Special Warning : אזהרת שימוש

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, 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- corticosteroid (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.
5.2 Infections
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 Infections
A 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.

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The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections
and bronchitis.
Herpes
In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in 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.
Hepatitis B Virus (HBV) Reactivation
Hepatitis B reactivation has been reported in MS patients treated with Ocrevus in the postmarketing setting.
Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with
anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with Ocrevus. Do not
administer Ocrevus to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For
patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are
carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants
When initiating Ocrevus after an immunosuppressive therapy or initiating an immunosuppressive therapy after
Ocrevus, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical
Pharmacology (12.1, 12.2)]. Ocrevus has not been studied in combination with other MS therapies.
Vaccinations
Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of Ocrevus
for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of Ocrevus for non-
live vaccines.
Ocrevus may interfere with the effectiveness of non-live vaccines [see Drug Interactions (7.2)].
The safety of immunization with live or live-attenuated vaccines following Ocrevus therapy has not been studied,
and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell
repletion [see Clinical Pharmacology (12.2)].
Vaccination of Infants Born to Mothers Treated with Ocrevus During Pregnancy
In infants of mothers exposed to Ocrevus during pregnancy, do not administer live or live-attenuated vaccines
before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Depletion of B-cells in these
infants may increase the risks from live or live-attenuated vaccines.
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 a
protective immune response was mounted [see Use in Specific Populations (8.1)].

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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 and
other MS therapies.
At the first sign or symptom suggestive of PML, withhold Ocrevus and perform an appropriate diagnostic evaluation.
Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness
on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation
leading to confusion and personality changes.
MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI
findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms
specific to PML, have been reported in patients treated with other MS medications associated with PML. Many
of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that
may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to
allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated
with PML, lower PML-related mortality and morbidity have been reported in patients who were initially
asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis.
It is not known whether these differences are due to early detection and discontinuation of MS treatment or due
to differences in disease in these patients.
If PML is confirmed, treatment with Ocrevus should be discontinued.
5.4       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.
5.5       Immune-Mediated Colitis
Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in
patients receiving Ocrevus in the postmarketing setting. Some cases of colitis were serious, requiring
hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in
many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few
weeks to years. Monitor patients for immune-mediated colitis during Ocrevus treatment, and evaluate promptly
if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other
gastrointestinal signs and symptoms, occur.
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)]
•    Malignancies [see Warnings and Precautions (5.4)]
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       •    Immune-Mediated Colitis [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in clinical practice.
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 a 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 patient-
years.
The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and
infusion reactions. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
Table 2          Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for Ocrevus and
Higher than Rebif

Studies 1 and 2
Ocrevus                    Rebif
Adverse Reactions                                                     600 mg IV                44 mcg SQ
Every 24 Weeks1        3 Times per Week
(n=825)                 (n=826)
%                       %
Upper respiratory tract infections                                         40                      33
Infusion reactions                                                         34                      10
Depression                                                                 8                       7
Lower respiratory tract infections                                         8                       5
Back pain                                                                  6                       5
Herpes virus- associated infections                                        6                       4
Pain in extremity                                                          5                       4
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 the
adverse reactions that occurred in the PPMS trial (Study 3).



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Table 3         Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for Ocrevus
and Higher than Placebo

Study 3
Ocrevus                Placebo
600 mg IV
Adverse Reactions
Every 24
Weeks1
(n=486)                 (n=239)
%                      %
Upper respiratory tract infections                     49                     43
Infusion reactions                                     40                     26
Skin infections                                        14                     11
Lower respiratory tract infections                     10                      9
Cough                                                  7                       3
Diarrhea                                               6                       5
Edema peripheral                                       6                       5
Herpes virus associated infections                     5                       4
1
One dose of Ocrevus (600 mg administered as two 300 mg infusions two weeks apart)


Laboratory Abnormalities
Decreased Immunoglobulins
Ocrevus decreased total immunoglobulins with the greatest decline seen in IgM levels. In MS clinical trials, there
was no apparent association between immunoglobulin decrease and risk for serious infections.
In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG,
IgA, and IgM below the lower limit of normal (LLN) in Ocrevus-treated patients was 0.5%, 1.5%, and 0.1%,
respectively. Following treatment, the proportion of Ocrevus-treated patients reporting IgG, IgA, and IgM below
the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and
IgM below the LLN in Ocrevus-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment,
the proportion of Ocrevus-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%,
0.5%, and 15.5%, respectively.
Decreased Neutrophil Levels
In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of Ocrevus-treated patients
compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once
for a given patient treated with Ocrevus and were between LLN - 1.5 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 associated with 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 result
in 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 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 6
months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated

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with 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 these reactions
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: Immune-mediated colitis [see Warnings and Precautions (5.5)]
Infections and Infestations: Serious herpes infections [see Warnings and Precautions (5.2)] and progressive
multifocal leukoencephalopathy [see Warnings and Precautions (5.3)].
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should
be reported to the Ministry of Health according to the National Regulation by using an online form:
https://sideeffects.health.gov.il

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