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

Assessments Prior to First Dose of OCREVUS

Hepatitis B Virus Screening

Prior to initiating OCREVUS, perform Hepatitis B virus (HBV) screening.  OCREVUS is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests.  For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment [see 4.4 Special warnings and precautions for use].

Serum Immunoglobulins

Prior to initiating OCREVUS, perform testing for quantitative serum immunoglobulins [see 4.4 Special warnings and precautions for use]. 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 4.4 Special warnings and precautions for use and 5.1 Pharmacodynamic Properties].

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 4.4 Special warnings and precautions for use].

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 4.4 Special warnings and precautions for use].  Pre-medicate with an antihistamine (e.g., diphenhydramine) approximately 30-60 minutes prior to each OCREVUS infusion to further reduce the frequency and severity of infusion reactions.

The addition of an antipyretic (e.g., acetaminophen) may also be considered.

Recommended Dosage and Dose Administration  

Administer OCREVUS under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions.

·         Initial dose: 300 mg intravenous infusion, followed two weeks later by 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 4.4 Special warnings and precautions for use].

Table 1           Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS

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.

² Administer 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 4.2 Posology and method of administration].

⁴ [see 4.8 Undesirable effects and 5.1 Pharmacodynamic Properties].

Delayed or Missed Doses

If a planned infusion of OCREVUS is missed, administer OCREVUS as soon as possible; do not wait until the next scheduled dose.  Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered.  Doses of OCREVUS must be separated by at least 5 months [see 4.2 Posology and method of administration].

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 4.4 Special warnings and precautions for use].  Provide appropriate supportive treatment.

Severe Infusion Reactions

Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see 4.4 Special warnings and precautions for use].  Restart the infusion only after all symptoms have resolved.  When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction [see 4.2 Posology and method of administration].  If this rate is tolerated, increase the rate as described in Table 1.  This change in rate will increase the total duration of the infusion but not the total dose.

Mild to Moderate Infusion Reactions

Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes [see 4.4 Special warnings and precautions for use].  If this rate is tolerated, increase the rate as described in Table 1.  This change in rate will increase the total duration of the infusion but not the total dose.

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 (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 4.2 Posology and method of administration].Management recommendations for infusion reactions depend on the type and severity of the reaction [see 4.2 Posology and method of administration].  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 [see 4.8 Undesirable effects].  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.

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability.  Although no cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants).  At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation.  MRI findings may be apparent before clinical signs or symptoms.  Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

Hepatitis 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 4.5 Interaction with other medicinal products and other forms of interaction and 5.1 Pharmacodynamic Properties]. 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 4.5 Interaction with other medicinal products and other forms of interaction].

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 5.1 Pharmacodynamic Properties].

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 4.6 Fertility, pregnancy and lactation].

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 [see 4.8 Undesirable effects].

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.

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 the risk of additive immune system effects when coadministering immunosuppressive therapies with OCREVUS. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS [see 4.4 Special warnings and precautions for use].

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 4.4 Special warnings and precautions for use].

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.

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 4.4 Special warnings and precautions for use].

Following administration of ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.  The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal 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 B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses. 

Intravenous administration of OCREVUS (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates.  The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the high dose.

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.

Lactation

Risk Summary

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

Contraception

Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS [see 5.1 Pharmacodynamic Properties].

Pediatric Use 

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

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.

Ocrevus has no or negligible influence on the ability to drive and use machines.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

·         Infusion Reactions [see 4.4 Special warnings and precautions for use]

·         Infections [see 4.4 Special warnings and precautions for use]

·         Reduction in Immunoglobulins [see 4.4 Special warnings and precautions for use]

·         Malignancies [see 4.4 Special warnings and precautions for use]

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 5.1 Pharmacodynamic properties, Clinical efficacy and safety].  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

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 5.1 Pharmacodynamic properties, Clinical efficacy and safety].  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).

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

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 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 5.1 Pharmacodynamic Properties].

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.

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.

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.

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.

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 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.

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 4.4 Special warnings and precautions for use].

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. Healthcare professionals are asked to report any suspected adverse reactions.

To report any side effect(s):

·  Saudi Arabia:

·  Other GCC States:

There is limited clinical trial experience with doses higher than the approved intravenous dose of Ocrevus. The highest dose tested to date in MS patients is 2000 mg, administered as two 1000 mg intravenous infusions separated by 2 weeks (Phase II dose finding study in RRMS).  The adverse drug reactions were consistent with the safety profile for Ocrevus in the pivotal clinical studies.

Please refer to section 4.8 for information about the Systemic Inflammatory Response Syndrome (SIRS) that occurred in a patient treated with  Ocrevus 2000 mg.

There is no specific antidote in the event of an overdose; interrupt the infusion immediately and observe the patient for IRRs (see section 4.4). 

Pharmacotherapeutic group: selective immunosuppressants group, ATC code: L04AA36.

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.

Pharmacodynamics

For B-cell counts, assays for CD19⁺ B-cells are used because the presence of OCREVUS interferes with the CD20 assay.  Treatment with OCREVUS reduces CD19⁺ B-cell counts in blood by 14 days after infusion.  In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of OCREVUS at least one time in 0.3% to 4.1% of patients.  In 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.

Clinical efficacy and safety

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 (Study1 and Study 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 was above 5.5.  Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening.  The primary population for analysis of confirmed disability progression was the pooled population from Studies 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 demographic and disease characteristics were balanced between the two treatment groups.  At baseline, the mean age of patients was 37 years; 66% were female.  The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8;  74% of patients had not been treated with 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 demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female.  The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8;  74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study.  At baseline, 40% of OCREVUS-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9).

In Study 1 and Study 2, OCREVUS significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF.  Results for Study 1 and Study 2 are presented in Table 4 and Figure 1. 

In exploratory subgroup analyses of Study 1 and Study 2, the effect of OCREVUS on annualized relapse rate and disability progression was similar in male and female patients.

Primary Progressive Multiple Sclerosis (PPMS)

Study 3 was a randomized, double-blind, placebo-controlled clinical trial in patients with PPMS.  Patients were randomized 2:1 to receive either OCREVUS 600 mg or placebo as two 300 mg intravenous infusions 2 weeks apart every 24 weeks for at least 120 weeks.  Selection criteria required a baseline EDSS of 3 to 6.5 and a score of 2 or greater for the EDSS pyramidal functional system due to lower extremity findings.  Neurological assessments were conducted every 12 weeks.  An MRI scan was obtained at baseline and at Weeks 24, 48, and 120.   

In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later.  Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points.  In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume.

Study 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 were balanced between the two treatment groups.  At baseline, the mean age of patients was 45;  49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with  a non-steroid treatment for MS.  The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for OCREVUS-treated patients than for placebo-treated patients (see Figure 2).  Results for Study 3 are presented in Table 5 and Figure 2.

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.

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 4.2 Posology and method of administration], every 24 weeks. The randomization was stratified by region and the dose at which patients were first randomized.

The primary endpoint of the substudy was the proportion of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion of OCREVUS. The primary analysis was performed when 580 patients were randomized, at which time 469/579 (81%) of the treated patients had received only 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 4.4 Special warnings and precautions for use]. There were no life-threatening, fatal, or serious infusion reactions in this substudy.

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 C_max of 212 mcg/mL. The pharmacokinetics of ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.

Distribution

The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 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 by catabolism.

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 the pharmacokinetics  of OCREVUS  was observed in those patients.

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 human dose of 600 mg, on a mg/kg basis.

Sodium Acetate Trihydrate

Glacial Acetic Acid

Trehalose Dihydrate

Polysorbate 20

Water for Injection

No incompatibilities between Ocrevus and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous  administration sets have been observed.

Do not use diluents other than the one detailed in section 6.6 to dilute Ocrevus since its use has not been tested.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Store in a refrigerator (2°C – 8°C).

Do not freeze or shake.

Keep the vials in the outer carton in order to protect from light. 

For storage conditions after dilution of the medicinal product, see section 6.3.

10 mL concentrate in a glass vial.  Pack size of 1 or 2 vials.  Not all pack sizes may be marketed. 

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 no preservative and is intended for single use only.

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.

Disposal

Disposal of unused/expired medicines

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.