HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
OCREVUS safely and effectively. See full prescribing information for
OCREVUS.
OCREVUS® (ocrelizumab) injection, for intravenous use
Initial U.S. Approval: 2017---------------------------RECENT MAJOR CHANGES --------------------------Warnings and Precautions (5.2)
1/2024--------------------------- INDICATIONS AND USAGE---------------------------OCREVUS is a CD20-directed cytolytic antibody indicated for the treatmentof: 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)








OCREVUS if a life-threatening or disabling infusion reaction occurs (2.3,
5.1)
Infections: Serious, including life-threatening and fatal infections, haveoccurred. Delay OCREVUS administration in patients with an active
infection until the infection is resolved. Vaccination with live-attenuated orlive vaccines is not recommended during treatment with OCREVUS andafter 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 oftreatment with OCREVUS, until B-cell repletion, and especially whenrecurrent 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 issuspected (5.6)-----------------------DOSAGE AND ADMINISTRATION ---------------------- Hepatitis B 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 infusiono Start dose: 300 mg intravenous infusion, followed two weeks later by asecond 300 mg intravenous infusion (2.3)
o Subsequent doses: 600 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)--------------------- DOSAGE FORMS AND STRENGTHS--------------------- Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial (3)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------ CONTRAINDICATIONS ----------------------------- Active hepatitis B virus infection (4) History of life-threatening infusion reaction to OCREVUS (4)----------------------- USE IN SPECIFIC POPULATIONS ----------------------
Pregnancy: Based on animal data, may cause fetal harm (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

7.1 Immunosuppressive or Immune-Modulating Therapies
7.2 Vaccinations
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Relapsing Forms of Multiple Sclerosis (RMS)
14.2 Primary Progressive Multiple Sclerosis (PPMS)
14.3 Safety Study of 2-Hour Infusions
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION------------------------------ ADVERSE REACTIONS -----------------------------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)

See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
----------------------- WARNINGS AND PRECAUTIONS-----------------------Revised: 6/2024
 Infusion Reactions: Management recommendations for infusion reactions
depend on the type and severity of the reaction. Permanently discontinue_______________________________________________________________________________________________________________________________________

1
2

INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
2.1 Assessments Prior to First Dose of OCREVUS
2.2 Preparation Before Every Infusion
2.3 Recommended Dosage and Dose Administration
2.4 Delayed or Missed Doses
2.5 Dose Modifications Because of Infusion Reactions
2.6 Preparation and Storage of the Dilute Solution for Infusion
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Infusion Reactions
5.2 Infections
5.3 Progressive Multifocal Leukoencephalopathy (PML)
5.4 Reduction in Immunoglobulins
5.5 Malignancies
5.6 Immune-Mediated Colitis
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience*Sections or subsections omitted from the full prescribing information are notlisted7 DRUG INTERACTIONS_______________________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION
1

INDICATIONS AND USAGEOCREVUS 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
2

DOSAGE AND ADMINISTRATION

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 inpatients 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 andPrecautions (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 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 ClinicalPharmacology (12.2)].
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
Pre-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 ofinfusion reactions.
The addition of an antipyretic (e.g., acetaminophen) may also be considered.
2.3 Recommended Dosage and Dose Administration
Administer OCREVUS under the close supervision of an experienced healthcare professional with access toappropriate medical support to manage severe reactions such as serious infusion reactions.


Initial dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous
infusion.
Subsequent doses: single 600 mg intravenous infusion every 6 months.

Observe the patient for at least one hour after the completion of the infusion [see Warnings andPrecautions (5.1)].

Table 1

Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS
Amount and Volume1

Initial Dose
(two infusions)

Infusion 1

300 mgin 250 mL

Infusion 2(2 weeks later)

300 mgin 250 mL

Option 1
Infusion of
approximately
3.5 hours
duration3

600 mgin 500 mL

Infusion Rate and Duration3
 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
OR

Subsequent
Doses(one infusion)
every 6 months)2

Option 2(If no priorseriousinfusionreaction withany previous
OCREVUSinfusion)4
Infusion of
approximately
2 hours
duration3

600 mgin 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 theremaining 60 minutes
 Duration: 2 hours or longer

1

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.
2Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.
3
Infusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5)].
4[see Adverse Reactions (6.1) and Clinical Studies (14.3)].

2.4 Delayed or Missed Doses
If a planned infusion of OCREVUS is missed, administer OCREVUS as soon as possible; do not wait until thenext 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 halfof 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 [see Dosage and Administration (2.3)]. This change in rate will increase the total durationof 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 atleast 30 minutes [see Warnings and Precautions (5.1)]. If this rate is tolerated, increase the rate as described inTable 1 [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 intended dose and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, to a
final drug concentration of approximately 1.2 mg/mL.
Withdraw 10 mL (300 mg) of OCREVUS and inject into 250 mLWithdraw 20 mL (600 mg) of OCREVUS and inject into 500 mL

Do not use other diluents to dilute OCREVUS since their use has not been tested. The product contains nopreservative and is intended for single use only.
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.
3

DOSAGE FORMS AND STRENGTHS

Injection: 300 mg/10 mL (30 mg/mL) clear or slightly opalescent, and colorless to pale brown solution in a singledose vial.
4

CONTRAINDICATIONSOCREVUS 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)]

5

WARNINGS AND PRECAUTIONS

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. In multiple sclerosis (MS) clinical trials, theincidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or anequivalent 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 (2.2)].
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 inpatients receiving OCREVUS. An increased risk of infections (including serious and fatal bacterial, fungal, andnew 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 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 in controlled trials.
Delay OCREVUS administration in patients with an active infection until the infection is resolved.
Respiratory Tract Infections
A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patientstaking 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 OCREVUStreated 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 onplacebo. 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-treatedpatients 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 OCREVUStreated 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 lifethreatening.
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+] orare 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) andClinical Pharmacology (12.1, 12.2)]. OCREVUS has not been studied in combination with other MS therapies.
Vaccinations
Administer all 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 beenstudied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until Bcell 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.
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 a qualified specialist, to assess whether aprotective immune response was mounted [see Use in Specific Populations (8.1)].
5.3

Progressive Multifocal Leukoencephalopathy (PML)

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 andother 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, andorientation 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. Manyof 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 toallow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associatedwith PML, lower PML-related mortality and morbidity have been reported in patients who were initiallyasymptomatic 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) and their open-label extensions (upto 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 thesetting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious
opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment withintravenous 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 OCREVUS-treated patients. Breast cancer 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 inpatients 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 inmany 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 orother gastrointestinal signs and symptoms, occur.
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)]






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)]

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect 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 ina 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 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 patientyears.
The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections andinfusion reactions. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
Table 2Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS
and Higher than REBIF
Studies 1 and 2

Adverse Reactions

Upper respiratory tract infections
Infusion reactions
Depression
Lower respiratory tract infections
Back pain
Herpes virus- associated infections
Pain in extremity

OCREVUS
600 mg IV
Every 24 Weeks1(n=825)
%
40
34
8
8
6
6
5

REBIF
44 mcg SQ
3 Times per Week
(n=826)
%
33
10
7
5
5
4
4

1 The first dose was given as two separate 300 mg infusions at Weeks 0 and 2.

Adverse Reactions in 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 3 summarizes theadverse 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 Reactions

Upper respiratory tract infections
Infusion reactions
Skin infections
Lower respiratory tract infections
Cough
Diarrhea
Edema peripheral
Herpes virus associated infections

Study 3
OCREVUS
Placebo
600 mg IV
Every 24
Weeks1(n=486)(n=239)
%
%
49
43
40
26
14
11
10
9
7
3
6
5
6
5
5
4

1 One dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart)

Adverse Reactions in Patients who Received 2-hour Infusions
Study 4 was designed to characterize the safety profile of OCREVUS infusions administered over 2 hours inpatients with Relapsing-Remitting Multiple Sclerosis who did not experience a serious infusion reaction withany 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 Immunoglobulins
OCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels; however, a decreasein 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, andIgM 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 patientstreated with OCREVUS.
Decreased Neutrophil Levels
In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patientscompared 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 x 109/L and 1.0 x 109/L. Overall, 1% of
the patients in the OCREVUS group had neutrophil counts less than 1.0 x 109/L and these were not associatedwith an infection.

6.2 Immunogenicity
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 a positive resultin a 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 incidenceof 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 6months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treatedwith OCREVUS, 12 (~1%) tested positive for ADAs, of which 2 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 thesereactions 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)]
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
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 therisk 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 havenot been assessed [see Warnings and Precautions (5.2)].
8
USE IN SPECIFIC POPULATIONS
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 beenreported 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 durationof B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, isunknown [see Warnings and Precautions (5.2)].

Following administration of ocrelizumab to pregnant monkeys at doses similar to or greater than those usedclinically, 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 clinicallyrecognized 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 Blymphocytes 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 dosesof 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through theneonatal 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 incirculating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affectedneonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the highdose.
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.
8.2 Lactation
Risk Summary
There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effectsof 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 theinfant is unknown. The developmental and health benefits of breastfeeding should be considered along with themother’s 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 6 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.
11 DESCRIPTION
Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells.
Ocrelizumab is a glycosylated immunoglobulin G1 (IgG1) with a molecular mass of approximately 145 kDa.
OCREVUS (ocrelizumab) injection for intravenous infusion is a 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), andtrehalose dihydrate (40 mg) at pH 5.3.

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, a cell surface antigen present on pre-B and mature B lymphocytes.
Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis
and complement-mediated lysis.
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 clinicalstudies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusionsof OCREVUS at least one time in 0.3% to 4.1% of patients. In a 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 a 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 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 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 ofocrelizumab 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 intercompartment clearance were estimated at 2.68 L and 0.29 L/day, respectively.
Elimination
Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which
declined with a half-life of 33 weeks. The terminal elimination half-life was 26 days.
Metabolism
The metabolism of OCREVUS has not been directly studied because antibodies are cleared principally bycatabolism.
Specific Populations
Renal Impairment
Patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics
of OCREVUS was observed in those patients.
Hepatic Impairment
Patients with mild hepatic impairment were included in clinical trials. No significant change in thepharmacokinetics of OCREVUS was observed in those patients.
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 8 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 2 and 10 times the recommended humandose of 600 mg, on a mg/kg basis.
14 CLINICAL STUDIES
14.1 Relapsing 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 1 andStudy 2). The dose of OCREVUS was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV
infusions administered 2 weeks apart, and subsequent doses were administered as a single 600 mg IV infusion)and placebo subcutaneous injections were given 3 times per week. The dose of REBIF, the active comparator,
was 44 mcg given as subcutaneous injections 3 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 0 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 a suspected relapse. Brain MRIs were performed at baseline and at
Weeks 24, 48, and 96.
The primary outcome of both Study 1 and Study 2 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 1 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 wasabove 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at aregularly 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 1 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 demographicand disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patientswas 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 beentreated with a non-steroid therapy for MS in the 2 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 demographicand disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patientswas 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 beentreated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of OCREVUS-treatedpatients had one or more T1 Gd-enhancing lesions (mean 1.9).
In Study 1 and Study 2, OCREVUS significantly lowered the annualized relapse rate and the proportion of patientswith disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study 1 and Study
2 are presented in Table 4 and Figure 1.

Table 4

Key Clinical and MRI Endpoints in RMS Patients from Study 1 and Study 2

Endpoints

Study 1
Study 2
OCREVUSREBIF 44
OCREVUSREBIF 44
600 mg
mcg three
600 mg
mcg three
times
a
week
times
a weekevery 24
every 24
weeks
weeks
N=410
N=411
N=417
N=418

Clinical Endpoints
Annualized Relapse Rate (Primary Endpoint)
Relative Reduction
Proportion Relapse-free

0.156

0.292

0.155

0.290

46% (p<0.0001)

47% (p<0.0001)

83%

82%

Proportion of Patients with 12-week Confirmed
Disability Progression1

71%

72%

9.8% OCREVUS vs 15.2% REBIF

Risk Reduction (Pooled Analysis2)

40%; p=0.0006

MRI Endpoints
Mean number of T1 Gd-enhancing lesions per MRI
scanRelative Reduction
Mean number of new and/or enlarging T2
hyperintense lesions per MRI
Relative Reduction
1

0.016
0.286
94% (p<0.0001)

0.021
0.416
95% (p<0.0001)

0.323

0.325

1.413

77% (p<0.0001)

1.904

83% (p<0.0001)

Defined 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 ormore when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96.
2
Data prospectively pooled from Study 1 and Study 2.

Figure 1 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 Pooled Studies 1 and 2 in Patients with RMS (Pooled ITT Population)*Pre-specified pooled analysis of Study 1 and 2

In exploratory subgroup analyses of Study 1 and Study 2, the effect of OCREVUS on annualized relapse rate anddisability progression was similar in male and female patients.
14.2 Primary Progressive Multiple Sclerosis (PPMS)
Study 3 was a randomized, double-blind, placebo-controlled clinical trial in patients with PPMS. Patients wererandomized 2:1 to receive either OCREVUS 600 mg or placebo as two 300 mg intravenous infusions 2 weeks
apart every 24 weeks for at least 120 weeks. Selection criteria required a baseline EDSS of 3 to 6.5 and a scoreof 2 or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurologicalassessments were conducted every 12 weeks. An MRI scan was obtained at baseline and at Weeks 24, 48, and120.
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 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, orby 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 participationin the study before the next assessment. Additional outcome measures included timed 25-foot walk, andpercentage change in T2 hyperintense lesion volume.
Study 3 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 werebalanced 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 Gdenhancing lesions at baseline; 88% of patients had not been treated previously with a non-steroid treatment forMS. 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 3 are presented inTable 5 and Figure 2.

Table 5

Key Clinical and MRI Endpoints in PPMS Patients for Study 3
Study 3

Endpoints

Clinical Outcomes
Proportion of patients with 12-week Confirmed Disability
Progression1
Risk reduction

OCREVUS
600 mg(two 300 mg
infusions
two weeksapartevery 24 weeks)
N=488
32.9%

Placebo

N=244
39.3%

24%; p=0.0321

MRI Endpoints
Mean change in volume of T2 lesions, from baseline to Week 120
(cm3)
1

-0.39

0.79
p<0.0001

Defined 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 thebaseline score is more than 5.5

Figure 2 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 3**All patients in this analysis had a 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.
14.3 Safety Study of 2-Hour Infusions
The safety of the 2-hour OCREVUS infusion was evaluated in Study 4 (NCT03085810), a prospective, multicenter,randomized, double-blind, controlled, parallel arm substudy in patients with Relapsing-Remitting Multiple Sclerosis
who were naïve to other non-steroid therapies for MS and did not experience a 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 a 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 orwithin 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 a 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.
16 HOW SUPPLIED/STORAGE AND HANDLINGOCREVUS (ocrelizumab) injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale
brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-15001).
Store OCREVUS vials at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze or shake.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Infusion Reactions
Inform 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 ofinfusion reactions [see Warnings and Precautions (5.1)].
Infection
Advise 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, dysuria, or signs of herpes such as
cold sores, shingles, or genital sores [see Warnings and Precautions (5.2)].
Advise patients that OCREVUS may cause reactivation of hepatitis B 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)].
Vaccination
Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible,
non-live vaccinations at least 2 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)].
Progressive Multifocal Leukoencephalopathy
Inform patients that PML has occurred in patients who received OCREVUS. Inform the patient that PML ischaracterized by a progression of deficits and usually leads to death or severe disability over weeks or months.
Instruct the patient of the importance of contacting their healthcare provider 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(5.3)].
Malignancies
Advise 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 (5.5)].
Immune-Mediated Colitis
Advise patients to promptly contact their healthcare provider if they experience any signs and symptoms of colitis,
including diarrhea, abdominal pain, and blood in stool [see Warnings and Precautions (5.6)].
Contraception
Females of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months
after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)]. Instruct patients that if they are pregnant
or plan to become pregnant while taking OCREVUS, they should inform their healthcare provider [see Use inSpecific Populations (8.1)].
OCREVUS® [ocrelizumab]
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA WaySouth San Francisco, CA 94080-4990
U.S. License No. 1048

OCREVUS is a registered trademark of Genentech, Inc.
©
2024 Genentech, Inc.

MEDICATION GUIDEOCREVUS® (oak-rev-us)(ocrelizumab)
injection,for intravenous use
What is the most important information I should know about OCREVUS?
OCREVUS can cause serious side effects, including: Infusion reactions: Infusion reactions are a 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 1 hour after each infusionof OCREVUS for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get anyof these symptoms:
o itchy skino trouble breathingo nauseao shortness of breatho rasho throat irritation or paino headacheo fatigueo hiveso feeling fainto swelling of the throato fast heart beato tiredness
o fevero dizzinesso coughing oro redness on your facewheezing(flushing)
These infusion reactions can happen for up to 24 hours after your infusion. It is important that you call yourhealthcare 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:o Infections are a common side effect. OCREVUS increases your risk of getting upper respiratory tract infections,lower respiratory tract infections, skin infections, and herpes infections. Serious infections can happen with
OCREVUS, which can be life-threatening or cause death. Tell your healthcare provider if you have an infectionor have any of the following signs of infection including fever, chills, a cough that does not go away, or painful
urination. Signs of herpes infection include: cold sores
 genital sores pain shingles
 skin rash
 itchingSigns of a more serious herpes infection include: changes in vision severe or persistent headache eye redness or eye pain
 stiff neck

o

o






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 yourtreatment with OCREVUS until your infection is gone.
Hepatitis B virus (HBV) reactivation: Before starting treatment with OCREVUS, your healthcare provider will
do blood tests to check for hepatitis B viral infection. If you have ever had hepatitis B virus infection, thehepatitis B virus may become active again during or after treatment with OCREVUS. Hepatitis B 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 B virus reactivation during treatment andafter 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.

Progressive Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually leads to death orsevere disability, and has been reported with OCREVUS. Symptoms of PML get worse over days to weeks. It is
important that you call your healthcare provider right away if you have any new or worsening neurologic signs or
symptoms that have lasted several days, including problems with:o thinkingo balanceo eyesighto weakness on 1 side of your bodyo strengtho using your arms or legs

Decreased immunoglobulins: OCREVUS may cause a 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 OCREVUS?
OCREVUS is a prescription medicine used to treat: relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, andactive 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 B virus (HBV) infection.
 Do not receive OCREVUS if you have had a 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 theingredients in OCREVUS?” for a 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 I 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 B or are a carrier of the hepatitis B virus.
 have a history of inflammatory bowel disease or colitis.
 have had a recent vaccination or are scheduled to receive any vaccinations.
o You should receive any required ‘live’ or ‘live-attenuated’ vaccines at least 4 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.
o When possible, you should receive any ‘non-live’ vaccines at least 2 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.
o If you have a baby and you received OCREVUS during your pregnancy, it is important to tell your baby’s
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 6 months
after your last infusion of OCREVUS. Talk with your healthcare provider about what birth control method is right foryou during this time. Tell your healthcare provider if you become pregnant while receiving OCREVUS.
 are breastfeeding or plan to breastfeed. It is not known if OCREVUS passes into your breast milk. Talk to yourhealthcare 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 I receive OCREVUS?
 OCREVUS is given through a needle placed in your vein (intravenous infusion) in your arm.
 Before treatment with OCREVUS, your healthcare provider will give you a 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 I should know
about OCREVUS?”
 Your first full dose of OCREVUS will be given as 2 separate infusions, 2 weeks apart. Each infusion will last about
2 hours and 30 minutes.
 Your next doses of OCREVUS will be given as 1 infusion every 6 months. These infusions will last about 2 hours to
3 hours and 30 minutes depending on the infusion rate prescribed by your healthcare provider.
What are the possible side effects of OCREVUS?
OCREVUS may cause serious side effects, including: see “What is the most important information I should know about OCREVUS?”
 risk of cancers (malignancies) including breast cancer. Follow your healthcare provider’s instructions aboutstandard screening guidelines for breast cancer.
 Inflammation of the colon, or colitis: Tell your healthcare provider if you have any symptoms of colitis, such as:o Diarrhea (loose stools) or more frequent bowel movements than usualo Stools that are black, tarry, sticky or have blood or mucus
o Severe stomach-area (abdomen) pain or tenderness
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 a Medication Guide. You can ask yourpharmacist or healthcare provider for information about OCREVUS that is written for health professionals.

What are the ingredients in OCREVUS?
Active ingredient: ocrelizumab.
Inactive ingredients: glacial acetic acid, polysorbate 20, sodium acetate trihydrate, trehalose dihydrate.
Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990
U.S. License No. 1048
For more information, go to www.OCREVUS.com or call 1-844-627-3887.
This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: 6/2024