Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Infections
(Additions and/or revisions underlined)
Serious, including
life-threatening or fatal, bacterial, viral, parasitic and fungal infections
have been reported in patients receiving OCREVUS. An increased risk of
infections (including serious and fatal bacterial, fungal, and new or
reactivated viral infections) has been observed in patients during and
following completion of treatment with anti-CD20 B-cell depleting therapies.
A higher proportion of 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.
6
Adverse Reactions
6.3 Postmarketing Experience
(Additions and/or revisions underlined)
The following adverse reactions have been
identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably
estimate their frequency or establish a causal relationship to drug
exposure.
Gastrointestinal Disorders: Immune-mediated colitis [see
Warnings and Precautions (5.6)]
Infections and Infestations: Serious
herpes infections [see Warnings and Precautions (5.2)], progressive
multifocal leukoencephalopathy [see Warnings and Precautions (5.3)], and
babesiosis
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE OCREVUS (oak-rev-us) (ocrelizumab)
injection, for intravenous use
…
Infection:
(Additions and/or revisions underlined)
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
infection or have
any of
the following
signs of
infection including
fever, chills, a cough that does not go away, or
painful urination…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Progressive Multifocal Leukoencephalopathy (PML)
Newly added subsection:
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.
5.6 Immune-Mediated Colitis
Newly added subsection:
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
Addition of the following
to the bulleted line listing:
6.3 Postmarketing Experience
Additions and/or revisions underlined:
The
following adverse reactions have been identified during postapproval use of
OCREVUS. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Gastrointestinal
Disorders: Immune-mediated colitis [see
Warnings and Precautions (5.6)]
Infections
and Infestations: Serious herpes infections [see
Warnings and Precautions (5.2)] and progressive multifocal
leukoencephalopathy [see Warnings and
Precautions (5.3)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
What is the most
important information I should know about OCREVUS? OCREVUS can cause serious
side effects, including:
Progressive
Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually
leads to death or severe 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:
…
Before
receiving OCREVUS, tell your healthcare provider about all of your medical conditions,
including if you:
…
- have a history of inflammatory bowel disease or colitis.
…
What
are the possible side effects of OCREVUS?
OCREVUS
may cause serious side effects, including:
…
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
…
Progressive
Multifocal Leukoencephalopathy
Inform
patients that PML has occurred in patients who received OCREVUS. Inform the
patient that PML is characterized 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)].
…
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)].
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
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 in patients with Relapsing-Remitting Multiple Sclerosis who did
not experience a serious infusion reaction with any previous OCREVUS infusion. In
this study, the incidence, intensity, and types of symptoms of infusion reactions
were consistent with those of infusions administered over 3.5 hours [see Clinical Studies (14.3)].
…
The
pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions
(up to approximately 7 years of exposure) have shown an association between decreased
levels of IgG and increased rates of serious infections. The type, severity, latency,
duration, and outcome of serious infections observed during episodes of immunoglobulins
below LLN were consistent with the overall serious infections observed in
patients treated with OCREVUS.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Extensive changes
to table; please refer to label)
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Infections
(Additions and/or
revisions underlined)
Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting.
5.3 Reduction in Immunoglobulins
(Newly added section)
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 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor
the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent
serious infections. Consider discontinuing OCREVUS therapy
in patients with serious
opportunistic or recurrent
serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous
immunoglobulins [see Adverse Reactions
(6.1)].
6
Adverse Reactions
(Newly added information)
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
Laboratory Abnormalities
Decreased Immunoglobulins
OCREVUS decreased
total immunoglobulins with the greatest decline seen in IgM levels; however, a decrease in IgG levels
was
associated with an increased
rate of serious infections.
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 SIs observed
during episodes of immunoglobulins below LLN were
consistent with the overall SIs
observed in patients treated with OCREVUS.
8
Use in Specific Populations
8.1 Pregnancy
(Newly added
information)
Pregnancy Exposure
Registry
There
is a 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Newly added
information)
• Low Immunoglobulins: OCREVUS may cause a decrease in some
types of antibodies. Your healthcare provider will do
blood tests to check your blood immunoglobulin levels.
Talk with your healthcare provider about what birth control
method is right for you during this
time.
o If you become pregnant while taking OCREVUS, talk to your
doctor about enrolling in the OCREVUS Pregnancy
Registry. You can enroll in this registry by calling
1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. The
purpose of this registry is to monitor the health of you and
your baby.
Patient Counseling Information
(Additions and/or
revisions underlined)
Contraception
Females of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months
after the last infusion
of OCREVUS [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
Pregnancy
Registry
Instruct 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)].
Approved Drug Label (PDF)
5
Warnings and Precautions
Infections
(Newly added information)
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)].
6
Adverse Reactions
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.
Serious herpes infections have been identified during postapproval use of OCREVUS
[see Warnings
and Precautions (5.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Additions and/or
revisions underlined)
Tell your healthcare provider if you have an infection or
have any
of the following signs of infection including fever, chills,
or a cough that does not go away. Signs of herpes infection include cold
sores, shingles, genital sores and, if more serious, a severe or persistent
headache, confusion, change in vision, eye redness, or eye pain.
PATIENT COUNSELING INFORMATION
(Newly added information)
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)].
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Infusion Reactions
Additions and/or reactions underlined:
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.
5.2 Infections
Additions
and/or reactions underlined:
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)].
7
Drug Interactions
Newly added subsection:
7.2 Vaccinations
A Phase 3b randomized,
open-label study examined the concomitant use of OCREVUS and several non-live
vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects
undergoing treatment with OCREVUS at the time of vaccination and 34 subjects not
undergoing treatment with OCREVUS at the time of vaccination). Concomitant
exposure to OCREVUS attenuated antibody responses to tetanus toxoid-containing
vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and
seasonal inactivated influenza vaccines. The impact of the observed attenuation
on vaccine effectiveness in this patient population is unknown. The safety and
effectiveness of live or live-attenuated vaccines administered concomitantly
with OCREVUS have not been assessed [see
Warnings and Precautions (5.2)].
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
OCREVUS is a humanized
monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are
known to cross the placental barrier. There are no adequate data on the
developmental risk associated with use of OCREVUS in pregnant women. However, transient peripheral B-cell
depletion and lymphocytopenia have been reported in infants born to mothers
exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following
maternal exposure to OCREVUS have not been studied in clinical
trials. The potential duration of B-cell
depletion in such infants, and the impact of B-cell depletion on vaccine
safety and effectiveness, is unknown [see
Warnings and Precautions (5.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined
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, and active secondary progressive disease, in
adults
- Primary progressive MS, in adults.
Before
receiving OCREVUS, tell your healthcare provider about all of your medical
conditions, including if you:
You should receive any required ‘live’ or
‘live-attenuated’ vaccines at least 4 weeks before you start treatment
with OCREVUS …
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.
If you are pregnant or planning to become pregnant
talk to your doctor about vaccinations for your baby, as some precautions may
be needed.
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
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 …
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Infections
(additions
underlined)
…
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.
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.
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.
7
Drug Interactions
7.2 Vaccinations
(new
subsection added)
A Phase 3b randomized,
open-label study examined the concomitant use of OCREVUS and several non-live
vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects
undergoing treatment with OCREVUS at the time of vaccination and 34 subjects
not undergoing treatment with OCREVUS at the time of vaccination). Concomitant
exposure to OCREVUS attenuated antibody responses to tetanus toxoid-containing
vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and
seasonal inactivated influenza vaccines. The impact of the observed attenuation
on vaccine effectiveness in this patient
population is unknown. The safety
and effectiveness of live or live-attenuated vaccines administered
concomitantly with OCREVUS have not been assessed.
8
Use in Specific Populations
8.1 Pregnancy
(subsection
revised, additions underlined)
Risk Summary
OCREVUS is a humanized monoclonal antibody of
an immunoglobulin G1 subtype and immunoglobulins are known to cross the
placental barrier.
There are no adequate data on the developmental risk associated with use
of OCREVUS in pregnant women. However, transient peripheral B-cell depletion
and lymphocytopenia have been reported in infants born to mothers exposed to
other anti-CD20 antibodies during pregnancy. B-cell levels in infants
following maternal exposure to OCREVUS have not been studied in clinical
trials. The potential duration of B-cell
depletion in such infants, and the impact of B-cell depletion on vaccine safety
and effectiveness, is unknown.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions underlined)
…
Before
receiving OCREVUS, tell your healthcare provider about all of your medical
conditions, including if you:
…
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.
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.
…
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
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.
…
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