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Ocrelizumab

Class: Immunomodulatory Agents
Brands: Ocrevus

Introduction

Ocrelizumab, a CD20-directed cytolytic antibody, is an immunomodulatory agent.

Uses for Ocrelizumab

Ocrelizumab has the following uses:

Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of patients with relapsing or primary progressive forms of multiple sclerosis.1

Ocrelizumab Dosage and Administration

General

Ocrelizumab is available in the following dosage form(s) and strength(s):

  • Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Hepatitis B virus screening is required before the first dose.1

  • Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion.1

  • Administer ocrelizumab by IV infusion. 1

  • Initial doses: 300 mg IV infusion, followed two weeks later by a second 300 mg IV infusion. 1

  • Subsequent doses: 600 mg IV infusion every 6 months.1

  • Must be diluted prior to administration.1

  • Monitor patients closely during and for at least one hour after infusion.1

Cautions for Ocrelizumab

Contraindications

  • Active hepatitis B virus infection.1

  • History of life-threatening infusion reaction to ocrelizumab.1

Warnings/Precautions

Infusion Reactions

Ocrelizumab 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, and tachycardia. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in ocrelizumab-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 ocrelizumab-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. 1

Observe patients treated with ocrelizumab 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. 1

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. 1

Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, immediately and permanently stop ocrelizumab 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. 1

Infections

A higher proportion of ocrelizumab-treated patients experienced infections compared to patients taking interferon beta-1a (i.e., Rebif) or placebo. In relapsing multiple sclerosis (RMS) trials, 58% of ocrelizumab-treated patients experienced one or more infections compared to 52% of interferon beta-1a-treated patients. In the primary progressive multiple sclerosis (PPMS) trial, 70% of ocrelizumab-treated patients experienced one or more infections compared to 68% of patients on placebo. Ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrelizumab was not associated with an increased risk of serious infections in MS patients. Delay ocrelizumab administration in patients with an active infection until the infection is resolved.1

Respiratory Tract Infections

A higher proportion of ocrelizumab-treated patients experienced respiratory tract infections compared to patients taking interferon beta-1a or placebo. In RMS trials, 40% of ocrelizumab-treated patients experienced upper respiratory tract infections compared to 33% of interferon beta-1a-treated patients, and 8% of ocrelizumab-treated patients experienced lower respiratory tract infections compared to 5% of interferon beta-1a-treated patients. In the PPMS trial, 49% of ocrelizumab-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of ocrelizumab-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.1

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in ocrelizumab-treated patients than in interferon beta-1a-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. There were no reports of disseminated herpes. 1

In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the ocrelizumab-treated patients than in the patients on placebo (2.7% vs 0.8%).1

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in ocrelizumab clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold ocrelizumab and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.1

Hepatitis B Virus (HBV) Reactivation

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 antibodies. Perform HBV screening in all patients before initiation of treatment with ocrelizumab. Do not administer ocrelizumab 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. 1

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

When initiating ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after ocrelizumab, consider the potential for increased immunosuppressive effects. Ocrelizumab has not been studied in combination with other MS therapies.1

Vaccinations

Administer all immunizations according to immunization guidelines at least 6 weeks prior to initiation of ocrelizumab. 1

The safety of immunization with live or live-attenuated vaccines following ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.1

No data are available on the effects of live or non-live vaccination in patients receiving ocrelizumab. 1

Malignancies

An increased risk of malignancy with ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in ocrelizumab-treated patients. Breast cancer occurred in 6 of 781 females treated with ocrelizumab and none of 668 females treated with interferon beta-1a or placebo. Patients should follow standard breast cancer screening guidelines.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risk associated with use of ocrelizumab in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. 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. 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.1

Following intravenous administration of ocrelizumab 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 ocrelizumab (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. 1

Lactation

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 ocrelizumab and any potential adverse effects on the breastfed infant from ocrelizumab or from the underlying maternal condition.1

Females And Males Of Reproductive Potential

Women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion of ocrelizumab.1

Pediatric Use

Safety and effectiveness of ocrelizumab in pediatric patients have not been established.1

Geriatric Use

Clinical studies of ocrelizumab did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

Common Adverse Effects

The most common adverse reactions were:1

  • RMS (incidence ≥10% and > interferon beta-1a): upper respiratory tract infections and infusion reactions.1

  • PPMS (incidence ≥10% and > placebo): upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.1

Actions

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. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 1

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.1

Infection

Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores. 1

Advise patients that PML has happened with drugs that are similar to ocrelizumab and may happen with ocrelizumab. 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 doctor 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. 1

Advise patients that ocrelizumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.1

Vaccination

Advise patients to complete any required vaccinations at least 6 weeks prior to initiation of ocrelizumab. Administration of live-attenuated or live vaccines is not recommended during ocrelizumab treatment and until B-cell recovery.1

Malignancies

Advise patients that an increased risk of malignancy, including breast cancer, may exist with ocrelizumab. Advise patients that they should follow standard breast cancer screening guidelines. 1

Pregnancy

Instruct patients that if they are pregnant or plan to become pregnant while taking ocrelizumab they should inform their healthcare provider. 1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ocrelizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

300 mg /10 mL

Ocrevus

Genentech Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions April 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Genentech, Inc. OCREVUS (ocrelizumab) INTRAVENOUS prescribing information. March 2017.

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