

Live and live-attenuated vaccines should not be given concurrently with satralizumab as clinical safetyhas not been established. The interval between live vaccinations and initiation of satralizumabtreatment should be in accordance with current vaccination guidelines regarding immunomodulatoryor immunosuppressive agents.

No data are available on the effects of vaccination in patients receiving satralizumab. It isrecommended that all patients be brought up to date with all immunisations in agreement with currentimmunisation guidelines prior to initiating satralizumab treatment.

Mild and moderate elevations of liver transaminases have been observed with satralizumab treatment,most elevations were below 5 x ULN (see section 4.8).

ALT and AST levels should be monitored every four weeks for the first three months of treatment,followed by every three months for one year, thereafter as clinically indicated.

Treatment with satralizumab should be discontinued in patients with ALT or AST >5 x ULN (seesection 4.2).

Neutrophil count

Decreases in neutrophil counts have occurred following treatment with satralizumab (see section 4.8).

Neutrophil counts should be monitored 4 to 8 weeks after start of treatment and thereafter as clinicallyindicated. For recommended dose interruption see section 4.2.

No interaction studies have been performed.

Population pharmacokinetic (PK) analyses did not detect any effect of azathioprine (AZA), oralcorticosteroids (OCs) or mycophenolate mofetil (MMF) on the clearance of satralizumab.

Both in vitro and in vivo studies have shown that the expression of specific hepatic CYP450 enzymes(CYP1A2, CYP2C9, CYP2C19, and CYP3A4) is suppressed by cytokines such as IL-6.

Therefore caution should be exercised when starting or discontinuing satralizumab treatment inpatients also receiving substrates of CYP450 3A4, 1A2, 2C9 or 2C19, particularly those with a narrowtherapeutic index (such as warfarin, carbamazepine, phenytoin and theophylline), and doses adjusted ifneeded.

Given the prolonged terminal half-life of satralizumab, the effect of satralizumab may persist forseveral weeks after stopping treatment.

There are no data from the use of satralizumab in pregnant women. Studies in monkeys do not indicateharmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Enspryng during pregnancy.

It is unknown whether satralizumab is excreted in human breast milk. Human IgG is known to beexcreted in breast milk during the first days after birth, which is decreasing to low concentrations soonafterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period.

Afterwards, use of Enspryng could be considered during breast-feeding only if clinically needed.

No clinical data are available on the effect of satralizumab on human fertility. Animal studies showedno impairment of male or female fertility (see section 5.3).

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

The most frequently reported adverse reactions observed were: headache (19.2%), arthralgia (13.5%),white blood cell count decreased (13.5%), hyperlipidaemia (13.5%), and injection-related reactions(12.5%).

Table 3 summarises the adverse reactions that have been reported in association with the use ofsatralizumab as a monotherapy or in combination with IST in clinical trials.

Adverse reactions from clinical trials (Table 3) are listed by MedDRA system organ class. Adversereactions are presented using number of adverse events per 100 patient years and by frequency figures.

The corresponding frequency category for each adverse reaction is based on frequency figures and thefollowing convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 3: Adverse reactions

System Organ Class Frequency

Very common Common

Blood and lymphatic system disorders Hypofibrinogenaemia

Metabolism and nutrition disorders Hyperlipidaemia

Psychiatric disorders Insomnia

Nervous system disorders Headache Migraine

Cardiac disorders Bradycardia

Vascular disorders Hypertension

Respiratory, thoracic and mediastinal Allergic rhinitisdisorders

Gastrointestinal disorders Gastritis

Skin and subcutaneous tissue disorders Rash,pruritus

Musculoskeletal and connective tissue Arthralgia Musculoskeletal stiffnessdisorders

General disorders and administration site Injection-related reactions Peripheral oedemaconditions

Investigations White blood cell count Neutrophil countdecreased decreasedplatelet count decreased,transaminases increased,blood bilirubin increased,weight increased

Injection-related reactions (IRRs)

IRRs reported in patients treated with satralizumab were predominantly mild to moderate, and mostoccurred within 24 hours after injections. The most commonly reported systemic symptoms werediarrhoea and headache. The most commonly reported local injection site reactions were flushing,erythema, pruritus, rash and pain.

In the double-blinded treatment period, body weight increase ≥15% from baseline were observed in3.8% of patients treated with satralizumab (monotherapy or in combination with IST) as comparedwith 2.7% of patients receiving placebo (or plus IST).

In the double-blinded treatment period, decreased neutrophils were observed in 31.7% of patientstreated with satralizumab (monotherapy or in combination with IST) as compared with 21.6% ofpatients receiving placebo (or placebo plus IST). The majority of neutrophil decreases were transientor intermittent.

9.6% of patients receiving satralizumab had neutrophils below 1 x 109/L, compared with 5.4%receiving placebo (or placebo plus IST).

Platelets

In the double-blinded treatment period, decreases in platelet count (below 150 × 109/l) occurred in24.0% of patients on satralizumab (monotherapy or in combination with IST) as compared with 9.5%of patients receiving placebo or placebo plus IST. The decreased platelet count was not associatedwith bleeding events.

The majority of the decreased platelets were transient and not below 75 × 109/l.

In the double-blinded treatment period, elevations in ALT or AST occurred in 27.9% and 18.3% ofpatients treated with satralizumab (monotherapy or in combination with IST) respectively, comparedwith 12.2% and 13.5% of patients receiving placebo or placebo plus IST. The majority of theelevations were below 3 x ULN, were transient and resolved without interruption of satralizumab.

Elevations in ALT or AST >3 x ULN occurred in 2.9% and 1.9% of patients treated with satralizumab(monotherapy or in combination with IST) respectively. These elevations were not associated withincreases in total bilirubin.

Elevations of ALT above 5 x ULN were observed 4 weeks after initiation of therapy in one (1%)patient receiving satralizumab in combination with IST; normalising after discontinuation oftreatment, and satralizumab was not reintroduced in this patient (see sections 4.2 and 4.4).

Lipid parameters

In the double-blinded treatment period, 10.6% of patients receiving satralizumab (monotherapy or incombination with IST) experienced elevations in total cholesterol above 7.75 mmol/l as comparedwith 1.4% of patients receiving placebo (or placebo plus IST); 20.2% of patients receivingsatralizumab experienced elevations in triglycerides above 3.42 mmol/l as compared with 10.8% ofpatients receiving placebo.

The safety and efficacy of satralizumab have been studied in 9 children ≥12 years of age. Frequency,type and severity of adverse reactions in children from 12 years of age are expected to be the same asin adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of an overdose, the patient should be closely supervised, treated symptomatically, andsupportive measures instituted as required.

Pharmacotherapeutic group: immunosuppressants, interleukin inhibitors, ATC code: L04AC19

Satralizumab is a recombinant humanised immunoglobuline G2 (IgG2) monoclonal antibody (mAb)that binds to soluble and membrane-bound human IL-6 receptor (IL-6R) and thereby prevents IL-6downstream signalling through these receptors.

IL-6 levels are increased in cerebrospinal fluid and serum of patients with NMO and NMOSD duringperiods of disease activity. IL-6 functions have been implicated in the pathogenesis of NMO and

NMOSD, including B-cell activation, differentiation of B-cells to plasmablasts and production ofpathological autoantibodies, e.g. against AQP4, a water channel protein mainly expressed byastrocytes in the CNS, Th17-cell activation and differentiation, T-regulatory cell inhibition, andchanges in blood-brain-barrier permeability.

In clinical studies with satralizumab in NMO and NMOSD, decreases in C-reactive protein (CRP),fibrinogen and complement (C3, C4 and CH50) were observed.

The efficacy and safety of satralizumab were evaluated in two pivotal phase III clinical trials inpatients with NMOSD (diagnosed as AQP4-IgG seropositive or seronegative NMO [Wingerchuck2006 criteria], or as AQP4-IgG seropositive NMOSD [Wingerchuk 2007 criteria]).

Study BN40898 included adult and adolescent NMOSD patients aged 12-74 years treated with stable

IST, with at least 2 relapses in the last 2 years prior screening (with at least one relapse within the 12months prior to screening) and expanded disability status scale (EDSS) of 0 to 6.5, whereas study

BN40900 included adult patients aged 18-74 years on no background IST, with at least 1 relapse orfirst attack within the last 12 months prior to screening and EDSS of 0 to 6.5.

Both studies included approximately 30% AQP4-IgG seronegative NMO patients.

Efficacy in both studies was evaluated based on time to first relapse as adjudicated by an independent

Clinical Endpoint Committee (CEC), with relapse defined by pre-specified worsening in the EDSSand functional system score (FSS) criteria, evaluated within 7 days after the patient reportedsymptoms (adjudicated relapse).

Study BN40898 (also known as SA-307JG or SAkuraSky)

Study BN40898 was a randomised, multicentre, double-blind, placebo-controlled clinical trial toevaluate the effect of satralizumab in combination with stable IST (OCs up to 15 mg/day[prednisolone equivalent], AZA up to 3 mg/kg/day or MMF up to 3000 mg/day, adolescents receiveda combination of AZA and OCs or MMF and OCs). The double blind period of the study included 83

AQP4-IgG seropositive and seronegative patients (76 adults and 7 adolescents). Patients received thefirst 3 single doses of satralizumab 120 mg or matching placebo by SC injection in the abdominal orfemoral region every 2 weeks for the first 4 weeks and once every 4 weeks thereafter.

Study design and baseline characteristics of the study population are presented in table 4.

Table 4: Study design and baseline characteristics in AQP4-IgG seropositive patients forstudy BN40898

Study name Study BN40898(AQP4-IgG seropositive: N=55; ITT*: N=83 )

Study design

Study population Adolescent and adult patients with NMO or NMOSD,treated with stable IST

Age 12-74 years, ≥ 2 relapses in the last 2 years priorscreening (with at least one relapse in the 12 monthsprior to screening), EDSS of 0 to 6.5

Study duration for efficacy evaluation Event-driven** (26 adjudicated relapses)

Median follow-up time: satralizumab 139.4 weeks,placebo 40.2 weeks (in ITT: 115.1 weeks and 42.5weeks, respectively)

Treatment groups, in 1:1 randomisation Group A: satralizumab 120 mg SC

Group B: placebo

Baseline characteristics of AQP4-IgG Satralizumab + IST (n=27) Placebo + IST (n=28)seropositive patients

Diagnosis, n (%):

NMO 19 (70.4) 14 (50.0)

NMOSD 8 (29.6) 14 (50.0)

Mean age in years (SD) 44.4 (15.7) 43.4 (12.9)(Min-Max) (13 - 73) (14 - 65)

Elderly (≥65 years), n (%) 3 (11.1) 1 (3.6)

Adolescents (≥12 to <18 years), n (%) 1 (3.7) 2 (7.1)

Gender distribution,n (%) male/ n (%) female 0/27 (100) 0/28 (100)

Immunosuppressive therapy (IST), n (%):

Oral corticosteroids (OCs) 14 (51.9) 13 (46.4)

Azathioprine (AZA) 11 (40.7) 11 (39.3)

Mycophenolate mofetil (MMF) 1 ( 3.7) 3 (10.7)

AZA + OCs*** 0 0

MMF + OCs*** 1 ( 3.7) 1 ( 3.6)

* Intention-To-Treat (ITT)

** Patients treated with rescue therapy with no adjudicated relapse were allowed to enter the OLE period of thestudy and were censored from the primary efficacy analysis

*** Combination allowed for adolescent patients

Study BN40900 (also known as SA-309JG or SAkuraStar)

Study BN40900 was a randomised, multicentre, double-blind, placebo-controlled clinical trial toevaluate the effect of satralizumab monotherapy compared to placebo. The study included 95 AQP4-

IgG seropositive and seronegative adult patients. Patients received the first 3 single doses ofsatralizumab 120 mg or matching placebo by SC injection in the abdominal or femoral region every 2weeks for the first 4 weeks and once every 4 weeks thereafter.

Study design and baseline characteristics of the study population are presented in table 5.

Table 5: Study design and baseline characteristics in AQP4-IgG seropositive patients forstudy BN40900

Study name Study BN40900(AQP4-IgG seropositive: N=64; ITT*: N=95)

Study design

Study population Adult patients with NMO or NMOSD

Age 18-74 years, ≥ 1 relapse or first attack in the last12 months prior to screening, EDSS of 0 to 6.5. Patientseither received prior relapse prevention treatment for

NMOSD or were treatment naïve

Study duration for efficacy evaluation Event-driven (44 adjudicated relapses, or 1.5 years afterthe date of randomisation of the last patient enrolled,whichever comes first)

Median follow-up time: satralizumab 96.7 weeks,placebo 60.1 weeks(in ITT: 95.4 weeks and 60.5 weeks,respectively)

Treatment groups, in 2:1 randomisation Monotherapy:

Group A: satralizumab 120 mg SC

Group B: placebo

Baseline characteristics of AQP4-IgG Satralizumab (n=41) Placebo (n=23)seropositive patients

Diagnosis, n (%):

NMO 26 (63.4) 15 (65.2)

NMOSD 15 (36.6) 8 (34.8)

Mean age in years (SD) 46.0 (12.0) 40.1 (11.5)(Min-Max) (22 - 70) (20 - 56)

Elderly (≥65 years), n (%) 1 (2.4) 0

Gender distribution,n (%) male/ n (%) female 10 (24.4)/31 (75.6) 1 (4.3)/22 (95.7)

* Intention-To-Treat (ITT)

Primary efficacy

In AQP4-IgG seropositive patients the relative risk of experiencing an adjudicated relapse in study

BN40898 was reduced by 79% (Hazard Ratio, HR [95% CI]: 0.21 [0.06-0.75]), in study BN40900 by74% (HR [95% CI]: 0.26 [0.11-0.63]) (see Figures 1 and 2). When data across studies BN40898 and

BN40900 were pooled, treatment with satralizumab with or without IST led to an overall riskreduction of 75% (HR [95% CI]; 0.25 (0.12-0.50]) in AQP4-IgG seropositive patients. At 48 weeks,85.7% of satralizumab-treated AQP4-IgG seropositive patients remained adjudicated relapse-freewhen used in combination with IST or as monotherapy compared to 58.7% in the placebo group. At96 weeks, 81.4% of satralizumab-treated AQP4-IgG seropositive patients remained adjudicatedrelapse-free when used in combination with IST or as monotherapy compared to 47.2% in the placebogroup. Efficacy was not significant in AQP4-IgG seronegative patients.

Figure 1: Study BN40898 - time to first adjudicated relapse during the double-blind period in

AQP4-IgG seropositive patients

Figure 2: Study BN40900 - time to first adjudicated relapse during the double-blind period in

AQP4-IgG seropositive patients

Treatment with satralizumab in AQP4-IgG seropositive patients reduced the annualized rate ofadjudicated relapses (ARR) by 88% (rate ratio [RR]=0.122, 95% CI: 0.027 - 0.546; p=0.0039) in study

BN40898 and 90% (RR=0.096, 95% CI: 0.020 - 0.473; p= 0.0086) in study BN40900 compared totreatment with placebo.

As compared to placebo-treated patients, the need for rescue therapy (e.g., corticosteroids, intravenousimmunoglobulin, and/or apheresis [including plasmapheresis or plasma exchange]) was reduced insatralizumab-treated AQP4-IgG seropositive patients by 61% (odds ratio [OR]= 0.3930, 95% CI:

0.1343 -1.1502; p=0.0883) in study BN40898 and by 74% (OR = 0.2617, 95% CI: 0.0862 - 0.7943;p=0.0180) in study BN40900.

Treatment with satralizumab in AQP4-IgG seropositive patients reduced the risk of experiencing asevere relapse defined as an EDSS increase ≥ 2 points from the previous EDSS assessment by 85%(time to severe adjudicated relapse during the double blind period; HR=0.15, 95% CI: 0.02 -1.25;p=0.0441) in study BN40898 and by 79% (HR=0.21, 95% CI: 0.05 - 0.91; p=0.0231) in study

BN40900 compared to treatment with placebo.

Key secondary endpoints

Change from baseline to week 24 in pain or fatigue were not met in studies BN40898 and BN40900.

Open-label extension

Analyses of longer term data including the OLE period (based on relapse treated with rescue therapy)showed that 58% and 73% of AQP4-IgG seropositive patients treated with satralizumab remainedrelapse-free after 120 weeks of treatment, when satralizumab was administered as add-on therapy or asmonotherapy, respectively.

In phase III study BN40898 (in combination with IST) and in phase III study BN40900 (inmonotherapy), anti-drug-antibodies (ADAs) were observed in 41% and 71% of patients receivingsatralizumab in the double-blind period, respectively. The ability of ADAs to neutralise satralizumabbinding is unknown.

Exposure was lower in ADA positive patients, however there was no impact of ADAs on safety andno clear impact on efficacy nor pharmacodynamic markers indicative of target engagement.

Treatment with satralizumab led to a similar reduction in the risk of experiencing an adjudicatedrelapse in patients in the phase III studies despite different ADA rates between those studies.

In study BN40898, there were 7 adolescent patients enrolled during the double blind period. Theirmean age was 15.4 years and the median body weight was 79.6 kg. The majority were female (n=6).

Four patients were White, 2 were Black/African American, and 1 was Asian. Three (42.9%)adolescent patients were AQP4-IgG seropositive at screening (2 in the placebo group and 1 in thesatralizumab group). During the double-blind period, 1 of 3 adolescents in the placebo group and 1 of4 adolescents in the satralizumab group experienced an adjudicated relapse. Due to the small samplesize, the hazard ratio for the primary endpoint of time to first adjudicated relapse in this subgroup wasnot calculated. Two additional adolescent patients were enrolled in the open-label period of the study.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Enspryng in one or more subsets of the paediatric population in treatment of NMOSD (see section 4.2for information on paediatric use).

The pharmacokinetics of satralizumab have been characterised both in Japanese and Caucasian healthyvolunteers, and in NMO and NMOSD patients. The pharmacokinetics in NMO and NMOSD patientsusing the recommended dose were characterised using population PK analysis methods based on adatabase of 154 patients.

The concentration-time course of satralizumab in patients with NMO or NMOSD was accuratelydescribed by a two-compartment population PK model with parallel linear and target-mediated(Michaelis-Menten) elimination and first-order SC absorption. Satralizumab clearance and volumeparameters allometrically scaled by body weight (through power function with the fixed powercoefficient of 0.75 and 1 for clearance and volume parameters, respectively). Bodyweight was shownto be a significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile ofthe weight distribution) increased by 71.3% and 105%, respectively, compared to a 60 kg patient.

Steady state pharmacokinetics were achieved after the loading period (8 weeks) for Cmin, Cmax and

AUC as follows (mean (±SD): Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL and AUC: 737(386) mcg. mL/day.

The absorption rate constant of satralizumab was 0.0104/h equating to an absorption half-life ofaround 3 days (66 hours) at the recommended dose (see section 4.2). The bioavailability was high(85.4%).

Satralizumab undergoes biphasic distribution. The central volume of distribution was 3.46 L, theperipheral volume of distribution was 2.07 L. The inter-compartmental clearance was 14 mL/h.

The metabolism of satralizumab has not been directly studied, as monoclonal antibodies areprincipally cleared by catabolism.

The total clearance of satralizumab is concentration-dependent. Linear clearance (accounting forapproximately half of the total clearance at steady state using the recommended dose in NMO and

NMOSD patients) is estimated to be 2.50 mL/h. The associated terminal t1/2 is approximately 30 days(range 22-37 days) based on data pooled from the phase 3 studies.

Population pharmacokinetic analyses in adult patients with NMO or NMOSD showed that age,gender, and race did not meaningfully influence the pharmacokinetics of satralizumab. Although bodyweight influenced the pharmacokinetics of satralizumab, no dose adjustments are recommended forany of these demographics.

Data obtained in 8 adolescent patients [13-17 years of age] who received the adult dosing regimenshow that population PK parameters for satralizumab are not significantly different from those in theadult population. Therefore, no dose adjustment is necessary.

No dedicated studies have been conducted to investigate the PK of satralizumab in patients ≥65 yearsof age, however patients with NMO or NMOSD between 65 and 74 years of age were included in the

BN40898 and BN40900 clinical studies.

No formal study of the effect of renal impairment on the PK of satralizumab has been conducted.

However, patients with mild renal impairment (creatinine clearance ≥50 mL/min and <80 mL/min)were included in the phase III studies. Based on population PK analysis there is no impact of renalimpairment on the PK of satralizumab which is in line with the known mechanisms of clearance forsatralizumab. Therefore no dose adjustment is required.

No formal study of the effect of hepatic impairment on the PK of satralizumab has been conducted(see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and toxicity to reproduction and development.

No rodent carcinogenicity studies have been performed to establish the carcinogenic potential ofsatralizumab. Proliferative lesions have not been observed in a chronic cynomolgus monkey 6-monthtoxicity study.

No studies have been performed to establish the mutagenic potential of satralizumab. Antibodies arenot expected to cause effects on DNA.

Prenatal treatment and postnatal exposure with satralizumab in pregnant monkeys and their offspringdid not elicit any adverse effects on maternal animals, foetal development, pregnancy outcome orinfant survival and development including learning ability.

The concentrations of satralizumab in breast milk were very low (<0.9% of the correspondingmaternal plasma levels).

No effects on male or female reproductive organs were seen with chronic treatment of satralizumab inmonkeys.

Cytokine release syndrome

Based on in vitro studies with human blood, the risk of the release of pro-inflammatory cytokines withsatralizumab is considered low in terms of incidence and increase in cytokines.

Histidine

Aspartic acid

Arginine

Poloxamer 188

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2°C - 8°C).

Do not freeze. Do not use the syringe if it has been frozen.

Always keep the syringe dry.

Keep the PFS in the outer carton in order to protect from light and moisture.

If unopened and kept in the outer carton, the syringe may be left out of the refrigerator below 30°C fora single period up to 8 days. After storage at room temperature the product should not be returned tothe refrigerator and should be either used or discarded.

1 mL solution in a PFS (polymer) with a staked-in, stainless steel needle, fitted with a chlorinatedbutyl rubber-polypropylene rigid needle shield and sealed with a chlorinated butyl rubber plungerstopper. The PFS is labelled and assembled with an automatic needle guard, plunger rod, and extendedfinger flanges (EFF).

Pack size of 1 PFS and multipack of 3 (3 packs of 1) PFS. Not all pack sizes may be marketed.

After removing the carton from the refrigerator, the sealed carton should be open and the PFScarefully lifted out of the carton by holding the barrel. It is important to let the PFS reach roomtemperature by waiting for 30 minutes before initiating the administration process.

The medicinal product should not be used if the liquid is cloudy, discoloured, has visible particles in itor if any part of the PFS appears to be damaged.

The injection must be performed right after removing the cap and no later than 5 minutes, to preventthe medicinal product from drying out and blocking the needle. If the pre-filled syringe is not usedwithin 5 minutes of removing the cap, you must dispose of it in a puncture resistant container and usea new pre-filled syringe.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/21/1559/001

EU/1/21/1559/002

Date of first authorisation: 24 June 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.