Ocrevus

— THERAPEUTIC CATEGORIES —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Ocrevus Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ocrelizumab 30mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL)—1

    How Supplied

    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.

    Storage

    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 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.

    Manufacturer

    Genentech, Inc.

    Generic Availability

    NO

    Ocrevus Indications

    Indications

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

    Ocrevus Dosage and Administration

    Prior to Treatment Evaluations

    • Screen all patients for hepatitis B virus (HBV) by measuring HBsAg and anti-HBV before initiating treatment with Ocrevus. Obtain complete blood counts (CBC) including platelets prior to the first dose.

    • Perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts.

    • Administer all according to immunization guidelines at least 4 weeks prior to initiating Ocrevus for live-attenuated or live vaccines, and at least 2 weeks prior to initiating Ocrevus for non-live vaccines.

    • Prior to every infusion, determine if there is an active infection. In the case of an active infection, delay infusion until the infection resolves.

    Adult

    Screen for HBV infection and test for serum immunoglobulins prior to initiation. Premedicate with corticosteroid and antihistamine prior to each infusion; may consider antipyretic. Initially 300mg by IV infusion, followed by a second 300mg infusion 2 weeks later, then subsequently as one 600mg infusion every 6 months. For infusion rates, duration, and dose modifications: see full labeling.

    Adult

    Recommended Premedication

    • Premedicate with methylprednisolone 100 mg (or an equivalent corticosteroid) administered IV approximately 30 minutes prior to each infusion.

    • Premeditated with an antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to each infusion.

    • An antipyretic (e.g., acetaminophen) may be considered.

    Recommended Dosage and Dose Administration

    • Initially 300 mg by IV infusion, followed by a second 300 mg infusion 2 weeks later, then subsequently as one 600mg infusion every 6 months.

    • Observe for at least 1 hour after the completion of the infusion.

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

    • Initial Dose (2 infusions) – Infusion 1 and Infusion 2 (2 weeks later): both 300 mg in 250 mL

      • Start at 30 mL per hour

      • Increase by 30 mL every 30 minutes

      • Maximum: 180 mL per hour

      • Duration: 2.5 hours or longer

    • Subsequent Doses (1 infusion every 6 months)

      • Option 1 – Infusion of approximately 3.5 hours duration: 600 mg in 500 mL

        • Start at 40 mL per hour

        • Increase by 40 mL every 30 minutes

        • Maximum: 200 mL per hour

        • Duration: 3.5 hours or longer

      • Option 2 (if no prior serious infusion reaction with any previous Ocrevus infusion) – 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

    Delayed or Missed Doses

    • If planned infusion is missed, administer Ocrevus as soon as possible and do not wait until the next scheduled dose. Doses of Ocrevus must be separated by at least 5 months.

    Children

    Not established.

    Ocrevus Contraindications

    Contraindications

    Active HBV infection. History of life-threatening infusion reaction to ocrelizumab.

    Ocrevus Boxed Warnings

    Not Applicable

    Ocrevus Warnings/Precautions

    Warnings/Precautions

    Monitor for infusion reactions during and at least 1hr after therapy completion; permanently discontinue if life-threatening infusion reactions occur; treat appropriately. Delay Ocrevus in those with active infection until resolved. Discontinue if serious herpes infection occur; withhold until resolved. Withhold at first sign/symptom of progressive multifocal leukoencephalopathy (PML) and evaluate; discontinue if PML is confirmed. HBV reactivation: screen all patients for HBV; if positive HBsAg/anti-HB results, do not administer Ocrevus. Monitor serum immunoglobulin levels during and after therapy, until B-cell repletion, and esp. during recurrent serious infections. Consider discontinuing therapy in those with opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires IV immunoglobulins. Increased risk of malignancy (including breast cancer). Monitor for immune-mediated colitis during therapy; evaluate promptly if signs/symptoms occur. Complete all immunizations according to guidelines at least 4 weeks (for live or live-attenuated vaccines) or at least 2 weeks (for non-live vaccines) prior to initiation. Infants born to mothers treated during pregnancy: do not administer live or live-attenuated vaccines before confirming B-cell recovery; non-live vaccines may be given prior to recovery, but should consider assessment of vaccine immune response. Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Infusion Reactions

    • Monitor for infusion reactions during and at least 1hr after therapy completion; permanently discontinue if life-threatening infusion reactions occur; treat appropriately. 

    • Infusion reactions can occur up to 24 hours after the infusion.

    • Administer premedications (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. May consider using an antipyretic.

    • Management recommendations for infusion reactions are based on type and severity of the reaction (see Other Modifications).

    Infections

    • Delay administration in patients with an active infection until the infection is resolved.

    • Respiratory Tract Infections: Infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

    • Herpes: Discontinue if serious herpes infection occurs; withhold until resolved, and treat appropriately.

    • Hepatitis B Virus (HBV) Reactivation: Screen all patients for HBV prior to initiation. Do not administer to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. Consult liver disease experts before starting and during treatment for patients who are negative for HBsAg and positive for HB core antibody (HBcAb+) or are carriers of HBsAg+. 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.

    • 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.

      • Non-live vaccines may be given prior to recovery, but should consider assessment of vaccine immune response.

    Progressive Multifocal Leukoencephalopathy (PML)

    • Withhold at first sign/symptom of PML and evaluate; discontinue if PML is confirmed. 

    • Monitoring with MRI for signs that may be consistent with PML may be useful.

    Reduction in Immunoglobulins

    • Monitor serum immunoglobulin levels during and after therapy, until B-cell repletion, and esp. during recurrent serious infections.

    • Consider discontinuing therapy in those with opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires IV immunoglobulin treatment.

    Malignancies

    • Increased risk of malignancy (including breast cancer).

    • Patients should follow standard breast cancer screening guidelines.

    Immune-Mediated Colitis

    • Monitor for immune-mediated colitis during therapy; evaluate promptly if signs/symptoms occur.

    Pregnancy Considerations

    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.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding along the mother’s clinical need for Ocrevus and any potential adverse effects on the breastfed infant from Ocrevus or from the underlying maternal condition.

    Pediatric Considerations

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

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Contraception: Advise to use effective contraception during and for 6 months after the last infusion of Ocrevus.

    Ocrevus Pharmacokinetics

    Absorption

    The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion over 3.5 hours) and 141 mcg/mL in patients with PPMS (two 300 mg infusions over 2.5 hours administered within two weeks). The mean maximum peak concentrations (Cmax) of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS) observed after the 3.5-hour infusion and 2-hour infusion were 202 ± 42 (mean ± SD) and 200 ± 46 mcg/mL, respectively, compared to the previously reported Cmax 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 intercompartment clearance were estimated at 2.68 L and 0.29 L/day, respectively.

    Metabolism

    The metabolism of Ocrevus has not been directly studied because antibodies are cleared principally by catabolism.

    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.

    Ocrevus Interactions

    Interactions

    Concomitant live or live-attenuated vaccines: not recommended during treatment and until B-cell repletion. May interfere with the effectiveness of non-live vaccines. Additive immunosuppressive effects with other immunosuppressants; consider the duration and effects when switching from immunomodulators (eg, corticosteroids, daclizumab, fingolimod, natalizumab, teriflunomide, mitoxantrone).

    Ocrevus Adverse Reactions

    Adverse Reactions

    Upper/lower respiratory tract infections, infusion reactions (eg, pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, others), skin infections; herpes virus-associated infections.

    Ocrevus Clinical Trials

    Clinical Trials

    Relapsing Forms of Multiple Sclerosis (RMS)

    • The efficacy was evaluated in 2 identical randomized, double-blind, double-dummy, active comparator-controlled clinical trials in patients with RMS treated for 96 weeks (Study 1 and Study 2). 

    • Patients received Ocrevus 600 mg every 24 weeks (given as an initial treatment of two 300 mg IV infusions administered 2 weeks apart, and subsequent doses as a single 600 mg IV infusion) and placebo SC injections 3 times per week. The active comparator, Rebif, was administered 44 mcg as SC injections 3 times per week and placebo IV infusions every 24 weeks.

    • The primary endpoint for both studies 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.

    • Study 1 included 821 patients who were randomly assigned 1:1 to receive Ocrevus or Rebif. Study 2 included 835 patients who were randomly assigned 1:1 to receive Ocrevus or Rebif.

    • Results from Study 1 showed the following key clinical and MRI endpoints for Ocrevus vs Rebif, respectively:

      • ARR: 0.156 vs 0.292 (relative reduction, 46%; P <.0001)

      • Proportion relapse-free: 83% vs 71%

      • Mean number of T1 Gd-enhancing lesions per MRI: 0.016 vs 0.286 (relative reduction, 94%; P <.0001)

      • Mean number of new and/or enlarging T2 hyperintense lesions per MRI: 0.323 vs 1.413 (relative reduction, 77%; P <.0001)

    • Results from Study 2 showed the following key clinical and MRI endpoints for Ocrevus vs Rebif, respectively:

      • ARR: 0.155 vs 0.290 (relative reduction, 47%; P <.0001)

      • Proportion relapse-free: 82% vs 72%

      • Mean number of T1 Gd-enhancing lesions per MRI: 0.021 vs 0.416 (relative reduction, 95%; P <.0001)

      • Mean number of new and/or enlarging T2 hyperintense lesions per MRI: 0.325 vs 1.904 (relative reduction, 83%; P <.0001)

    • In a pooled analysis of Study 1 and Study 2, the proportion of patients with 12-week confirmed disability progression was significantly lower for the Ocrevus arm compared with the Rebif arm, 9.8% vs 15.2%, respectively (risk reduction, 40%; P =.0006).

     

    Primary Progressive Multiple Sclerosis (PPMS)

    • The efficacy of Ocrevus was evaluated in 488 patients with PPMS in a randomized, double-blind, placebo-controlled clinical trial (Study 3). Patients were randomly assigned 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.

    • Neurological assessments were conducted every 12 weeks. Patients were evaluated using an MRI scan at baseline and at weeks 24, 48, and 120. The primary endpoint 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. 

    • Results showed following key clinical and MRI endpoints for Ocrevus vs placebo, respectively:

      • Proportion of patients with 12-week confirmed disability progression: 32.9% vs 39.3% (risk reduction, 24%; P =.0321)

      • Mean change in volume of T2 lesions from baseline to week 120: -0.39 vs 0.79 (P <.0001)

    • In the overall population, 49% of Ocrevus-treated patients had a 20% worsening of the timed 25-foot walk confirmed at 12 weeks compared with 59% of placebo-treated patients (risk reduction, 25%).

    Ocrevus Note

    Not Applicable

    Ocrevus Patient Counseling

    Patient Counseling

    Infusion Reactions 

    • Infusion-related reactions are possible and can occur up to 24 hours after infusion.

    Infection

    • Infections, including hepatitis, are possible; signs include fever, chills, constant cough, or signs of herpes (e.g., cold sore, shingles, or genital sores).

    • May cause reactivation of hepatitis B infection and monitoring will be required if patient is at risk. 

    • Herpes infections, including serious herpes infections affecting the CNS, skin, and eyes, are possible during treatment; promptly contact health care provider if signs or symptoms of herpes infections occur.

    Vaccination

    • 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.

    • Not recommended to administer live-attenuated or live vaccines during treatment and until B-cell recovery.

    Progressive Multifocal Leukoencephalopathy (PML)

    • PML may occur. Contact health care provider if symptoms suggestive of PML occur. Typical symptoms 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.

    Malignancies

    • Increased risk of malignancy, including breast cancer. Follow standard breast cancer screening guidelines.

    Immune-Mediated Colitis

    • Promptly contact health care provider if any signs and symptoms of colitis including diarrhea, abdominal pain, and blood in stool occur.

    Contraception

    • Advise females of childbearing potential to use effective contraception during and for 6 months after the last infusion.

    Pregnancy Registry

    • Inform health care provider if you are pregnant or plan to become pregnant during treatment.

    • Enroll patients in the Ocrevus Pregnancy Registry if they become pregnant.

    Cost Savings Program

    Ocrevus Patient Support & Co-Pay Programs

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