Common adverse events (AEs)1

For complete safety information, please see the full Prescribing Information.

As of November 2020, 5688 patients have received OCREVUS in the all-exposure trial population, resulting in 21,675 PY of exposure4

In Phase III trials, the most common adverse events (AEs) were infusion reactions and infections (mainly mild to moderate)1

  • Other common AE rates were similar with Rebif and placebo
  • In the OCREVUS all-exposure population, reported rates of AEs continue to be consistent with those seen during the controlled RMS and primary-progressive multiple sclerosis (PPMS) trials4

AEs PER 100 PATIENT-YEARS (PY) IN OCREVUS TRIAL POPULATION4,55

  • Potential serious opportunistic infections in the OCREVUS all-exposure population: 0.02 per 100 PY (95% CI: 0.01, 0.05) as of November 202055

AEs were classified according to Medical Dictionary for Regulatory Activities (MedDRA) versions 18.0, 18.1, and 22.1. Multiple occurrences of the same AE in one patient are counted multiple times, except for malignancies.
*Data as of April–July 2015.
Includes patients who received any dose of OCREVUS during the controlled period and associated OLE periods of the Phase II and Phase III studies plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO, and CONSONANCE, including patients originally randomized to comparator (IFN β-1a or placebo) who switched to open-label OCREVUS treatment (data as of November 2020).
Serious infections are defined using AEs falling into the MedDRA system organ class “Infections and infestations,” and using “Is the event nonserious or serious?” from the AE case report form.
§Malignancies are identified using AEs falling into the standard MedDRA query “Malignant tumours (narrow).”
||For malignancies, incidence rates are reported and exposure in PY was calculated from first treatment to onset of first malignancy.
OPERA I and II (RMS): Two randomized, double-blind, double-dummy, active comparator–controlled clinical trials of identical design vs Rebif in 1656 patients (OCREVUS; OPERA I [n=410], OPERA II [n=417]; Rebif; OPERA I [n=411], OPERA II [n=418]) with RMS treated for 96 weeks. Both studies included patients who had experienced ≥1 relapse within the prior year, or ≥2 relapses within the prior 2 years, and had an EDSS score between 0 and 5.5.
ORATORIO (PPMS): A randomized, double-blind, placebo-controlled clinical trial in 732 patients (OCREVUS, n=488; placebo, n=244) with PPMS treated for at least 120 weeks. Selection criteria included patients aged 18 to 55 and required a baseline EDSS score of 3.0 to 6.5 and a score of 2.0 or greater for the EDSS pyramidal functional systems score due to lower extremity findings. Patients also had no history of RMS, SPMS (secondary progressive multiple sclerosis), or PRMS (progressive relapsing multiple sclerosis).1,56


Infusion reactions1

  • OCREVUS (ocrelizumab) can cause infusion reactions that can be serious and require hospitalization
    • Management recommendations for infusion reactions depend on the type and severity of the reaction
    • Permanently discontinue OCREVUS if a life-threatening or disabling infusion reaction occurs
  • In clinical studies, all patients received premedications for infusion reactions before treatment with OCREVUS. In these studies, the rate of infusion reactions was 34%-40%
  • Infusion reactions were highest with the first infusion

INFUSION REACTIONS OVER TIME IN RMS (CONTROLLED PERIOD)57

Graph showing infusion reactions over time in RMS

Infusion reaction rates in ORATORIO (PPMS) were similar to those in the OPERA I and II (RMS) clinical trials1


Observed rates of infection1

Patients who experienced ≥1 infection in the controlled period

INFECTIONS IN THE CONTROLLED PERIOD WERE MAINLY MILD TO MODERATE IN SEVERITY1

  • OCREVUS did not increase the risk of serious infections vs Rebif, although serious infections have occurred

 

RATE OF SERIOUS INFECTIONS OBSERVED for 8+ YEARS (PHASE III TRIALS AND OLE)4,49

Graph showing serious infection rates vs Rebif for Phase 3 trials and OLE

The exposure in PY during Year 8 is limited for meaningful interpretation, so these data are presented in the plots with dotted lines.

  • Serious infections in the OCREVUS all-exposure population: 2.00 per 100 PY (95% CI: 1.82, 2.20) as of November 20204
  • The most common serious infections were urinary tract infections, pneumonia, and cellulitis49

IgG levels

There is an association between decreased levels of immunoglobulin (IgG) and serious infections1

MOST PATIENTS TAKING OCREVUS REMAINED AT OR ABOVE THE LOWER LIMIT OF NORMAL FOR IgG (LLN; 5.65 g/L) (DATA AS OF JANUARY 2020)49

RATE OF SERIOUS INFECTIONS (DATA AS OF JANUARY 2020)49

  • Serious infections during episodes of IgG<LLN were consistent with overall serious infections observed in patients treated with OCREVUS in terms of type, severity, latency, duration, and outcome

Reported malignancies

An increased risk of malignancy, including breast cancer, may exist in OCREVUS-treated patients1

AGE-STANDARDIZED INCIDENCE RATE OF FEMALE BREAST CANCER OVER OCREVUS STUDIED POPULATIONS AND SEER POPULATION (PER 100 PY) (CONTROLLED AND OLE PERIOD)55

Breast cancer was found in:

  • 6/781 females treated with OCREVUS and 0/668 females treated with Rebif or placebo in the controlled period1
  • 24/3557 females on OCREVUS (12,928 PY) in the all-exposure population as of November 202055

The FDA recommends that OCREVUS patients follow standard breast cancer screening guidelines1

The American Cancer Society recommends that patients age <40 with risk factors for breast cancer should ask their HCP whether mammograms are advisable and how often to have them. Patients age 45 to 54 should get mammograms every year.58

“Age-at-enrollment” methodology only captures how old a patient was at the trial baseline, and not when the event occurred. However, as study follow-up continues and patients become older, the “age-at-event onset” methodology, based on the age of the patient at the onset of malignancy, is a more precise method of calculating the standardized incidence rate.
#Nonmelanoma Skin Cancer (NMSC) is not reported in the Surveillance, Epidemiology, and End Results (SEER) program.
**Includes patients who received any dose of OCREVUS during the controlled period, extended-controlled period, and associated OLE periods of the Phase II and Phase III studies, including patients originally randomized to comparator (Rebif or placebo) who switched to open-label OCREVUS treatment.
††Includes patients described in footnote b plus VELOCE, CHORDS, CASTING, and OBOE.
‡‡Includes patients described in footnote c plus ENSEMBLE.
§§Includes patients described in footnote d plus LIBERTO.
∥∥Includes patients described in footnote d plus CONSONANCE.
¶¶Includes patients who received any dose of OCREVUS during the controlled period, and associated OLE periods of the Phase II and Phase III studies, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO, and CONSONANCE, including patients originally randomized to comparator (Rebif or placebo) who switched to open-label OCREVUS treatment.
The SEER Program of the National Cancer Institute (NCI) is an authoritative source of information reporting data on cancer incidence in 48% of the general US (non-MS specific) population. No comparisons should be made due to limitations that have not been fully accounted for, such as variations in patient populations, as well as differences in sample size, temporal changes, and other potential confounding factors.59

Dosing and administration

Visit the OCREVUS dosing schedule for your patients.

Request information

Speak to an OCREVUS Representative to learn more about OCREVUS.

EDSS=Expanded Disability Status Scale; OLE=open-label extension; PY=patient-years; RMS=relapsing multiple sclerosis; SEER=Surveillance, Epidemiology, and End Results.


Important Safety Information & Indications

Indications

OCREVUS is indicated for the treatment of:

  • Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
  • Primary progressive MS, in adults.
Contraindications

OCREVUS is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reaction to OCREVUS.

Warnings and Precautions
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 34-40%, 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. 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. 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.

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. 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. 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 effect. 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. 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.

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 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.

Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms of PML. Monitoring with MRI for signs 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.

If PML is confirmed, treatment with OCREVUS should be discontinued.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 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.

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.

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.

Use in Specific Populations
Pregnancy

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.

There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to OCREVUS. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier.

Lactation

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

Females and Males of Reproductive Potential

Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS.

Most Common Adverse Reactions

RMS: The most common adverse reactions in RMS trials (incidence ≥10% and >REBIF) were upper respiratory tract infections (40%) and infusion reactions (34%).

PPMS: The most common adverse reactions in PPMS trials (incidence ≥10% and >placebo) were upper respiratory tract infections (49%), infusion reactions (40%), skin infections (14%), and lower respiratory tract infections (10%).

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see additional Important Safety Information throughout and click here for full Prescribing Information and Medication Guide.

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