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Ocrelizumab

Pronunciation

(ok re LIZ ue mab)

Index Terms

  • Ocrevus

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Ocrevus: 300 mg/10 mL (10 mL)

Brand Names: U.S.

  • Ocrevus

Pharmacologic Category

  • Anti-CD20 Monoclonal Antibody
  • Monoclonal Antibody

Pharmacology

Ocrelizumab is a recombinant humanized IgG monoclonal antibody directed against B-cells which express the cell surface antigen CD20; CD20 is present on pre-B and mature B lymphocytes. B-cells are thought to influence the course of multiple sclerosis through antigen presentation, autoantibody production, cytokine regulation, and formation of ectopic lymphoid aggregates in the meninges (Hauser 2017). Ocrelizumab selectively targets and binds with high affinity to the cell surface to deplete CD20 expressing B-cells through antibody-dependent cell-mediated phagocytosis and cytotoxicity, as well as complement-mediated cytolysis (Hauser 2017; Montalban 2017).

Distribution

Central Vd: 2.78 L; Peripheral: 2.68 L

Metabolism

Antibodies are primarily cleared by catabolism

Excretion

Constant clearance (estimated): 0.17 L/day; Initial time-dependent clearance: 0.05 L/day.

Onset of Action

Serum CD-19+ B-cell counts (used as a marker for B-cell counts) are reduced within 14 days after infusion.

Duration of Action

Median time for B-cell recovery (to baseline or the lower limit of normal): 72 weeks (range: 27 to 175 weeks).

Half-Life Elimination

26 days

Use: Labeled Indications

Multiple sclerosis: Treatment of relapsing or primary progressive forms of multiple sclerosis (MS) in adult patients.

Contraindications

History of life-threatening infusion reaction to ocrelizumab or any component of the formulation; active hepatitis B virus (HBV) infection.

Dosing: Adult

Note: Premedicate with methylprednisolone (100 mg IV) 30 minutes prior to each infusion, and an antihistamine (eg, diphenhydramine) 30 to 60 minutes prior each infusion; may also consider premedication with acetaminophen. Assess for infection; delay administration for active infection.

Multiple sclerosis, relapsing or progressive: IV: 300 mg on day 1, followed by 300 mg 2 weeks later; subsequent doses of 600 mg are administered once every 6 months (beginning 6 months after the first 300 mg dose) (Hauser 2017; Montalban 2017).

Missed doses: If a dose is missed, administer as soon as possible (do not wait until the next scheduled dose), then adjust the dose schedule to administer the next sequential dose 6 months after the missed dose was administered. Doses must be separated by at least 5 months.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, no significant change in pharmacokinetics was observed in patients with renal impairment.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, no significant change in pharmacokinetics was observed in patients with hepatic impairment.

Dosing: Adjustment for Toxicity

Dosage adjustment for infusion reactions:

Mild to moderate reactions: Reduce the infusion rate to one-half of the rate at which the reaction occurred; maintain reduced rate for at least 30 minutes. If the reduced rate is tolerated, increase the rate every 30 minutes by 30 mL/hour to a maximum rate of 180 mL/hour (for the 300 mg dose) or 40 mL/hour to a maximum rate of 200 mL/hours (for the 600 mg dose).

Severe reactions: Interrupt infusion immediately and administer supportive management as needed. After all symptoms have resolved, restart infusion beginning at a rate one-half of the rate at onset of reaction. If the reduced rate is tolerated, increase the rate every 30 minutes by 30 mL/hour to a maximum rate of 180 mL/hour (for the 300 mg dose) or 40 mL/hour to a maximum rate of 200 mL/hours (for the 600 mg dose).

Life-threatening reactions: Immediately stop and permanently discontinue infusion for life-threatening or disabling infusion reaction.

Reconstitution

Dilute for infusion in NS (dilute 300 mg dose in a 250 mL bag and 600 mg dose in a 500 mL bag) to a final concentration of approximately 1.2 mg/mL. Do not dilute in any other solutions. Do not shake. Incompatibilities between polyvinyl chloride (PVC) or polyolefin bags and ocrelizumab have not been observed.

Administration

Administer though a dedicated IV line using a 0.2 or 0.22 micron in-line filter. Premedicate with methylprednisolone (100 mg IV) 30 minutes prior to each infusion, and an antihistamine (eg, diphenhydramine) 30 to 60 minutes prior each infusion; may also consider premedication with acetaminophen.

First 2 infusions (300 mg dose): Begin infusion at 30 mL/hour; increase by 30 mL/hour every 30 minutes to a maximum rate of 180 mL/hour. Infusion duration is 2.5 hours or longer.

Subsequent infusions (600 mg dose): Begin infusion at 40 mL/hour; increase by 40 mL/hour every 30 minutes to a maximum rate of 200 mL/hour. Infusion duration is 3.5 hours or longer.

Monitor for infusion reactions during infusion and observe for at least one hour after infusion is complete. If infusion reaction occurs, interrupt infusion, discontinue or decrease the rate, depending on the severity of the reaction.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze. Do not shake. Solutions diluted for infusion should be used immediately, however may be stored for up to 24 hours refrigerated and 8 hours at room temperature (including infusion time); discard if infusion cannot be completed on the same day.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Immunosuppressants: Ocrelizumab may enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Ocrelizumab may enhance the adverse/toxic effect of Vaccines (Live). Ocrelizumab may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Test Interactions

Ocrelizumab interferes with the CD20 assay for B-cell counts; use the CD19+ assay to measure B-cell counts.

Adverse Reactions

>10%:

Dermatologic: Skin infection (14%)

Hematologic & oncologic: Decreased serum immunoglobulins (≤17%, IgM most affected), decreased neutrophils (13%)

Respiratory: Upper respiratory tract infection (40% to 49%)

Miscellaneous: Infusion related reaction (34% to 40%)

1% to 10%:

Cardiovascular: Peripheral edema (6%)

Central nervous system: Depression (8%)

Gastrointestinal: Diarrhea (6%)

Infection: Herpes virus infection (5% to 6%)

Neuromuscular & skeletal: Back pain (6%), limb pain (5%)

Respiratory: Lower respiratory tract infection (8% to 10%), cough (7%)

<1%, postmarketing, and/or case reports: Antibody development, malignant neoplasm of breast

Warnings/Precautions

Concerns related to adverse effects:

• Hepatitis B reactivation: Screen for hepatitis B virus in all patients (HBsAg and anti-HBc measurements) prior to treatment initiation. Although there were no reports of hepatitis B reactivation in MS patients treated with ocrelizumab, fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with other anti-CD20 monoclonal antibodies. Perform HBV screening in all patients prior to treatment initiation. Do not administer ocrelizumab to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. Consult liver disease specialist prior to starting and during treatment in patients who are negative for surface antigen (HBsAg) and positive for HB core antibody (HBcAb+) or are carriers of HBV (HBsAg+).

• Herpes infection: In clinical studies, herpes infections (herpes zoster, herpes simplex, oral herpes, genital herpes, and herpes virus infection) were reported more frequently in patients who received ocrelizumab compared to patients who received comparator drug and oral herpes was reported more frequently with ocrelizumab than with placebo. Infections were predominantly mild to moderate in severity. There were no reports of disseminated herpes.

• Infection: Assess for infections prior to treatment initiation and delay treatment in patients with an active infection until the infection is resolved. In clinical studies, a slightly higher incidence of infections was reported in patients receiving ocrelizumab, compared to patients receiving the comparator drug or placebo. Over half of patients who received ocrelizumab experienced one or more infections. In multiple sclerosis patients, ocrelizumab is associated with an increased risk for respiratory tract infections (upper and lower), skin infections, and herpes-related infections, although was not associated with an increased risk of serious infections. Respiratory tract infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

• Infusion reactions: Ocrelizumab may cause infusion reactions; symptoms include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. The incidence of infusion reactions in patients who received methylprednisolone (or an equivalent steroid) and potentially other pre-medication to reduce the risk of infusion reactions prior to each infusion was 34% to 40% in multiple sclerosis studies; the highest incidence was with the first infusion. There were no fatal infusion reactions, although serious infusion reactions occurred (rarely), some reactions required hospitalization. Monitor for infusion reactions during the infusion and for at least one hour after the end of the infusion. Infusion reactions can occur up to 24 hours after the infusion. Administer premedications (methylprednisolone [or equivalent] and an antihistamine, with or without acetaminophen) to reduce the frequency and severity of infusion reactions. Depending on the severity of the reaction, infusion reaction may require infusion interruption, decreased infusion rate, or discontinuation; may also require symptomatic supportive management.

• Malignancy: Ocrelizumab may be associated with an increased risk of malignancy. Malignancies (including breast cancer) occurred more frequently in ocrelizumab-treated patients in clinical studies. Breast cancer occurred in 0.8% of females who received ocrelizumab and none of the females who received the comparator drug or placebo. Patients should follow standard breast cancer screening guidelines.

• Progressive multifocal leukoencephalopathy: Although no cases of progressive multifocal leukoencephalopathy (PML) were identified in ocrelizumab studies, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors such as patients who are immunocompromised or use polytherapy with immunosuppressants. PML is an opportunistic viral infection of the brain caused by the JC virus and usually leads to death or severe disability; PML typically only occurs in patients who are immunocompromised. Symptoms associated with PML are diverse and progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, vision disturbance, and changes in thinking, memory, and/or orientation leading to confusion and personality changes. Withhold treatment and perform appropriate diagnostic evaluation at the first sign or symptom suggestive of PML (MRI findings may be apparent prior to clinical signs/symptoms).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Administer all necessary immunizations at least 6 weeks prior to treatment initiation. Immunization with live-attenuated or live vaccines is not recommended during treatment or after discontinuation until B-cell repletion.

Other warnings/precautions:

• Appropriate use: Ocrelizumab has not been studied in combination with other MS therapies. When initiating ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive following ocrelizumab therapy, consider the potential for increased immunosuppressive effects.

Monitoring Parameters

Hepatitis B virus screening in all patients (HBsAg and anti-HBc measurements) prior to therapy initiation.

Screening recommendations for other anti-CD20 monoclonal antibodies (American Society of Clinical Oncology provisional clinical opinion update [Hwang 2015]): Hepatitis B virus (HBV): Screen for HBV infection with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both immunoglobulin G [IgG] and immunoglobulin M [IgM]) or anti-HBc IgG test should be used to screen for chronic or unresolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg-negative/anti-HBc–positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Monitor for infusion reactions during infusion and for at least 1 hour following the end of the infusion; monitor for signs/symptoms of infection, malignancy, and progressive multifocal leukoencephalopathy.

Pregnancy Considerations

Ocrelizumab is a humanized monoclonal IgG antibody which targets CD20-expressing B-cells. Immunoglobulins are known to cross the placenta. Although data is not available related to the use of ocrelizumab during pregnancy, transient peripheral B-cell depletion and lymphocytopenia have been observed in infants born to mothers who received similar agents. Women of reproductive potential should use effective contraception during therapy and for 6 months after the last infusion.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience common cold symptoms, back pain, or diarrhea. Have patient report immediately to prescriber sign of infection; infusion reaction; signs of skin infection; burning, numbness, or tingling feeling in genitals; shingles; shortness of breath; flushing; dizziness; passing out; loss of strength and energy; headache; nausea; tachycardia; lump in breast; breast soreness; swelling in the arms or legs; depression; or signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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