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| Product NDC Code | 50242-150 | ||||
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| Drug Name | Ocrevus |
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| Type | Brand | ||||
| Pharm Class | Antibodies, Monoclonal [CS], Antibodies, Monoclonal, Humanized [CS], CD20-directed Antibody Interactions [MoA], CD20-directed Cytolytic Antibody [EPC] |
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| Active Ingredients |
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| Route | INTRAVENOUS | ||||
| Dosage Form | INJECTION | ||||
| RxCUI drug identifier | 1876380, 1876385 |
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| Application Number | BLA761053 | ||||
| Labeler Name | Genentech, Inc. | ||||
| Packages |
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Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Infusion Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3) ] Reduction in Immunoglobulins [see Warnings and Precautions (5.4) ] Malignancies [see Warnings and Precautions (5.5) ] Immune-Mediated Colitis [see Warnings and Precautions (5.6) ] The most common adverse reactions were: RMS (incidence ≥10% and > REBIF ® ): upper respiratory tract infections and infusion reactions ( 6.1 ) PPMS (incidence ≥10% and > placebo): upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 Adverse Reactions Studies 1 and 2 OCREVUS 600 mg IV Every 24 Weeks The first dose was given as two separate 300 mg infusions at Weeks 0 and 2. (n=825) % REBIF 44 mcg SQ 3 Times per Week (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 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). Table 3 Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo Adverse Reactions Study 3 OCREVUS 600 mg IV Every 24 Weeks One dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart) Placebo (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 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) ] . 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 × 10 9 /L and 1.0 × 10 9 /L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 × 10 9 /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 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 (5.6) ] Infections and Infestations: Serious herpes infections [see Warnings and Precautions (5.2) ] , progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3) ] , and babesiosis Skin: Pyoderma gangrenosum
| Adverse Reactions | Studies 1 and 2 | |
|---|---|---|
| OCREVUS 600 mg IV Every 24 Weeks | REBIF 44 mcg SQ 3 Times per Week (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 |
| Adverse Reactions | Study 3 | |
|---|---|---|
| OCREVUS 600 mg IV Every 24 Weeks | Placebo | |
| (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 |
OCREVUS Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies The concomitant use of OCREVUS and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider 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 Warnings and Precautions (5.2) ]. 7.2 Vaccinations A Phase 3b randomized, open-label study examined the concomitant use of OCREVUS and several non-live vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects undergoing treatment with OCREVUS at the time of vaccination and 34 subjects not undergoing treatment with OCREVUS at the time of vaccination). Concomitant exposure to OCREVUS attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and seasonal inactivated influenza vaccines. The impact of the observed attenuation on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with OCREVUS have not been assessed [see Warnings and Precautions (5.2) ] .
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. 12.2 Pharmacodynamics For B-cell counts, assays for CD19 + B-cells are used because the presence of OCREVUS interferes with the CD20 assay. Treatment with OCREVUS reduces CD19 + B-cell counts in blood by 14 days after infusion. In 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. 12.3 Pharmacokinetics Pharmacokinetics (PK) of OCREVUS in MS clinical studies fit a two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of OCREVUS was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of ocrelizumab were either 600 mg every 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion over 3.5 hours) and 141 mcg/mL in patients with PPMS (two 300 mg infusions over 2.5 hours administered within two weeks). The mean maximum peak concentrations (C max ) 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.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics For B-cell counts, assays for CD19 + B-cells are used because the presence of OCREVUS interferes with the CD20 assay. Treatment with OCREVUS reduces CD19 + B-cell counts in blood by 14 days after infusion. In 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Pharmacokinetics (PK) of OCREVUS in MS clinical studies fit a two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of OCREVUS was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of ocrelizumab were either 600 mg every 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion over 3.5 hours) and 141 mcg/mL in patients with PPMS (two 300 mg infusions over 2.5 hours administered within two weeks). The mean maximum peak concentrations (C max ) 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.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS OCREVUS is contraindicated in patients with: Active HBV infection [see Dosage and Administration (2.1) and Warnings and Precautions (5.2) ] A history of life-threatening infusion reaction to OCREVUS [see Warnings and Precautions (5.1) ] Active hepatitis B virus infection ( 4 ) History of life-threatening infusion reaction to OCREVUS ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells. Ocrelizumab is a glycosylated immunoglobulin G1 (IgG1) with a molecular mass of approximately 145 kDa. OCREVUS (ocrelizumab) Injection for intravenous infusion is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied in single-dose vials. Each mL of solution contains 30 mg ocrelizumab, glacial acetic acid (0.25 mg), polysorbate 20 (0.2 mg), sodium acetate trihydrate (2.14 mg), and trehalose dihydrate (40 mg) at pH 5.3.
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Hepatitis B virus and quantitative serum immunoglobulin screening are required before the first dose ( 2.1 ) Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion ( 2.2 ) Administer OCREVUS by intravenous infusion Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion ( 2.3 ) Subsequent doses: 600 mg intravenous infusion every 6 months ( 2.3 ) Must be diluted prior to administration ( 2.3 , 2.6 ) Monitor patients closely during and for at least one hour after infusion ( 2.3 , 2.5 ) 2.1 Assessments Prior to First Dose of OCREVUS Hepatitis B Virus Screening Prior to initiating OCREVUS, perform Hepatitis B virus (HBV) screening. OCREVUS is contraindicated 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 Warnings and Precautions (5.2) ] . Serum Immunoglobulins Prior to initiating OCREVUS, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions (5.4) ] . For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with OCREVUS. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . 2.2 Preparation Before Every Infusion Infection Assessment Prior to every infusion of OCREVUS, determine whether there is an active infection. In case of active infection, delay infusion of OCREVUS until the infection resolves [see Warnings and Precautions (5.2) ]. Recommended Premedication Pre-medicate with 100 mg of methylprednisolone (or an equivalent corticosteroid) administered intravenously approximately 30 minutes prior to each OCREVUS infusion to reduce the frequency and severity of infusion reactions [see Warnings and Precautions (5.1) ] . Pre-medicate with an antihistamine (e.g., diphenhydramine) approximately 30-60 minutes prior to each OCREVUS infusion to further reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. 2.3 Recommended Dosage and Dose Administration Administer OCREVUS under the close supervision of an experienced healthcare professional with access 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 Warnings and Precautions (5.1) ] . Table 1 Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS Amount and Volume 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. Infusion Rate and Duration Infusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5) ] . Initial Dose (two infusions) Infusion 1 300 mg in 250 mL Start at 30 mL per hour Increase by 30 mL per hour every 30 minutes Maximum: 180 mL per hour Duration: 2.5 hours or longer Infusion 2 (2 weeks later) 300 mg in 250 mL Subsequent Doses (one infusion) every 6 months) Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose. Option 1 Infusion of approximately 3.5 hours duration 600 mg in 500 mL Start at 40 mL per hour Increase by 40 mL per hour every 30 minutes Maximum: 200 mL per hour Duration: 3.5 hours or longer OR Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1) and Clinical Studies (14.3) ] . Infusion of approximately 2 hours duration 600 mg in 500 mL Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer 2.4 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 Dosage and Administration (2.3) ] . 2.5 Dose Modifications Because of Infusion Reactions Dose modifications in response to infusion reactions depends on the severity. Life-threatening Infusion Reactions Immediately stop and permanently discontinue OCREVUS if there are signs of a life-threatening or disabling infusion reaction [see Warnings and Precautions (5.1) ] . Provide appropriate supportive treatment. Severe Infusion Reactions Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see Warnings and Precautions (5.1) ] . Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction. If this rate is tolerated, increase the rate as described in Table 1 [see Dosage and Administration (2.3) ] . This change in rate will increase the total 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 Warnings and Precautions (5.1) ] . If this rate is tolerated, increase the rate as described in Table 1 [see Dosage and Administration (2.3) ] . This change in rate will increase the total duration of the infusion but not the total dose. 2.6 Preparation and Storage of the Dilute Solution for Infusion Preparation OCREVUS must be prepared by a healthcare professional using aseptic technique. A sterile needle and syringe should be used to prepare the diluted infusion solution. Visually inspect for particulate matter and discoloration prior to administration. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter. Do not shake. Withdraw intended dose and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, to a final drug concentration of approximately 1.2 mg/mL. Withdraw 10 mL (300 mg) of OCREVUS and inject into 250 mL Withdraw 20 mL (600 mg) of OCREVUS and inject into 500 mL Do not use other diluents to dilute OCREVUS since their use has not been tested. The product contains no preservative and is intended for single use only. Storage of Infusion Solution Prior to the start of the intravenous infusion, the content of the infusion bag should be at room temperature. Use the prepared infusion solution immediately. If not used immediately, store up to 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F) and 8 hours at room temperature up to 25°C (77°F), which includes infusion time. In the event an intravenous infusion cannot be completed the same day, discard the remaining solution. No incompatibilities between OCREVUS and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed. Administration Administer the diluted infusion solution through a dedicated line using an infusion set with a 0.2 or 0.22 micron in-line filter.
| Amount and Volume | Infusion Rate and Duration | ||
|---|---|---|---|
| Infusion 1 | 300 mg in 250 mL |
| |
| Infusion 2 (2 weeks later) | 300 mg in 250 mL | ||
| Option 1 Infusion of approximately 3.5 hours duration | 600 mg in 500 mL |
| |
| OR | |||
| Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) | 600 mg in 500 mL |
| |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/10 mL (30 mg/mL) clear or slightly opalescent, and colorless to pale brown solution in a single-dose vial. Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE 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 OCREVUS is a CD20-directed cytolytic antibody 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 ( 1 ) Primary progressive MS, in adults ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.OCREVUS ocrelizumab OCRELIZUMAB OCRELIZUMAB SODIUM ACETATE ACETIC ACID TREHALOSE DIHYDRATE POLYSORBATE 20 WATER
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been performed to assess the carcinogenic potential of OCREVUS. No studies have been performed to assess the mutagenic potential of OCREVUS. As an antibody, OCREVUS is not expected to interact directly with DNA. No effects on reproductive organs were observed in male monkeys administered ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks. There were also no effects on estrus cycle in female monkeys administered ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been performed to assess the carcinogenic potential of OCREVUS. No studies have been performed to assess the mutagenic potential of OCREVUS. As an antibody, OCREVUS is not expected to interact directly with DNA. No effects on reproductive organs were observed in male monkeys administered ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks. There were also no effects on estrus cycle in female monkeys administered ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 300 mg/10 mL Vial Carton NDC 50242-150-01 Ocrevus ® (ocrelizumab) Injection 300 mg/10 mL (30 mg/mL) For Intravenous Infusion. Must Be Diluted. Single-Dose Vial. Discard Unused Portion. Attention Pharmacist: Dispense the accompanying Medication Guide to each patient. Rx only 1 vial Genentech 10233065 PRINCIPAL DISPLAY PANEL - 300 mg/10 mL Vial Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Warnings and Precautions ( 5.2 ) 1/2024
| Warnings and Precautions ( | 1/2024 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.OCREVUS ® [ocrelizumab] Manufactured by: Genentech, Inc . A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 OCREVUS is a registered trademark of Genentech, Inc. © 2024 Genentech, Inc. U.S. License No. 1048
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):
OCREVUS: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Infusion Reactions Inform patients about the signs and symptoms of infusion reactions, and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions [see Warnings and Precautions (5.1) ] . Infection Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose [see Clinical Pharmacology (12.2) ]. Signs include fever, chills, constant cough, dysuria, or signs of herpes such as cold sore, shingles, or genital sores [see Warnings and Precautions (5.2) ] . Advise patients that OCREVUS may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk [see Warnings and Precautions (5.2) ] . Advise patients that herpes infections, including serious herpes infections affecting the central nervous system, skin, and eyes, have occurred during treatment with OCREVUS. Advise patients to promptly contact their healthcare provider if they experience any signs or symptoms of herpes infections including oral or genital symptoms, fever, skin rash, pain, itching, decreased visual acuity, eye redness, eye pain, headache, neck stiffness, or change in mental status [see Warnings and Precautions (5.2) ]. Vaccination Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible, non-live vaccinations at least 2 weeks prior to initiation of OCREVUS. Administration of live-attenuated or live vaccines is not recommended during OCREVUS treatment and until B-cell recovery [see Warnings and Precautions (5.2) ] . Progressive Multifocal Leukoencephalopathy Inform patients that PML has occurred in patients who received OCREVUS. Inform the patient that PML 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) ]. Malignancies Advise patients that an increased risk of malignancy, including breast cancer, may exist with OCREVUS. Advise patients that they should follow standard breast cancer screening guidelines [see Warnings and Precautions (5.5) ] . Immune-Mediated Colitis Advise patients to promptly contact their healthcare provider if they experience any signs and symptoms of colitis, including diarrhea, abdominal pain, and blood in stool [see Warnings and Precautions (5.6) ]. Contraception Females of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3) ] . 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) ].
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 1/2024 MEDICATION GUIDE OCREVUS ® (oak-rev-us) (ocrelizumab) injection, for intravenous use What is the most important information I should know about OCREVUS? OCREVUS can cause serious side effects, including: Infusion reactions : Infusion reactions are a common side effect of OCREVUS, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least 1 hour after each infusion of OCREVUS for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms: itchy skin rash hives tiredness coughing or wheezing trouble breathing throat irritation or pain feeling faint fever redness on your face (flushing) nausea headache swelling of the throat dizziness shortness of breath fatigue fast heart beat These infusion reactions can happen for up to 24 hours after your infusion . It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion. If you get infusion reactions, your healthcare provider may need to stop or slow down the rate of your infusion. Infection: 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. Signs of herpes infection include: cold sores shingles genital sores skin rash pain itching Signs of a more serious herpes infection include: changes in vision eye redness or eye pain severe or persistent headache stiff neck confusion Signs of infection can happen during treatment or after you have received your last dose of OCREVUS. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with OCREVUS until your infection is gone. Hepatitis B virus (HBV) reactivation : Before starting treatment with OCREVUS, your healthcare provider will do blood tests to check for hepatitis B viral infection. If you have ever had hepatitis B virus infection, the hepatitis B virus may become active again during or after treatment with OCREVUS. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop receiving OCREVUS. Weakened immune system : OCREVUS taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Progressive Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually leads to death 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: thinking eyesight strength balance weakness on 1 side of your body using your arms or legs Decreased immunoglobulins: OCREVUS may cause a decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels. See "What are the possible side effects of OCREVUS? " for more information about side effects. What is OCREVUS? OCREVUS is a prescription medicine used to treat: relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. primary progressive MS, in adults. It is not known if OCREVUS is safe and effective in children. Who should not receive OCREVUS? Do not receive OCREVUS if you have an active hepatitis B virus (HBV) infection. Do not receive OCREVUS if you have had a life-threatening allergic reaction to OCREVUS. Tell your healthcare provider if you have had an allergic reaction to OCREVUS or any of its ingredients in the past. See " What are the ingredients in OCREVUS? " for a complete list of ingredients in OCREVUS. Before receiving OCREVUS, tell your healthcare provider about all of your medical conditions, including if you: have or think you have an infection. See " What is the most important information I should know about OCREVUS? " have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS. These medicines could increase your risk of getting an infection. have ever had hepatitis B or are a carrier of the hepatitis B virus. have a history of inflammatory bowel disease or colitis. have had a recent vaccination or are scheduled to receive any vaccinations. 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. If you have a baby and you received OCREVUS during your pregnancy, it is important to tell your baby's healthcare provider about receiving OCREVUS so they can decide when your baby should be vaccinated. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if OCREVUS will harm your unborn baby. You should use birth control (contraception) during treatment with OCREVUS and for 6 months after your last infusion of OCREVUS. Talk with your healthcare provider about what birth control method is right for you during this time. Pregnancy Registry . There is a pregnancy registry for women who take OCREVUS during pregnancy. If you become pregnant while receiving OCREVUS, tell your healthcare provider right away. Talk to your healthcare provider about registering with the OCREVUS Pregnancy Registry. The purpose of this registry is to collect information about your health and your baby's health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. are breastfeeding or plan to breastfeed. It is not known if OCREVUS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take OCREVUS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive OCREVUS? OCREVUS is given through a needle placed in your vein (intravenous infusion) in your arm. Before treatment with OCREVUS, your healthcare provider will give you a corticosteroid medicine and an antihistamine to help reduce infusion reactions (make them less frequent and less severe). You may also receive other medicines to help reduce infusion reactions. See " What is the most important information I should know about OCREVUS? " Your first full dose of OCREVUS will be given as 2 separate infusions, 2 weeks apart. Each infusion will last about 2 hours and 30 minutes. Your next doses of OCREVUS will be given as 1 infusion every 6 months. These infusions will last about 2 hours to 3 hours and 30 minutes depending on the infusion rate prescribed by your healthcare provider. What are the possible side effects of OCREVUS? OCREVUS may cause serious side effects, including: see " What is the most important information I should know about OCREVUS? " risk of cancers (malignancies) including breast cancer. Follow your healthcare provider's instructions about standard screening guidelines for breast cancer. Inflammation of the colon, or colitis: Tell your healthcare provider if you have any symptoms of colitis, such as: Diarrhea (loose stools) or more frequent bowel movements than usual Stools that are black, tarry, sticky or have blood or mucus Severe stomach-area (abdomen) pain or tenderness These are not all the possible side effects of OCREVUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of OCREVUS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about OCREVUS that is written for health professionals. What are the ingredients in OCREVUS? Active ingredient: ocrelizumab. Inactive ingredients: glacial acetic acid, polysorbate 20, sodium acetate trihydrate, trehalose dihydrate. Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 U.S. License No. 1048 For more information, go to www.OCREVUS.com or call 1-844-627-3887.
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| Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about OCREVUS that is written for health professionals. | |||||||
| Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 | |||||||
| U.S. License No. 1048 | |||||||
| For more information, go to www.OCREVUS.com or call 1-844-627-3887. | |||||||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Relapsing Forms of Multiple Sclerosis (RMS) The efficacy of OCREVUS was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks (Study 1 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 . Table 4 Key Clinical and MRI Endpoints in RMS Patients from Study 1 and Study 2 Endpoints Study 1 Study 2 OCREVUS 600 mg every 24 weeks REBIF 44 mcg three times a week OCREVUS 600 mg every 24 weeks REBIF 44 mcg three times a week N=410 N=411 N=417 N=418 Clinical Endpoints Annualized Relapse Rate (Primary Endpoint) 0.156 0.292 0.155 0.290 Relative Reduction 46% (p<0.0001) 47% (p<0.0001) Proportion Relapse-free 83% 71% 82% 72% Proportion of Patients with 12-week Confirmed Disability Progression Defined as an increase of 1.0 point or more from the baseline Expanded Disability Status Scale (EDSS) score for patients with baseline score of 5.5 or less, or 0.5 or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96. 9.8% OCREVUS vs 15.2% REBIF Risk Reduction (Pooled Analysis Data prospectively pooled from Study 1 and Study 2. ) 40%; p=0.0006 MRI Endpoints Mean number of T1 Gd-enhancing lesions per MRI scan 0.016 0.286 0.021 0.416 Relative Reduction 94% (p<0.0001) 95% (p<0.0001) Mean number of new and/or enlarging T2 hyperintense lesions per MRI 0.323 1.413 0.325 1.904 Relative Reduction 77% (p<0.0001) 83% (p<0.0001) Figure 1 Kaplan-Meier Plot Pre-specified pooled analysis of Study 1 and 2 of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Pooled Studies 1 and 2 in Patients with RMS (Pooled ITT Population) 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. Figure 1 14.2 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 . Table 5 Key Clinical and MRI Endpoints in PPMS patients for Study 3 Endpoints Study 3 OCREVUS 600 mg (two 300 mg infusions two weeks apart every 24 weeks) Placebo N=488 N=244 Clinical Outcomes Proportion of patients with 12-week Confirmed Disability Progression Defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or an increase of 0.5 or more when the baseline score is more than 5.5 32.9% 39.3% Risk reduction 24%; p=0.0321 MRI Endpoints Mean change in volume of T2 lesions, from baseline to Week 120 (cm 3 ) -0.39 0.79 p<0.0001 Figure 2 Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Study 3 All patients in this analysis had a minimum of 120 weeks of follow-up. The primary analysis is based on all disability progression events accrued including 21 without confirmatory EDSS at 12 weeks. In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in OCREVUS-treated patients compared to 59% in placebo-treated patients (25% risk reduction). In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in OCREVUS-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in OCREVUS-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored OCREVUS numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions. Figure 2 14.3 Safety Study of 2-Hour Infusions The safety of the 2-hour OCREVUS infusion was evaluated in Study 4 (NCT03085810), a prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy in patients with Relapsing-Remitting Multiple Sclerosis who were naïve to other non-steroid therapies for MS and did not experience a serious infusion reaction with any previous OCREVUS infusion. The first dose of OCREVUS was administered as two 300 mg infusions (600 mg total) separated by 14 days. After enrollment in the substudy, patients were randomized in a 1:1 ratio to receive infusions over approximately 3.5-hours or 2-hours, after appropriate premedication [see Dosage and Administration (2.2) ] , every 24 weeks. The randomization was stratified by region and the dose at which patients were first randomized. The primary endpoint of the substudy was the proportion of patients with infusion reactions occurring during 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 Warnings and Precautions (5.1) ] . There were no life-threatening, fatal, or serious infusion reactions in this substudy.
| Endpoints | Study 1 | Study 2 | ||
|---|---|---|---|---|
| OCREVUS 600 mg every 24 weeks | REBIF 44 mcg three times a week | OCREVUS 600 mg every 24 weeks | REBIF 44 mcg three times a week | |
| N=410 | N=411 | N=417 | N=418 | |
| Annualized Relapse Rate (Primary Endpoint) | 0.156 | 0.292 | 0.155 | 0.290 |
| Relative Reduction | 46% (p<0.0001) | 47% (p<0.0001) | ||
| Proportion Relapse-free | 83% | 71% | 82% | 72% |
| Proportion of Patients with 12-week Confirmed Disability Progression | 9.8% OCREVUS vs 15.2% REBIF | |||
| Risk Reduction (Pooled Analysis | 40%; p=0.0006 | |||
| Mean number of T1 Gd-enhancing lesions per MRI scan | 0.016 | 0.286 | 0.021 | 0.416 |
| Relative Reduction | 94% (p<0.0001) | 95% (p<0.0001) | ||
| Mean number of new and/or enlarging T2 hyperintense lesions per MRI | 0.323 | 1.413 | 0.325 | 1.904 |
| Relative Reduction | 77% (p<0.0001) | 83% (p<0.0001) | ||
| Endpoints | Study 3 | |
|---|---|---|
| OCREVUS 600 mg (two 300 mg infusions two weeks apart every 24 weeks) | Placebo | |
| N=488 | N=244 | |
| Proportion of patients with 12-week Confirmed Disability Progression | 32.9% | 39.3% |
| Risk reduction | 24%; p=0.0321 | |
| Mean change in volume of T2 lesions, from baseline to Week 120 (cm3) | -0.39 | 0.79 |
| p<0.0001 | ||
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of OCREVUS in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 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. 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) ] . 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 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. 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) ] . 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. 8.2 Lactation Risk Summary There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the 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. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3) ] . 8.4 Pediatric Use Safety and effectiveness of OCREVUS in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING OCREVUS (ocrelizumab) injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01). Store OCREVUS vials at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze or shake.
Storage and handling
Information about safe storage and handling of the drug product.Store OCREVUS vials at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze or shake.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API