Ocrelizumab and Hyaluronidase

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 )

DOSAGE AND ADMINISTRATION OCREVUS ZUNOVO should be administered by a healthcare professional ( 2.1 ) For subcutaneous use in the abdomen only ( 2.1 ) OCREVUS ZUNOVO has different dosage and administration instructions than intravenous ocrelizumab ( 2.1 ) Before initiating OCREVUS ZUNOVO, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin ( 2.2 ) Pre-medicate orally with dexamethasone (or an equivalent corticosteroid) and an antihistamine (e.g., desloratadine) at least 30 minutes prior to each injection ( 2.3 ) Administer 23 mL of OCREVUS ZUNOVO (920 mg ocrelizumab and 23,000 units hyaluronidase) subcutaneously in the abdomen over approximately 10 minutes every 6 months ( 2.4 ) Monitor patients closely during all injections, for at least one hour after the initial injection, and for at least 15 minutes after subsequent injections ( 2.4 ) 2.1 Important Administration Information OCREVUS ZUNOVO is for subcutaneous use in the abdomen only. OCREVUS ZUNOVO has different dosage and administration instructions than intravenous ocrelizumab. OCREVUS ZUNOVO should be administered via subcutaneous injection by a healthcare professional. 2.2 Assessments Prior to First Dose of OCREVUS ZUNOVO Hepatitis B Virus Screening Prior to initiating ocrelizumab treatment, perform Hepatitis B virus (HBV) screening. OCREVUS ZUNOVO is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment [see Warnings and Precautions (5.2) ] . Serum Immunoglobulins Prior to initiating ocrelizumab treatment, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions (5.4) ] . For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with ocrelizumab. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ocrelizumab treatment for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ocrelizumab treatment for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . Liver Function Tests Prior to initiating OCREVUS ZUNOVO, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels [see Warnings and Precautions (5.7) ] . 2.3 Assessments and Premedication Prior to Every Dose Infection Assessment Prior to every dose of OCREVUS ZUNOVO, determine whether there is an active infection. In case of active infection, delay administration of OCREVUS ZUNOVO until the infection resolves [see Warnings and Precautions (5.2) ]. Recommended Premedication Pre-medicate orally with 20 mg of dexamethasone (or an equivalent corticosteroid) and an antihistamine (e.g., desloratadine) administered at least 30 minutes prior to each OCREVUS ZUNOVO administration to reduce the risk of local and systemic injection reactions [see Warnings and Precautions (5.1) ] . The addition of an antipyretic (e.g., acetaminophen) may also be considered. 2.4 Recommended Dosage The recommended dosage of OCREVUS ZUNOVO is 920 mg/23,000 units (920 mg ocrelizumab and 23,000 units of hyaluronidase) administered as a single 23 mL subcutaneous injection in the abdomen over approximately 10 minutes every 6 months. Monitor the patient closely during injections, with access to appropriate medical support to manage severe injection reactions . For the initial dose, monitor the patient for at least one hour post-injection. For subsequent doses, monitor the patient for at least 15 minutes post-injection [see Warnings and Precautions (5.1) ] . 2.5 Delayed or Missed Doses If a planned injection of OCREVUS ZUNOVO is missed, administer OCREVUS ZUNOVO as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered. Doses of OCREVUS ZUNOVO must be separated by at least 5 months [see Dosage and Administration (2.4) ]. 2.6 Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OCREVUS ZUNOVO and not intravenous ocrelizumab. Visually inspect the vial for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vial if particulates or discoloration are present. Do not shake. Discard any unused portion remaining in the vial. OCREVUS ZUNOVO is compatible with polypropylene (PP), polycarbonate (PC), polyethylene (PE), stainless steel (SS), polyvinylchloride (PVC), and polyurethane (PUR). Preparation of the Syringe OCREVUS ZUNOVO should be prepared by a healthcare professional. Immediate use is recommended, as OCREVUS ZUNOVO does not contain any antimicrobial preservative. If the dose is not administered immediately, refer to "Storage of the Syringe" below. Remove the vial from refrigerated storage and allow the solution to acclimate to room temperature at or below 25°C (77°F). Withdraw the entire contents of OCREVUS ZUNOVO solution from the vial with a syringe and transfer needle (21G needle recommended). Do not dilute. Remove the transfer needle from the syringe and replace with a subcutaneous infusion set (e.g., winged/butterfly) containing a 24G-26G needle for injection. Use a subcutaneous infusion set with a priming volume NOT to exceed 0.8 mL for administration. Prime the subcutaneous infusion line with the drug product solution to eliminate the air in the infusion line and stop before the fluid reaches the needle. Ensure the syringe contains exactly 23 mL of drug product solution after priming and expelling any excess volume from the syringe. Administer immediately to avoid needle clogging. DO NOT store the prepared syringe that has been attached to the already primed subcutaneous infusion set. Administration Administer 23 mL of OCREVUS ZUNOVO subcutaneously in the abdomen over approximately 10 minutes. DO NOT administer the remaining priming volume in the subcutaneous infusion set to the patient. The recommended injection site is the abdomen, except for 2 inches (5 cm) around the navel. Do not administer OCREVUS ZUNOVO injections into areas where the skin is red, bruised, tender, or hard, or areas where there are moles or scars. Storage of the Syringe If the dose is not to be administered immediately, use aseptic technique to withdraw the entire OCREVUS ZUNOVO contents from the vial into the syringe to account for the dose volume (23 mL) plus the priming volume for the subcutaneous infusion set. Replace the transfer needle with a syringe closing cap. DO NOT attach a subcutaneous infusion set. If not used immediately, the closed syringe can be refrigerated (2°C to 8°C [36°F to 46°F]) for up to 72 hours followed by 8 hours at ambient temperatures at or below 25°C (77°F) in diffuse daylight. If the prepared syringe was stored at 2°C to 8°C (36°F to 46°F), allow the syringe to acclimate to room temperature prior to administration.

WARNINGS AND PRECAUTIONS Injection Reactions: Management recommendations for injection reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS ZUNOVO if a life-threatening injection reaction occurs ( 4 , 5.1 ) Infections: Serious, including life-threatening and fatal, infections have occurred in patients treated with ocrelizumab. Delay OCREVUS ZUNOVO administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with OCREVUS ZUNOVO and after discontinuation, until B-cell repletion ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold OCREVUS ZUNOVO at the first sign or symptom suggestive of PML ( 5.3 ) Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning of treatment. Monitor during and after discontinuation of treatment with OCREVUS ZUNOVO, until B-cell repletion, and especially when recurrent serious infections are suspected. Consider discontinuing OCREVUS ZUNOVO in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins ( 2.1 , 5.4 ) Malignancies: An increased risk of malignancy, including breast cancer, may exist with OCREVUS ZUNOVO ( 5.5 ) Immune-Mediated Colitis: Immune-mediated colitis has been reported in the postmarketing setting. Monitor patients for new or persistent diarrhea or other gastrointestinal symptoms, and evaluate promptly if colitis is suspected ( 5.6 ) Liver Injury: Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating OCREVUS ZUNOVO, and during treatment as clinically indicated. Discontinue OCREVUS ZUNOVO in patients with evidence of liver injury in the absence of an alternative etiology ( 5.7 ) 5.1 Injection Reactions OCREVUS ZUNOVO can cause injection reactions, which can be local or systemic. Common symptoms of local injection reactions reported by patients treated with OCREVUS ZUNOVO in multiple sclerosis (MS) clinical trials included erythema, pain, swelling, and pruritus. Common symptoms of systemic injection reactions reported by patients included headache and nausea. In an open-label, active-controlled trial, injection reactions were more frequently reported with the first injection; 49% of patients experienced an injection reaction with the first injection [see Adverse Reactions (6.1) ] . In MS clinical trials where ocrelizumab was administered intravenously, the incidence of infusion reactions in patients [who received methylprednisolone (or an equivalent steroid) and possibly other premedication to reduce the risk of infusion reactions prior to infusion] was 34% to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of intravenous ocrelizumab-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. Symptoms of infusion reactions can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. Monitor patients during and after injections [see Dosage and Administration (2.4) ] . Inform patients that injection reactions can occur during or within 24 hours of the injection. Reducing the Risk of Injection Reactions and Managing Injection Reactions Administer oral premedication (e.g., dexamethasone or an equivalent corticosteroid, and an antihistamine) at least 30 minutes prior to each OCREVUS ZUNOVO injection to reduce the risk of injection reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered [see Dosage and Administration (2.3) ]. Management recommendations for injection reactions depend on the type and severity of the reaction. For life-threatening injection reactions, immediately and permanently stop OCREVUS ZUNOVO and administer appropriate supportive treatment. For less severe injection reactions, the injection should be interrupted immediately, and the patient should receive symptomatic treatment. The injection should be completed at the healthcare provider's discretion and only after all symptoms have resolved. 5.2 Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving ocrelizumab. An increased risk of infections (including serious and fatal bacterial, fungal, and new or reactivated viral infections) has been observed in patients during and following completion of treatment with anti-CD20 B-cell depleting therapies. A higher proportion of intravenous ocrelizumab-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of intravenous ocrelizumab-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of intravenous ocrelizumab-treated patients experienced one or more infections compared to 68% of patients on placebo. Intravenous ocrelizumab was not associated with an increased risk of serious infections in MS patients in controlled trials. Ocrelizumab increases the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections [see Adverse Reactions (6.1) ]. Delay OCREVUS ZUNOVO administration in patients with an active infection until the infection is resolved. Respiratory Tract Infections A higher proportion of intravenous ocrelizumab-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of patients treated with intravenous ocrelizumab experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of patients treated with intravenous ocrelizumab experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of patients treated with intravenous ocrelizumab experienced upper respiratory tract infections compared to 43% of patients on placebo, and 10% of patients treated with intravenous ocrelizumab experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis. Herpes In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in patients treated with intravenous ocrelizumab than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the patients treated with intravenous ocrelizumab than in the patients on placebo (2.7% vs. 0.8%). Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving ocrelizumab. Some cases were life-threatening. Serious herpes virus infections may occur at any time during treatment with OCREVUS ZUNOVO. If serious herpes infections occur, OCREVUS ZUNOVO should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered [see Patient Counseling Information (17) ]. Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation has been reported in MS patients treated with ocrelizumab in the postmarketing setting. Fulmin

CONTRAINDICATIONS OCREVUS ZUNOVO is contraindicated in patients with: Active HBV infection [see Dosage and Administration (2.2) and Warnings and Precautions (5.2) ] A history of life-threatening administration reaction to ocrelizumab [see Warnings and Precautions (5.1) ] A history of hypersensitivity to ocrelizumab, hyaluronidase, or any component of OCREVUS ZUNOVO [see Warnings and Precautions (5.1) ] . Active hepatitis B virus infection ( 4 ) History of life-threatening administration reactions to ocrelizumab ( 4 ) History of hypersensitivity to ocrelizumab, hyaluronidase, or to any component of OCREVUS ZUNOVO ( 4 )

DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies The concomitant use of OCREVUS ZUNOVO and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with OCREVUS ZUNOVO. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS ZUNOVO [see Warnings and Precautions (5.2) ]. 7.2 Vaccinations A Phase 3b randomized, open-label study examined the concomitant use of intravenous ocrelizumab and several non-live vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects undergoing treatment with intravenous ocrelizumab at the time of vaccination and 34 subjects not undergoing treatment with intravenous ocrelizumab at the time of vaccination). Concomitant exposure to intravenous ocrelizumab attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and seasonal inactivated influenza vaccines. The impact of the observed attenuation on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with ocrelizumab have not been assessed [see Warnings and Precautions (5.2) ].

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 withi

Mechanism of Action The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in OCREVUS ZUNOVO acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.