Ocrevus

1 INDICATIONS AND USAGE OCREVUS 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 Relapsing-remitting MS, in pediatric patients 10 years of age and older who weigh 25 kg or more. OCREVUS 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 ) Relapsing-remitting MS, in pediatric patients 10 years of age and older who weigh 25 kg or more ( 1 )

2 DOSAGE AND ADMINISTRATION Before initiating OCREVUS, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin ( 2.1 ) Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion ( 2.2 ) Administer OCREVUS by intravenous infusion ( 2.3 ) Adults and pediatric patients (10 years of age and older), who weigh 35 kg or more: Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion ( 2.3 ) Subsequent doses: 600 mg intravenous infusion every 6 months ( 2.3 ) Pediatric patients (10 years of age and older) who weigh 25 kg to less than 35 kg: Start dose: 150 mg intravenous infusion, followed two weeks later by a second 150 mg intravenous infusion ( 2.3 ) Subsequent doses: 300 mg intravenous infusion every 6 months ( 2.3 ) Must be diluted prior to administration ( 2.3 , 2.6 ) Monitor patients closely during and for at least one hour after infusion ( 2.3 , 2.5 ) 2.1 Assessments Prior to First Dose of OCREVUS Hepatitis B Virus Screening Prior to initiating OCREVUS, perform Hepatitis B virus (HBV) screening. OCREVUS 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 OCREVUS, 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 OCREVUS. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all age-appropriate immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . Liver Function Tests Prior to initiating OCREVUS, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels [see Warnings and Precautions (5.7) ] . 2.2 Preparation Before Every Infusion Infection Assessment Prior to every infusion of OCREVUS, determine whether there is an active infection. In case of active infection, delay infusion of OCREVUS until the infection resolves [see Warnings and Precautions (5.2) ]. Recommended Premedication To reduce the frequency and severity of infusion reactions, administer the following premedications [see Warnings and Precautions (5.1) ] : Methylprednisolone (or an equivalent corticosteroid) by intravenous infusion to be completed approximately 30 minutes prior to each OCREVUS infusion, as follows: Adults and pediatric patients who weigh 40 kg or more: 100 mg Pediatric patients who weigh less than 40 kg: 2 mg/kg An antihistamine (e.g., diphenhydramine) 30 to 60 minutes prior to each OCREVUS infusion. An antipyretic (e.g., acetaminophen) may also be considered. Administer the antipyretic 30 minutes to 60 minutes prior to OCREVUS infusion. 2.3 Recommended Dosage and Dose Administration Administer OCREVUS under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions. Observe the patient for at least one hour after the completion of the infusion [see Warnings and Precautions (5.1) ] . OCREVUS is administered as an intravenous infusion. The initial dose is split into two equal infusions administered two weeks apart. Subsequent doses are administered every 6 months thereafter (see Table 1 ). Dosing for pediatric patients (10 years of age and older) is according to body weight (see Table 2 ). Table 1 Recommended Dose, Infusion Rate, and Infusion Duration for Adult Patients with RMS and PPMS Amount and Volume Solutions of OCREVUS for intravenous infusion are prepared by dilution of the drug product into an infusion bag containing 0.9% Sodium Chloride Injection, to a final drug concentration of approximately 1.2 mg/mL. Infusion Rate and Duration Infusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5) ] . Initial Dose (two infusions) Infusion 1 300 mg in 250 mL Start at 30 mL per hour Increase by 30 mL per hour every 30 minutes Maximum: 180 mL per hour Duration: 2.5 hours or longer Infusion 2 (2 weeks later) 300 mg in 250 mL Subsequent Doses (one infusion) every 6 months) Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose. Option 1 Infusion of approximately 3.5 hours duration 600 mg in 500 mL Start at 40 mL per hour Increase by 40 mL per hour every 30 minutes Maximum: 200 mL per hour Duration: 3.5 hours or longer OR Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1) and Clinical Studies (14.3) ] . Infusion of approximately 2 hours duration 600 mg in 500 mL Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer Table 2 Recommended Dose, Infusion Rate, and Infusion Duration for Pediatric Patients 10 Years of Age and Older Infusion Amount and Volume Solutions of OCREVUS for intravenous infusion are prepared by dilution of the drug product into an infusion bag containing 0.9% Sodium Chloride for Injection [see Dosage and Administration (2.6) ] . Infusion Rate and Duration Infusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5) ] . Body Weight 25 kg to Less Than 35 kg Initial Dose (two infusions) Infusion 1 150 mg in 250 mL Start at 30 mL per hour Increase by 30 mL per hour every 30 minutes Maximum: 180 mL per hour Duration: 2.5 hours or longer Infusion 2 (2 weeks later) 150 mg in 250 mL Subsequent Doses (one infusion every 6 months) Single infusion once every 6 months 300 mg in 250 mL Body Weight 35 kg or More Initial Dose (two infusions) Infusion 1 300 mg in 250 mL Start at 30 mL per hour Increase by 30 mL per hour every 30 minutes Maximum: 180 mL per hour Duration: 2.5 hours or longer Infusion 2 (2 weeks later) 300 mg in 250 mL Subsequent Doses (one infusion every 6 months) Single infusion once every 6 months 600 mg in 500 mL Start at 40 mL per hour Increase by 40 mL per hour every 30 minutes Maximum: 200 mL per hour Duration: 3.5 hours or longer 2.4 Delayed or Missed Doses If a planned infusion of OCREVUS is missed, administer OCREVUS 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 must be separated by at least 5 months [see Dosage and Administration (2.3) ] . 2.5 Dose Modifications Because of Infusion Reactions Dose modifications in response to infusion reactions depends on the severity. Life-threatening Infusion Reactions Immediately stop and permanently discontinue OCREVUS if there are signs of a life-threatening or disabling infusion reaction [see Warnings and Precautions (5.1) ] . Provide appropriate supportive treatment. Severe Infusion Reactions Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see Warnings and Precautions (5.1) ] . Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction. If this rate is tolerated, increase the rate as described in Table 1 and Table 2 [see Dosage and Administration (2.3) ] . This change in rate will increase the total duration of the infusion but not the total dose. Mild to Moderate Infusion Reactions Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes [see Warnings and Precautions (5.1) ] . If this rate is tolerated, increase the rate as described in Table 1 and Table 2 [see Dosage and Administration (2.3) ] . This change in rate will increase the total duration of the infusion but not the total dose. 2.6 Preparation and Storage of the Dilute Solution for Infusion Preparation OCREVUS must be prepared by a healthcare professional using aseptic technique. A sterile needle and syringe should be used to prepare the diluted infusion solution. Visually inspect for particulate matter and discoloration prior to administration. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter. Do not shake. Withdraw the required dose of OCREVUS and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, as described in Table 3. Table 3: Dilution of OCREVUS Dose of OCREVUS (mg) Volume of OCREVUS (mL) Volume of 0.9% Sodium Chloride Injection (mL) Final Drug Concentration (mg/mL) 150 mg 5 mL 250 mL 0.6 mg/mL 300 mg 10 mL 250 mL 1.2 mg/mL 600 mg 20 mL 500 mL 1.2 mg/mL Do not use other diluents to dilute OCREVUS because their use has not been tested. The product contains no preservative and is intended for single use only. Discard any unused portion left in the vial. Storage of Infusion Solution Prior to the start of the intravenous infusion, the content of the infusion bag should be at room temperature. Use the prepared infusion solution immediately. If not used immediately, store up to 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F) and 8 hours at room temperature up to 25°C (77°F), which includes infusion time. In the event an intravenous infusion cannot be completed the same day, discard the remaining solution. No incompatibilities between OCREVUS and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed. Administration Administer the diluted infusion solution through a dedicated line using an infusion set with a 0.2 or 0.22 micron in-line filter.

4 CONTRAINDICATIONS OCREVUS is contraindicated in patients with: Active HBV infection [see Dosage and Administration (2.1) and Warnings and Precautions (5.2) ] A history of life-threatening infusion reaction to OCREVUS [see Warnings and Precautions (5.1) ] Active hepatitis B virus infection ( 4 ) History of life-threatening infusion reaction to OCREVUS ( 4 )

5 WARNINGS AND PRECAUTIONS Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS if a life-threatening or disabling infusion reaction occurs ( 2.3 , 5.1 ) Infections: Serious, including life-threatening and fatal infections, have occurred. Delay OCREVUS 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 and after discontinuation, until B-cell repletion ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold OCREVUS 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, until B-cell repletion, and especially when recurrent serious infections are suspected. Consider discontinuing OCREVUS 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 ( 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, and during treatment as clinically indicated. Discontinue OCREVUS in patients with evidence of liver injury in the absence of an alternative etiology ( 5.7 ). 5.1 Infusion Reactions OCREVUS can cause infusion reactions, which 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. These reactions are more commonly reported with the first infusion. In multiple sclerosis (MS) clinical trials, all adult and pediatric patients who were treated with OCREVUS received premedication with methylprednisolone (or an equivalent steroid), and may have also received an antihistamine (all pediatric patients) and/or an analgesic/antipyretic to reduce the risk of infusion reactions prior to each infusion. In adults, the incidence of infusion reactions in patients treated with OCREVUS was 34 to 40%. There were no fatal infusion reactions, but 0.3% of patients with MS who were treated with OCREVUS experienced infusion reactions that were serious, some requiring hospitalization. In pediatric patients, the incidence of infusion reactions in patients treated with OCREVUS was 48%, compared with an incidence of 24% in patients who received placebo infusion (fingolimod-treated patients). There were no fatal infusion reactions, but one pediatric patient (1.1%) treated with OCREVUS experienced an infusion reaction that was serious because it required hospitalization [see Adverse Reactions (6.1) ] . Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Reducing the Risk of Infusion Reactions and Managing Infusion Reactions Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered [see Dosage and Administration (2.2) ]. Management recommendations for infusion reactions depend on the type and severity of the reaction [see Dosage and Administration (2.5) ]. For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment. 5.2 Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic and fungal infections have been reported in patients receiving OCREVUS. 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 adult patients treated with OCREVUS experienced infections compared to patients taking REBIF or placebo. In RMS trials in adults, 58% of patients treated with OCREVUS experienced one or more infections compared to 52% of patients treated with REBIF. In the PPMS trial, 70% of patients treated with OCREVUS experienced one or more infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections [see Adverse Reactions (6.1) ]. In the pediatric study, infections occurred in 73% of patients treated with OCREVUS (1.5 infections per patient-year) and 59% of patients treated with fingolimod (1.2 infections per patient-year) [see Adverse Reactions (6.1) ] . Upper respiratory tract infections, nasopharyngitis, and influenza, all of which were mild to moderate, were more frequently reported in patients treated with OCREVUS compared to patients treated with fingolimod. Delay OCREVUS administration in patients with an active infection until the infection is resolved. Respiratory Tract Infections A higher proportion of adult patients treated with OCREVUS experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials in adults, 40% of patients treated with OCREVUS experienced upper respiratory tract infections compared to 33% of patients treated with REBIF, and 8% of patients treated with OCREVUS experienced lower respiratory tract infections compared to 5% of patients treated with REBIF. In the PPMS trial, 49% of patients treated with OCREVUS experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of patients treated with OCREVUS 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 in adults, herpes infections were reported more frequently in patients treated with OCREVUS than in patients treated with REBIF, 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 OCREVUS 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 OCREVUS. Serious herpes virus infections may occur at any time during treatment with OCREVUS. Some cases were life-threatening. If serious herpes infections occur, OCREVUS should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered [see Patient Counseling Information (17) ]. Hepatitis B Virus (HBV) Reactivation Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB 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. Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical Pharmacology (12.1 , 12.2) ]. OCREVUS has not been studied in combination with other MS therapies. Vaccinations Administer all age-appropriate immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines [see Drug Interactions (7.2) ]. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion [see Clinical Pharmacology (12.2) ] . Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19 + B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. If indicated, non-live vaccines may be administered prior to recovery from B-cell depletion, but assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to assess whether a protective immune response was mounted [see Use in Specific Populations (8.1) ]. 5.3 Progressive Multifocal Leukoencephalopathy Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients with MS treated with OCREVUS in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in OCREVUS-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any immunosuppressive or immunomodulatory medications associated with the risk of PML prior to or concomitantly with OCREVUS, and did not have any known ongoing systemic medical conditions resulting in compromised immune system function. JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients. If PML is confirmed, treatment with OCREVUS should be discontinued. 5.4 Reduction in Immunoglobulins As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) in adults and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins [see Adverse Reactions (6.1) ] . 5.5 Malignancies An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in patients treated with OCREVUS. Breast cancer in adults occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines. 5.6 Immune-Mediated Colitis Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving OCREVUS in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during OCREVUS treatment, and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur. 5.7 Liver Injury Clinically significant liver injury, without findings of viral hepatitis, has been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including OCREVUS. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from weeks to months after administration. Patients treated with OCREVUS found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3× the upper limit of normal (ULN) with serum total bilirubin greater than 2× ULN are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with OCREVUS [see Dosage and Administration (2.1) ] and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue OCREVUS.

7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies The concomitant use of OCREVUS 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. 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 [see Warnings and Precautions (5.2) ]. 7.2 Vaccinations A Phase 3b randomized, open-label study examined the concomitant use of OCREVUS and several non-live vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects undergoing treatment with OCREVUS at the time of vaccination and 34 subjects not undergoing treatment with OCREVUS at the time of vaccination). Concomitant exposure to OCREVUS 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 OCREVUS have not been assessed [see Warnings and Precautions (5.2) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Infusion 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 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 ) RRMS in pediatric patients 10 years of age and older: Adverse reactions were consistent with those observed in adults with RMS ( 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 reactions 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. Adults The safety of OCREVUS has been evaluated in 1311 adult patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS). Adverse Reactions in Adult Patients with Relapsing Forms of MS In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received OCREVUS 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 4 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2). Table 4 Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIF Adverse Reactions Studies 1 and 2 OCREVUS 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 Adverse Reactions in Adult Patients with Primary Progressive MS In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of OCREVUS (600 mg of OCREVUS 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 5 summarizes the adverse reactions that occurred in the PPMS trial (Study 3). Table 5 Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo Adverse Reactions Study 3 OCREVUS 600 mg IV Every 24 Weeks One dose of OCREVUS (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 Adverse Reactions in Adult Patients who Received 2-hour Infusions Study 4 was designed to characterize the safety profile of OCREVUS infusions administered over 2 hours in patients with Relapsing-Remitting Multiple Sclerosis who did not experience a serious infusion reaction with any previous OCREVUS infusion. In this study, the incidence, intensity, and types of symptoms of infusion reactions were consistent with those of infusions administered over 3.5 hours [see Clinical Studies (14.3) ] . Laboratory Abnormalities in Adults Decreased Immunoglobulins OCREVUS 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 OCREVUS-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of OCREVUS-treated patients 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 OCREVUS-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively. The pooled data of OCREVUS 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 OCREVUS. Decreased Neutrophil Levels In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with OCREVUS and were between LLN - 1.5 × 10 9 /L and 1.0 × 10 9 /L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 × 10 9 /L and these were not associated with an infection. Pediatric Patients Adverse Reactions in Patients 10 to Less Than 18 Years of Age with Relapsing-Remitting MS The safety of OCREVUS in pediatric patients with relapsing-remitting MS was evaluated in one randomized, double-blind clinical study in 185 patients, 93 of whom received OCREVUS and 92 of whom received fingolimod [see Clinical Studies (14.4) ] . In the controlled pediatric trial (Study 5), the safety profile in pediatric patients was consistent with that observed in adult patients. Infusion Reactions Infusion reactions were the most common adverse reactions in patients treated with OCREVUS with an incidence of 48%, compared to an incidence of 24% in fingolimod-treated patients (placebo infusion). The incidence of infusion reactions was highest at 31% with infusion 1 of the initial dose (on day 1), and decreased to 9% with infusion 2 of the initial dose (on day 15). At the first subsequent dose (at 6 months), 16% of patients had an infusion reaction. The incidence and severity of infusion reactions decreased with additional subsequent infusions. The majority of infusion reactions were mild to moderate. One infusion reaction with infusion 1 of the initial dose was reported as serious because it required hospitalization. Infections Infections were observed in 73% of patients treated with OCREVUS (1.5 infections per patient-year) and 59% of patients treated with fingolimod (1.2 infections per patient-year). Serious infections occurred in 3% of patients treated with OCREVUS (0.03 serious infections per patient-year) compared to 3% of fingolimod-treated patients (0.03 serious infections per patient-year). Laboratory Abnormalities Decreased Immunoglobulins OCREVUS decreased total immunoglobulins over the controlled period of Study 5, with the greatest decline seen in IgM levels. Similar to the pattern observed in the adult population, reduction in IgM occurred earlier and in a higher proportion of patients compared to IgG and IgA. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of OCREVUS. 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

8.1 Pregnancy Risk Summary OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to OCREVUS have not been studied in clinical trials. The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown [see Warnings and Precautions (5.2) ] . Following administration of ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity [see Data ] . 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Following intravenous administration of OCREVUS to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses. Intravenous administration of OCREVUS (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the high dose. A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.