1 INDICATIONS AND USAGE OCREVUS ZUNOVO is indicated for the treatment of: Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults Primary progressive MS, in adults OCREVUS ZUNOVO is a CD20-directed cytolytic antibody indicated for the treatment of: Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults ( 1 ) Primary progressive MS, in adults ( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Injection Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3) ] Reduction in Immunoglobulins [see Warnings and Precautions (5.4) ] Malignancies [see Warnings and Precautions (5.5) ] Immune-Mediated Colitis [see Warnings and Precautions (5.6) ] Liver Injury [see Warnings and Precautions (5.7) ] The most common adverse reactions in patients treated with intravenous ocrelizumab were: RMS (incidence ≥10% and > REBIF ® ): upper respiratory tract infections and infusion reactions ( 6.1 ) PPMS (incidence ≥10% and > placebo): upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections ( 6.1 ) The most common adverse reaction observed with OCREVUS ZUNOVO in patients with RMS and PPMS was injection reactions (incidence of 49%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 clinical practice.

The safety of ocrelizumab has been evaluated in active-controlled clinical trials of ocrelizumab administered intravenously in patients with relapsing forms of MS (RMS) (Study 1 and Study 2) [see Clinical Studies (14.1) ] and primary progressive MS (PPMS) (Study 3) [see Clinical Studies (14.2) ] , and in an open-label, active-controlled trial of OCREVUS ZUNOVO administered subcutaneously in patients with RMS and PPMS (Study 4) [see Clinical Studies (14.3) ] .

Adverse Reactions With Ocrelizumab Intravenous in Patients With RMS and PPMS The safety of intravenous ocrelizumab has been evaluated in 1311 patients across the MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with RMS and 486 patients in a placebo-controlled study in patients with PPMS.

RMS In active-controlled intravenous ocrelizumab clinical trials (Study 1 and Study 2), 825 patients with RMS received ocrelizumab 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2) [see Clinical Studies (14.1) ].

The overall exposure in the 96-week controlled treatment periods was 1448 patient-years.

The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions.

Table 1 summarizes the adverse reactions that occurred in active-controlled intravenous ocrelizumab RMS trials (Study 1 and Study 2).

Table 1 Adverse Reactions in Adult Patients With RMS With an Incidence of at least 5% for Intravenous Ocrelizumab and Higher than REBIF Adverse Reactions Studies 1 and 2 Ocrelizumab 600 mg IV Every 24 Weeks The first dose was given as two separate 300 mg infusions at Weeks 0 and 2.

(n=825) % REBIF 44 mcg SQ 3 Times per Week (n=826) % Upper respiratory tract infections 40 33 Infusion reactions 34 10 Depression 8 7 Lower respiratory tract infections 8 5 Back pain 6 5 Herpes virus- associated infections 6 4 Pain in extremity 5 4 PPMS In a placebo-controlled intravenous ocrelizumab clinical trial (Study 3), a total of 486 patients with PPMS received one course of ocrelizumab (600 mg of ocrelizumab administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously [see Clinical Studies (14.2) ].

The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years.

The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections.

Table 2 summarizes the adverse reactions that occurred in the placebo-controlled intravenous ocrelizumab PPMS trial (Study 3).

Table 2 Adverse Reactions in Adult Patients With PPMS With an Incidence of at Least 5% for Intravenous Ocrelizumab and Higher Than Placebo Adverse Reactions Study 3 Ocrelizumab 600 mg IV Every 24 Weeks One dose of intravenous ocrelizumab (600 mg administered as two 300 mg infusions two weeks apart) Placebo (n=486) % (n=239) % Upper respiratory tract infections 49 43 Infusion reactions 40 26 Skin infections 14 11 Lower respiratory tract infections 10 9 Cough 7 3 Diarrhea 6 5 Edema peripheral 6 5 Herpes virus associated infections 5 4 Laboratory Abnormalities Decreased Immunoglobulins Ocrelizumab decreased total immunoglobulins, with the greatest decline seen in IgM levels; however, a decrease in IgG levels was associated with an increased rate of serious infections .

In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in patients treated with intravenous ocrelizumab was 0.5%, 1.5%, and 0.1%, respectively.

Following treatment, the proportion of patients treated with intravenous ocrelizumab reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.

In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in patients treated with intravenous ocrelizumab was 0.0%, 0.2%, and 0.2%, respectively.

Following treatment, the proportion of patients treated with intravenous ocrelizumab reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.

The pooled data of intravenous ocrelizumab clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of IgG and increased rates of serious infections.

The type, severity, latency, duration, and outcome of serious infections observed during episodes of immunoglobulins below LLN were consistent with the overall serious infections observed in patients treated with intravenous ocrelizumab.

Decreased Neutrophil Levels In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of patients treated with intravenous ocrelizumab compared to 10% in placebo patients.

The majority of the decreased neutrophil counts were only observed once for a given patient treated with intravenous ocrelizumab and were between the LLN and 1.0 × 10 9 /L.

Overall, 1% of the patients in the intravenous ocrelizumab group had neutrophil counts less than 1.0 × 10 9 /L and these were not associated with an infection.

Adverse Reactions With OCREVUS ZUNOVO in Patients With RMS and PPMS The safety of OCREVUS ZUNOVO was evaluated in Study 4, an active-controlled, open-label, randomized study in ocrelizumab-naïve patients with RMS or PPMS [see Clinical Studies (14.3) ] .

One hundred eighteen patients received OCREVUS ZUNOVO as their first dose and 118 patients received intravenous ocrelizumab for their first dose (two separate 300 mg infusions at Weeks 0 and 2).

The most common adverse reactions (reported in at least 10% of OCREVUS ZUNOVO-treated patients) were injection reactions.

In Study 4, injection reactions occurred in 49% (58/118) of patients after the first injection of OCREVUS ZUNOVO.

Of these 118 patients, 47% and 11% experienced at least one local injection reaction and one systemic injection reaction, respectively.

The most common symptoms reported by patients with local and systemic injection reactions included: injection site erythema, injection site pain, injection site swelling, injection site pruritus, headache, and nausea.

Among the patients experiencing an injection reaction, the majority of patients (83%) had injection reactions occur within 24 hours after the end of the injection, as opposed to during the injection (19%).

All injection reactions were of mild (73%) or moderate (27%) severity.

The median duration of symptoms was 3 days for systemic injection reactions and 3.5 days for local injection reactions.

All patients recovered from injection reactions, of which 26% required symptomatic treatment.

For subsequent injections, among the 118 patients who received OCREVUS ZUNOVO only throughout the study, the frequency of local injection reactions ranged from 31% to 43% and the frequency of systemic injection reactions ranged from 3% to 7% from Injection 2 to Injection 4.

All injection reactions were of mild or moderate severity.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ocrelizumab.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Immune-mediated colitis [see Warnings and Precautions (5.6) ] Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.7) ] Infections and Infestations: Serious herpes infections [see Warnings and Precautions (5.2) ] , progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3) ] , and babesiosis Skin: Pyoderma gangrenosum