ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the labeling:Infusion Reactions [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Reduction in Immunoglobulins [see Warnings and Precautions (5.3)] Malignancies [see Warnings and Precautions (5.4)] Infusion Reactions [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Reduction in Immunoglobulins [see Warnings and Precautions (5.3)] Malignancies [see Warnings and Precautions (5.4)] 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)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 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). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of 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 OCREVUS has been evaluated in 1311 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 placebo-controlled study in patients with primary progressive MS (PPMS). Adverse Reactions in Patients with Relapsing Forms of MS In active-controlled clinical trials (Study 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 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 summarizes the adverse reactions that occurred in RMS trials (Study and Study 2). Table 2Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIFAdverse ReactionsStudies and 2OCREVUS600 mg IVEvery 24 WeeksThe first dose was given as two separate 300 mg infusions at Weeks and 2. (n=825)%REBIF44 mcg SQ3 Times per Week(n=826)%Upper respiratory tract infections4033Infusion reactions3410Depression87Lower respiratory tract infections85Back pain65Herpes virus- associated infections64Pain in extremity54. Adverse Reactions in Patients with Primary Progressive MSIn placebo-controlled clinical trial (Study 3), 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 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 summarizes the adverse reactions that occurred in the PPMS trial (Study 3). Table 3Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo Adverse ReactionsStudy 3OCREVUS600 mg IV Every 24 WeeksOne dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart) Placebo(n=486)%(n=239)%Upper respiratory tract infections4943Infusion reactions4026Skin infections1411Lower respiratory tract infections109Cough73Diarrhea65Edema peripheral65Herpes virus associated infections54. Adverse Reactions in Patients who Received 2-hour InfusionsStudy was designed to characterize the safety profile of OCREVUS infusions administered over hours in patients with Relapsing-Remitting Multiple Sclerosis who did not experience 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 Decreased ImmunoglobulinsOCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels; however, decrease in IgG levels was associated with an increased rate of serious infections.In the active-controlled (RMS) trials (Study 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 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 LevelsIn 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 given patient treated with OCREVUS and were between LLN 1.5 109/L and 1.0 109/L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 109/L and these were not associated with an infection. 6.2Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of positive result in test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to OCREVUS with the incidence of antibodies to other products may be misleading.Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with OCREVUS, 12 (~1%) tested positive for ADAs, of which patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of OCREVUS.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Serious herpes infections have been identified during postapproval use of OCREVUS [see Warnings and Precautions (5.2)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies have been performed to assess the carcinogenic potential of OCREVUS.No studies have been performed to assess the mutagenic potential of OCREVUS. As an antibody, OCREVUS is not expected to interact directly with DNA. No effects on reproductive organs were observed in male monkeys administered ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for weeks. There were also no effects on estrus cycle in female monkeys administered ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are and 10 times the recommended human dose of 600 mg, on mg/kg basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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, cell surface antigen present on pre-B and mature lymphocytes. Following cell surface binding to lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. 12.2 Pharmacodynamics. For B-cell counts, assays for CD19+ B-cells are used because the presence of OCREVUS interferes with the CD20 assay. Treatment with OCREVUS reduces CD19+ B-cell counts in blood by 14 days after infusion. In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of OCREVUS at least one time in 0.3% to 4.1% of patients. In clinical study of 51 patients, the median time for B-cell counts to return to either baseline or LLN was 72 weeks (range 27-175 weeks) after the last OCREVUS infusion. Within 2.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 90% of patients.. 12.3 Pharmacokinetics. Pharmacokinetics (PK) of OCREVUS in MS clinical studies fit two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of OCREVUS was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of ocrelizumab were either 600 mg every months (RMS patients) or two 300 mg infusions separated by 14 days every months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion over 3.5 hours) and 141 mcg/mL in patients with PPMS (two 300 mg infusions over 2.5 hours administered within two weeks). The mean maximum peak concentrations (Cmax) of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS) observed after the 3.5-hour infusion and 2-hour infusion were 202 +- 42 (mean +- SD) and 200 +- 46 mcg/mL, respectively, compared to the previously reported Cmax of 212 mcg/mL. The pharmacokinetics of ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.. Distribution The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 and 0.29 L/day, respectively.. EliminationConstant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which declined with half-life of 33 weeks. The terminal elimination half-life was 26 days.. MetabolismThe metabolism of OCREVUS has not been directly studied because antibodies are cleared principally by catabolism.. Specific Populations Renal impairmentPatients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics of OCREVUS was observed in those patients.. Hepatic impairmentPatients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics of OCREVUS was observed in those patients.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Relapsing Forms of Multiple Sclerosis (RMS). The efficacy of OCREVUS was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks (Study and Study 2). The dose of OCREVUS was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV infusions administered weeks apart, and subsequent doses were administered as single 600 mg IV infusion) and placebo subcutaneous injections were given times per week. The dose of REBIF, the active comparator, was 44 mcg given as subcutaneous injections times per week and placebo IV infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from to 5.5. Patients with primary progressive forms of multiple sclerosis (MS) were excluded. Neurological evaluations were performed every 12 weeks and at the time of suspected relapse. Brain MRIs were performed at baseline and at Weeks 24, 48, and 96. The primary outcome of both Study and Study was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of point or more from the baseline EDSS score attributable to MS when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at regularly scheduled visit 12 weeks after the initial documentation of neurological worsening. The primary population for analysis of confirmed disability progression was the pooled population from Studies and 2.In Study 1, 410 patients were randomized to OCREVUS and 411 to REBIF; 11% of OCREVUS-treated and 17% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with non-steroid therapy for MS in the years prior to the study. At baseline, 40% of patients had one or more T1 Gd-enhancing lesions (mean 1.8). In Study 2, 417 patients were randomized to OCREVUS and 418 to REBIF; 14% of OCREVUS-treated and 23% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with non-steroid therapy for MS in the years prior to the study. At baseline, 40% of OCREVUS-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9). In Study and Study 2, OCREVUS significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study and Study are presented in Table and Figure 1. Table 4Key Clinical and MRI Endpoints in RMS Patients from Study and Study 2EndpointsStudy 1Study 2OCREVUS 600 mg every 24 weeksREBIF 44 mcg three times weekOCREVUS 600 mg every 24 weeksREBIF 44 mcg three times weekN=410N=411N=417N=418Clinical EndpointsAnnualized Relapse Rate (Primary Endpoint)0.1560.2920.1550.290 Relative Reduction46% (p<0.0001)47% (p<0.0001)Proportion Relapse-free83%71%82%72%Proportion of Patients with 12-week Confirmed Disability ProgressionDefined as an increase of 1.0 point or more from the baseline Expanded Disability Status Scale (EDSS) score for patients with baseline score of 5.5 or less, or 0.5 or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96. 9.8% OCREVUS vs 15.2% REBIF Risk Reduction (Pooled AnalysisData prospectively pooled from Study and Study 2.)40%; p=0.0006MRI EndpointsMean number of T1 Gd-enhancing lesions per MRI scan0.0160.2860.0210.416 Relative Reduction94% (p<0.0001)95% (p<0.0001)Mean number of new and/or enlarging T2 hyperintense lesions per MRI 0.3231.4130.3251.904 Relative Reduction77% (p<0.0001)83% (p<0.0001)Figure Kaplan-Meier PlotPre-specified pooled analysis of Study and of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Pooled Studies and in Patients with RMS (Pooled ITT Population)In exploratory subgroup analyses of Study and Study 2, the effect of OCREVUS on annualized relapse rate and disability progression was similar in male and female patients.. Figure 1. 14.2Primary Progressive Multiple Sclerosis (PPMS). Study was randomized, double-blind, placebo-controlled clinical trial in patients with PPMS. Patients were randomized 2:1 to receive either OCREVUS 600 mg or placebo as two 300 mg intravenous infusions weeks apart every 24 weeks for at least 120 weeks. Selection criteria required baseline EDSS of to 6.5 and score of or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurological assessments were conducted every 12 weeks. An MRI scan was obtained at baseline and at Weeks 24, 48, and 120. In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume.Study randomized 488 patients to OCREVUS and 244 to placebo; 21% of OCREVUS-treated patients and 34% of placebo-treated patients did not complete the trial. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 45; 49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with non-steroid treatment for MS. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for OCREVUS-treated patients than for placebo-treated patients (see Figure 2). Results for Study are presented in Table and Figure 2.Table 5Key Clinical and MRI Endpoints in PPMS patients for Study 3EndpointsStudy OCREVUS 600 mg (two 300 mg infusions two weeks apart every 24 weeks)PlaceboN=488N=244Clinical OutcomesProportion of patients with 12-week Confirmed Disability ProgressionDefined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or an increase of 0.5 or more when the baseline score is more than 5.5 32.9%39.3% Risk reduction24%; p=0.0321MRI EndpointsMean change in volume of T2 lesions, from baseline to Week 120 (cm3) -0.390.79p<0.0001Figure Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Study 3All patients in this analysis had minimum of 120 weeks of follow-up. The primary analysis is based on all disability progression events accrued including 21 without confirmatory EDSS at 12 weeks. In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in OCREVUS-treated patients compared to 59% in placebo-treated patients (25% risk reduction). In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in OCREVUS-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in OCREVUS-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored OCREVUS numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions. Figure 2. 14.3 Safety Study of 2-Hour Infusions. The safety of the 2-hour OCREVUS infusion was evaluated in Study (NCT03085810), prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy in patients with Relapsing-Remitting Multiple Sclerosis who were naive to other non-steroid therapies for MS and did not experience serious infusion reaction with any previous OCREVUS infusion. The first dose of OCREVUS was administered as two 300 mg infusions (600 mg total) separated by 14 days. After enrollment in the substudy, patients were randomized in 1:1 ratio to receive infusions over approximately 3.5-hours or 2-hours, after appropriate premedication [see Dosage and Administration (2.2)], every 24 weeks. The randomization was stratified by region and the dose at which patients were first randomized.The primary endpoint of the substudy was the proportion of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion of OCREVUS. The primary analysis was performed when 580 patients were randomized, at which time 469/579 (81%) of the treated patients had received only single randomized infusion of OCREVUS. The proportions of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion in this substudy were similar between the 2-hour and 3.5-hour infusion groups (24.4% versus 23.3%, respectively). Overall, in all randomized doses, 27.1% of the patients in the 2-hour infusion group and 25.0% of the patients in the 3.5-hour infusion group reported mild or moderate infusion reactions; two infusion reactions were severe in intensity, with one severe infusion reaction (0.3%) reported in one patient in each group in this substudy [see Warnings and Precautions (5.1)]. There were no life-threatening, fatal, or serious infusion reactions in this substudy.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. OCREVUS is contraindicated in patients with:Active HBV infection [see Dosage and Administration (2.6) and Warnings and Precautions (5.2)] history of life-threatening infusion reaction to OCREVUS [see Warnings and Precautions (5.1)] Active HBV infection [see Dosage and Administration (2.6) and Warnings and Precautions (5.2)] A history of life-threatening infusion reaction to OCREVUS [see Warnings and Precautions (5.1)] Active hepatitis virus infection (4)History of life-threatening infusion reaction to OCREVUS (4). Active hepatitis virus infection (4). History of life-threatening infusion reaction to OCREVUS (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ocrelizumab is recombinant humanized monoclonal antibody directed against CD20-expressing B-cells. Ocrelizumab is glycosylated immunoglobulin G1 (IgG1) with molecular mass of approximately 145 kDa.OCREVUS (ocrelizumab) Injection for intravenous infusion is preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied in single-dose vials. Each mL of solution contains 30 mg ocrelizumab, glacial acetic acid (0.25 mg), polysorbate 20 (0.2 mg), sodium acetate trihydrate (2.14 mg), and trehalose dihydrate (40 mg) at pH 5.3.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Hepatitis virus and quantitative serum immunoglobulin screening are required before the first dose (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 Start dose: 300 mg intravenous infusion, followed two weeks later by second 300 mg intravenous infusion (2.3)Subsequent doses: 600 mg intravenous infusion every 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). Hepatitis virus and quantitative serum immunoglobulin screening are required before the first dose (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 Start dose: 300 mg intravenous infusion, followed two weeks later by second 300 mg intravenous infusion (2.3)Subsequent doses: 600 mg intravenous infusion every months (2.3) Start dose: 300 mg intravenous infusion, followed two weeks later by second 300 mg intravenous infusion (2.3). Subsequent doses: 600 mg intravenous infusion every 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 Virus ScreeningPrior to initiating OCREVUS, perform Hepatitis 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 ImmunoglobulinsPrior to initiating OCREVUS, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions (5.3)]. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with OCREVUS.. VaccinationsBecause 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 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of OCREVUS for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].. 2.2Preparation Before Every Infusion. Infection AssessmentPrior 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 PremedicationPre-medicate with 100 mg of methylprednisolone (or an equivalent corticosteroid) administered intravenously approximately 30 minutes prior to each OCREVUS infusion to reduce the frequency and severity of infusion reactions [see Warnings and Precautions (5.1)]. Pre-medicate with an antihistamine (e.g., diphenhydramine) approximately 30-60 minutes prior to each OCREVUS infusion to further reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.. 2.3Recommended 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. Initial dose: 300 mg intravenous infusion, followed two weeks later by second 300 mg intravenous infusion.Subsequent doses: single 600 mg intravenous infusion every months. Observe the patient for at least one hour after the completion of the infusion [see Warnings and Precautions (5.1)].Table 1Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS Amount and VolumeSolutions of OCREVUS for intravenous infusion are prepared by dilution of the drug product into an infusion bag containing 0.9% Sodium Chloride Injection, to final drug concentration of approximately 1.2 mg/mL. Infusion Rate and DurationInfusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5)]. Initial Dose(two infusions)Infusion 1300 mg in 250 mLStart at 30 mL per hourIncrease by 30 mL per hour every 30 minutesMaximum: 180 mL per hourDuration: 2.5 hours or longerInfusion 2(2 weeks later)300 mg in 250 mLSubsequent Doses(one infusion)every months)Administer the first Subsequent Dose months after Infusion of the Initial Dose.Option Infusion of approximately 3.5 hours duration 600 mg in 500 mLStart at 40 mL per hourIncrease by 40 mL per hour every 30 minutesMaximum: 200 mL per hourDuration: 3.5 hours or longerOROption 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 hours duration 600 mg in 500 mLStart at 100 mL per hour for the first 15 minutesIncrease to 200 mL per hour for the next 15 minutesIncrease to 250 mL per hour for the next 30 minutesIncrease to 300 mL per hour for the remaining 60 minutesDuration: hours or longer. Initial dose: 300 mg intravenous infusion, followed two weeks later by second 300 mg intravenous infusion.. Subsequent doses: single 600 mg intravenous infusion every months. Observe the patient for at least one hour after the completion of the infusion [see Warnings and Precautions (5.1)].. 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. 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. 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 minutesDuration: hours or longer. 2.4Delayed or Missed Doses If 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 months after the missed dose is administered. Doses of OCREVUS must be separated by at least months [see Dosage and Administration (2.3)]. 2.5Dose 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 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 [see Dosage and Administration (2.2)]. If this rate is tolerated, increase the rate as described in Table 1. 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. This change in rate will increase the total duration of the infusion but not the total dose. 2.6Preparation and Storage of the Dilute Solution for Infusion PreparationOCREVUS must be prepared by healthcare professional using aseptic technique. 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 intended dose and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, to final drug concentration of approximately 1.2 mg/mL. Withdraw 10 mL (300 mg) of OCREVUS and inject into 250 mLWithdraw 20 mL (600 mg) of OCREVUS and inject into 500 mLDo not use other diluents to dilute OCREVUS since their use has not been tested. The product contains no preservative and is intended for single use only. Withdraw 10 mL (300 mg) of OCREVUS and inject into 250 mL. Withdraw 20 mL (600 mg) of OCREVUS and inject into 500 mL. Storage of Infusion SolutionPrior 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 2C to 8C (36F to 46F) and hours at room temperature up to 25C (77F), 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.. AdministrationAdminister the diluted infusion solution through dedicated line using an infusion set with 0.2 or 0.22 micron in-line filter.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 300 mg/10 mL (30 mg/mL) clear or slightly opalescent, and colorless to pale brown solution in single-dose vial.. Injection: 300 mg/10 mL (30 mg/mL) in single-dose vial (3). Injection: 300 mg/10 mL (30 mg/mL) in single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1Immunosuppressive 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. 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)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Contraception Women of childbearing potential should use effective contraception while receiving OCREVUS and for months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. OCREVUS (ocrelizumab) injection is preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01). Store OCREVUS vials at 2C to 8C (36F to 46F) in the outer carton to protect from light. Do not freeze or shake.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Serious herpes infections have been identified during postapproval use of OCREVUS [see Warnings and Precautions (5.2)].

INDICATIONS & USAGE SECTION.

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 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 is 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 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Infusion ReactionsInform patients about the signs and symptoms of infusion reactions, and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions [see Warnings and Precautions (5.1)].. InfectionAdvise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose [see Clinical Pharmacology (12.2)]. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores [see Warnings and Precautions (5.2)]. Advise patients that PML has happened with drugs that are similar to OCREVUS and may happen with OCREVUS. Inform the patient that PML is characterized by progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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 [see Warnings and Precautions (5.2)]. Advise patients that OCREVUS may cause reactivation of hepatitis infection and that monitoring will be required if they are at risk [see Warnings and Precautions (5.2)].Advise patients that herpes infections, including serious herpes infections affecting the central nervous system, skin, and eyes, have occurred during treatment with OCREVUS. Advise patients to promptly contact their healthcare provider if they experience any signs or symptoms of herpes infections including oral or genital symptoms, fever, skin rash, pain, itching, decreased visual acuity, eye redness, eye pain, headache, neck stiffness, or change in mental status [see Warnings and Precautions (5.2)]. VaccinationAdvise patients to complete any required live or live-attenuated vaccinations at least weeks and, whenever possible, non-live vaccinations at least weeks prior to initiation of OCREVUS. Administration of live-attenuated or live vaccines is not recommended during OCREVUS treatment and until B-cell recovery [see Warnings and Precautions (5.2)].. MalignanciesAdvise patients that an increased risk of malignancy, including breast cancer, may exist with OCREVUS. Advise patients that they should follow standard breast cancer screening guidelines [see Warnings and Precautions (5.4)]. ContraceptionFemales of childbearing potential should use effective contraception while receiving OCREVUS and for months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)]. Pregnancy RegistryInstruct patients that if they are pregnant or plan to become pregnant while taking OCREVUS they should inform their healthcare provider [see Use in Specific Populations (8.1)]. Encourage patients to enroll in the OCREVUS Pregnancy Registry if they become pregnant while taking OCREVUS [see Use in Specific Populations (8.1)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 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, cell surface antigen present on pre-B and mature lymphocytes. Following cell surface binding to lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies have been performed to assess the carcinogenic potential of OCREVUS.No studies have been performed to assess the mutagenic potential of OCREVUS. As an antibody, OCREVUS is not expected to interact directly with DNA. No effects on reproductive organs were observed in male monkeys administered ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for weeks. There were also no effects on estrus cycle in female monkeys administered ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are and 10 times the recommended human dose of 600 mg, on mg/kg basis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 300 mg/10 mL Vial Carton. NDC 50242-150-01Ocrevus(R) (ocrelizumab) Injection300 mg/10 mL (30 mg/mL)For Intravenous Infusion. Must Be Diluted.Single-Dose Vial. Discard Unused Portion.Attention Pharmacist: Dispense the accompanying Medication Guide to each patient.Rx only1 vialGenentech10233065. PRINCIPAL DISPLAY PANEL 300 mg/10 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of OCREVUS in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. For B-cell counts, assays for CD19+ B-cells are used because the presence of OCREVUS interferes with the CD20 assay. Treatment with OCREVUS reduces CD19+ B-cell counts in blood by 14 days after infusion. In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of OCREVUS at least one time in 0.3% to 4.1% of patients. In clinical study of 51 patients, the median time for B-cell counts to return to either baseline or LLN was 72 weeks (range 27-175 weeks) after the last OCREVUS infusion. Within 2.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 90% of patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics (PK) of OCREVUS in MS clinical studies fit two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of OCREVUS was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of ocrelizumab were either 600 mg every months (RMS patients) or two 300 mg infusions separated by 14 days every months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion over 3.5 hours) and 141 mcg/mL in patients with PPMS (two 300 mg infusions over 2.5 hours administered within two weeks). The mean maximum peak concentrations (Cmax) of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS) observed after the 3.5-hour infusion and 2-hour infusion were 202 +- 42 (mean +- SD) and 200 +- 46 mcg/mL, respectively, compared to the previously reported Cmax of 212 mcg/mL. The pharmacokinetics of ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.. Distribution The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 and 0.29 L/day, respectively.. EliminationConstant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which declined with half-life of 33 weeks. The terminal elimination half-life was 26 days.. MetabolismThe metabolism of OCREVUS has not been directly studied because antibodies are cleared principally by catabolism.. Specific Populations Renal impairmentPatients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics of OCREVUS was observed in those patients.. Hepatic impairmentPatients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics of OCREVUS was observed in those patients.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to OCREVUS during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.. Risk SummaryOCREVUS is 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 DataFollowing 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. no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are and 10 times the recommended human dose of 600 mg, on mg/kg basis.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1, 2.3)12/2020Warnings and Precautions (5.2, 5.3)11/2020.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: 12/2020 MEDICATION GUIDEOCREVUS(R) (oak-rev-us)(ocrelizumab)injection, for intravenous useWhat is the most important information should know about OCREVUS OCREVUS can cause serious side effects, including:Infusion reactions: Infusion reactions are common side effect of OCREVUS, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least hour after each infusion of OCREVUS for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms: itchy skinrash hivestirednesscoughing or wheezingtrouble breathingthroat irritation or pain feeling faint fever redness on your face (flushing)nauseaheadacheswelling of the throat dizzinessshortness of breath fatiguefast heart beat These infusion reactions can happen for up to 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion.If you get infusion reactions, your healthcare provider may need to stop or slow down the rate of your infusion.Infection:OCREVUS increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Infections are common side effect, which can be serious. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, or cough that does not go away. Signs of herpes infection include:cold soresshinglesgenital soresskin rashpainitching Signs of more serious herpes infection include:changes in visioneye redness or eye painsevere or persistent headachestiff neckconfusion Signs of infection can happen during treatment or after you have received your last dose of OCREVUS. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with OCREVUS until your infection is gone.Progressive Multifocal Leukoencephalopathy (PML): Although no cases have been seen with OCREVUS treatment in clinical trials, PML may happen with OCREVUS. PML is rare brain infection that usually leads to death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These may include problems with thinking, balance, eyesight, weakness on side of your body, strength, or using your arms or legs.Hepatitis virus (HBV) reactivation: Before starting treatment with OCREVUS, your healthcare provider will do blood tests to check for hepatitis viral infection. If you have ever had hepatitis virus infection, the hepatitis virus may become active again during or after treatment with OCREVUS. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop receiving OCREVUS.Weakened immune system: OCREVUS taken before or after other medicines that weaken the immune system could increase your risk of getting infections.Decreased immunoglobulins: OCREVUS may cause decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels.See What are the possible side effects of OCREVUS for more information about side effects.What is OCREVUSOCREVUS is prescription medicine used to treat: 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. It is not known if OCREVUS is safe and effective in children.Who should not receive OCREVUS Do not receive OCREVUS if you have an active hepatitis virus (HBV) infection.Do not receive OCREVUS if you have had life-threatening allergic reaction to OCREVUS. Tell your healthcare provider if you have had an allergic reaction to OCREVUS or any of its ingredients in the past. See What are the ingredients in OCREVUS for complete list of ingredients in OCREVUS.Before receiving OCREVUS, tell your healthcare provider about all of your medical conditions, including if you:have or think you have an infection. See What is the most important information should know about OCREVUS have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS. These medicines could increase your risk of getting an infection. have ever had hepatitis or are carrier of the hepatitis virus. have had recent vaccination or are scheduled to receive any vaccinations. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with OCREVUS. You should not receive live or live-attenuated vaccines while you are being treated with OCREVUS and until your healthcare provider tells you that your immune system is no longer weakened.When possible, you should receive any non-live vaccines at least weeks before you start treatment with OCREVUS. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with OCREVUS, talk to your healthcare provider. If you have baby and you received OCREVUS during your pregnancy, it is important to tell your babys healthcare provider about receiving OCREVUS so they can decide when your baby should be vaccinated. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if OCREVUS will harm your unborn baby. You should use birth control (contraception) during treatment with OCREVUS and for months after your last infusion of OCREVUS. Talk with your healthcare provider about what birth control method is right for you during this time.Pregnancy Registry. There is pregnancy registry for women who take OCREVUS during pregnancy. If you become pregnant while receiving OCREVUS, tell your healthcare provider right away. Talk to your healthcare provider about registering with the OCREVUS Pregnancy Registry. The purpose of this registry is to collect information about your health and your babys health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. are breastfeeding or plan to breastfeed. It is not known if OCREVUS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take OCREVUS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive OCREVUSOCREVUS is given through needle placed in your vein (intravenous infusion) in your arm. Before treatment with OCREVUS, your healthcare provider will give you corticosteroid medicine and an antihistamine to help reduce infusion reactions (make them less frequent and less severe). You may also receive other medicines to help reduce infusion reactions. See What is the most important information should know about OCREVUS Your first full dose of OCREVUS will be given as separate infusions, weeks apart. Each infusion will last about hours and 30 minutes.Your next doses of OCREVUS will be given as infusion every months. These infusions will last about hours to hours and 30 minutes depending on the infusion rate prescribed by your healthcare provider.What are the possible side effects of OCREVUSOCREVUS may cause serious side effects, including: see What is the most important information should know about OCREVUS risk of cancers (malignancies) including breast cancer. Follow your healthcare providers instructions about standard screening guidelines for breast cancer.These are not all the possible side effects of OCREVUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of OCREVUS.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about OCREVUS that is written for health professionals.What are the ingredients in OCREVUSActive ingredient: ocrelizumab.Inactive ingredients: glacial acetic acid, polysorbate 20, sodium acetate trihydrate, trehalose dihydrate.Manufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990U.S. License No. 1048For more information, go to www.OCREVUS.com or call 1-844-627-3887.. Infusion reactions: Infusion reactions are common side effect of OCREVUS, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least hour after each infusion of OCREVUS for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms: itchy skin. rash hives. tiredness. coughing or wheezing. trouble breathing. throat irritation or pain feeling faint fever redness on your face (flushing). nausea. headache. swelling of the throat dizziness. shortness of breath fatigue. fast heart beat. Infection:OCREVUS increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Infections are common side effect, which can be serious. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, or cough that does not go away. Signs of herpes infection include:. OCREVUS increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Infections are common side effect, which can be serious. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, or cough that does not go away. Signs of herpes infection include:. cold sores. shingles. genital sores. skin rash. pain. itching. Signs of more serious herpes infection include:. changes in vision. eye redness or eye pain. severe or persistent headache. stiff neck. confusion. Signs of infection can happen during treatment or after you have received your last dose of OCREVUS. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with OCREVUS until your infection is gone.. Progressive Multifocal Leukoencephalopathy (PML): Although no cases have been seen with OCREVUS treatment in clinical trials, PML may happen with OCREVUS. PML is rare brain infection that usually leads to death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These may include problems with thinking, balance, eyesight, weakness on side of your body, strength, or using your arms or legs.. Hepatitis virus (HBV) reactivation: Before starting treatment with OCREVUS, your healthcare provider will do blood tests to check for hepatitis viral infection. If you have ever had hepatitis virus infection, the hepatitis virus may become active again during or after treatment with OCREVUS. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop receiving OCREVUS.. Weakened immune system: OCREVUS taken before or after other medicines that weaken the immune system could increase your risk of getting infections.. Decreased immunoglobulins: OCREVUS may cause decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels.. 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.. Do not receive OCREVUS if you have an active hepatitis virus (HBV) infection.. Do not receive OCREVUS if you have had life-threatening allergic reaction to OCREVUS. Tell your healthcare provider if you have had an allergic reaction to OCREVUS or any of its ingredients in the past. See What are the ingredients in OCREVUS for complete list of ingredients in OCREVUS.. have or think you have an infection. See What is the most important information should know about OCREVUS have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS. These medicines could increase your risk of getting an infection. have ever had hepatitis or are carrier of the hepatitis virus. have had recent vaccination or are scheduled to receive any vaccinations. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with OCREVUS. You should not receive live or live-attenuated vaccines while you are being treated with OCREVUS and until your healthcare provider tells you that your immune system is no longer weakened.When possible, you should receive any non-live vaccines at least weeks before you start treatment with OCREVUS. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with OCREVUS, talk to your healthcare provider. If you have baby and you received OCREVUS during your pregnancy, it is important to tell your babys healthcare provider about receiving OCREVUS so they can decide when your baby should be vaccinated. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with OCREVUS. You should not receive live or live-attenuated vaccines while you are being treated with OCREVUS and until your healthcare provider tells you that your immune system is no longer weakened.. When possible, you should receive any non-live vaccines at least weeks before you start treatment with OCREVUS. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with OCREVUS, talk to your healthcare provider. If you have baby and you received OCREVUS during your pregnancy, it is important to tell your babys healthcare provider about receiving OCREVUS so they can decide when your baby should be vaccinated.. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if OCREVUS will harm your unborn baby. You should use birth control (contraception) during treatment with OCREVUS and for months after your last infusion of OCREVUS. Talk with your healthcare provider about what birth control method is right for you during this time.Pregnancy Registry. There is pregnancy registry for women who take OCREVUS during pregnancy. If you become pregnant while receiving OCREVUS, tell your healthcare provider right away. Talk to your healthcare provider about registering with the OCREVUS Pregnancy Registry. The purpose of this registry is to collect information about your health and your babys health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. Pregnancy Registry. There is pregnancy registry for women who take OCREVUS during pregnancy. If you become pregnant while receiving OCREVUS, tell your healthcare provider right away. Talk to your healthcare provider about registering with the OCREVUS Pregnancy Registry. The purpose of this registry is to collect information about your health and your babys health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.. are breastfeeding or plan to breastfeed. It is not known if OCREVUS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take OCREVUS. OCREVUS is given through needle placed in your vein (intravenous infusion) in your arm. Before treatment with OCREVUS, your healthcare provider will give you corticosteroid medicine and an antihistamine to help reduce infusion reactions (make them less frequent and less severe). You may also receive other medicines to help reduce infusion reactions. See What is the most important information should know about OCREVUS Your first full dose of OCREVUS will be given as separate infusions, weeks apart. Each infusion will last about hours and 30 minutes.. Your next doses of OCREVUS will be given as infusion every months. These infusions will last about hours to hours and 30 minutes depending on the infusion rate prescribed by your healthcare provider.. see What is the most important information should know about OCREVUS risk of cancers (malignancies) including breast cancer. Follow your healthcare providers instructions about standard screening guidelines for breast cancer.

SPL UNCLASSIFIED SECTION.

2.1 Assessments Prior to First Dose of OCREVUS Hepatitis Virus ScreeningPrior to initiating OCREVUS, perform Hepatitis 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 ImmunoglobulinsPrior to initiating OCREVUS, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions (5.3)]. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with OCREVUS.. VaccinationsBecause 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 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of OCREVUS for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

STORAGE AND HANDLING SECTION.

Store OCREVUS vials at 2C to 8C (36F to 46F) in the outer carton to protect from light. Do not freeze or shake.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to OCREVUS during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.. Risk SummaryOCREVUS is 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 DataFollowing 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. no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are and 10 times the recommended human dose of 600 mg, on mg/kg basis.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. Contraception Women of childbearing potential should use effective contraception while receiving OCREVUS and for months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)].. 8.4 Pediatric Use. Safety and effectiveness of OCREVUS in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS if life-threatening or disabling infusion reaction occurs (2.3, 5.1)Infections: 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)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, 5.3)Malignancies: An increased risk of malignancy, including breast cancer, may exist with OCREVUS (5.4). Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS if life-threatening or disabling infusion reaction occurs (2.3, 5.1). Infections: 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). 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, 5.3). Malignancies: An increased risk of malignancy, including breast cancer, may exist with OCREVUS (5.4). 5.1Infusion 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. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34 to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.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 (2.3)]. 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. 5.2Infections A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients 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)]. OCREVUS was not associated with an increased risk of serious infections in MS patients. Delay OCREVUS administration in patients with an active infection until the infection is resolved.. Respiratory Tract InfectionsA higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of OCREVUS-treated patients 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.. HerpesIn active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients 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 OCREVUS-treated patients 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)]. Progressive Multifocal Leukoencephalopathy (PML)PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. 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.. Hepatitis Virus (HBV) ReactivationHepatitis 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 ImmunosuppressantsWhen 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.. VaccinationsAdminister all immunizations according to immunization guidelines at least weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 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 PregnancyIn 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.You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with qualified specialist, to assess whether protective immune response was mounted [see Use in Specific Populations (8.1)]. 5.3 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) and their open-label extensions (up to approximately years of exposure) have shown an association between decreased levels of immunoglobulin (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)].. 5.4 Malignancies. An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.