Ocrelizumab

Q: Is Ocrelizumab available over the counter?

Ocrelizumab is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Ticari adlar: OCREVUS

Farmasötik Form

Injection

Uygulama Yolu

INTRAVENOUS

Üretici

Genentech, Inc.

About This Medication

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.

Etken Maddeler

Bileşen	Güç
Ocrelizumab	-

Endikasyonlar ve Kullanım

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 )

Nasıl çalışır

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.

Dozaj ve Uygulama

2 DOSAGE AND ADMINISTRATION Before initiating OCREVUS, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin ( 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) ] . Liver Function Tests Prior to initiating OCREVUS, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels [see Warnings and Precautions (5.7) ] . 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.

Side Effects Overview

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) ] Liver Injury [see Warnings and Precautions (5.7) ] 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) ] Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.7) ] 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

Uyarılar ve Önlemler

5 WARNINGS AND PRECAUTIONS Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS if a life-threatening or disabling infusion reaction occurs ( 2.3 , 5.1 ) Infections: Serious, including life-threatening and fatal infections, have occurred. Delay OCREVUS administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with OCREVUS and after discontinuation, until B-cell repletion ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold OCREVUS at the first sign or symptom suggestive of PML ( 5.3 ) Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning of treatment. Monitor during and after discontinuation of treatment with OCREVUS, until B-cell repletion, and especially when recurrent serious infections are suspected. Consider discontinuing OCREVUS in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins ( 2.1 , 5.4 ) Malignancies: An increased risk of malignancy, including breast cancer, may exist with OCREVUS ( 5.5 ) Immune-Mediated Colitis: Immune-mediated colitis has been reported in the postmarketing setting. Monitor patients for new or persistent diarrhea or other gastrointestinal symptoms, and evaluate promptly if colitis is suspected ( 5.6 ) Liver Injury: Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating OCREVUS, and during treatment as clinically indicated. Discontinue OCREVUS in patients with evidence of liver injury in the absence of an alternative etiology ( 5.7 ). 5.1 Infusion Reactions OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34 to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Reducing the Risk of Infusion Reactions and Managing Infusion Reactions Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered [see Dosage and Administration (2.2) ]. Management recommendations for infusion reactions depend on the type and severity of the reaction [see Dosage and Administration (2.5) ]. For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment. 5.2 Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic and fungal infections have been reported in patients receiving OCREVUS. An increased risk of infections (including serious and fatal bacterial, fungal, and new or reactivated viral infections) has been observed in patients during and following completion of treatment with anti-CD20 B-cell depleting therapies. A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections [see Adverse Reactions (6.1) ]. OCREVUS was not associated with an increased risk of serious infections in MS patients in controlled trials. 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 [see Patient Counseling Information (17) ]. Hepatitis B Virus (HBV) Reactivation Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment. Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical Pharmacology (12.1 , 12.2) ]. OCREVUS has not been studied in combination with other MS therapies. Vaccinations Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines [see Drug Interactions (7.2) ]. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion [see Clinical Pharmacology (12.2) ] . Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19 + B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted [see Use in Specific Populations (8.1) ]. 5.3 Progressive Multifocal Leukoencephalopathy (PML) Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients with MS treated with OCREVUS in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in OCREVUS-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any immunosuppressive or immunomodulatory medications associated with the risk of PML prior to or concomitantly with OCREVUS, and did not have any known ongoing systemic medical conditions resulting in compromised immune system function. JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients. If PML is confirmed, treatment with OCREVUS should be discontinued. 5.4 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 Adverse Reactions (6.1) ] . 5.5 Malignancies An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines. 5.6 Immune-Mediated Colitis Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving OCREVUS in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during OCREVUS treatment, and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur. 5.7 Liver Injury Clinically significant liver injury, without findings of viral hepatitis, has been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including OCREVUS. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from weeks to months after administration. Patients treated with OCREVUS found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3× the upper limit of normal (ULN) with serum total bilirubin greater than 2× ULN are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with OCREVUS [see Dosage and Administration (2.1) ] , and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue OCREVUS.

Kontrendikasyonlar

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 )

Farmakokinetik

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.

Frequently Asked Questions

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 )

2 DOSAGE AND ADMINISTRATION Before initiating OCREVUS, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin ( 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 …

5 WARNINGS AND PRECAUTIONS Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue OCREVUS if a life-threatening or disabling infusion reaction occurs ( 2.3 , 5.1 ) Infections: Serious, including life-threatening and fatal infections, have occurred. Delay OCREVUS administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with OCREVUS and after discontinuation, until B-cell repletion ( 5.2 …

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 )

Ocrelizumab is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Ocrelizumab drug label (National Library of Medicine)
• openFDA — Ocrelizumab label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1876380 (NLM Normalized Drug Names)
• NDC Directory — Ocrelizumab (FDA National Drug Code)

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Veri kaynakları: DailyMed (NLM), openFDA, MFDS