OCREVUS

Ocrelizumab is a

CD20-directed cytolytic antibody indicated for the treatment of patients with primary progressive or relapsing forms of multiple sclerosis (MS).

It is a second-generation recombinant humanized monoclonal IgG1 antibody that selectively targets B-cells that express the CD20 antigen.

Compared to non-humanized

CD20 antibodies such as rituximab, ocrelizumab is expected to be less immunogenic with repeated infusions, improving the benefit-to-risk profile for patients with MS. 1, 7 MS is a chronic, inflammatory, autoimmune disease of the central nervous system that leads to neurological disabilities and a significantly reduced quality of life.

Most patients with

MS experience episodes of relapses with worsening function, followed by recovery periods or remissions.

Primary progressive multiple sclerosis (PPMS) accounts for 10-15% of the overall population of patients with MS, and leads to the gradual worsening of neurologic disability from symptom onset, often without early relapses or remissions 3.

Developed by

Genentech/Roche, ocrelizumab was approved by the FDA in March 2017 under the market name Ocrevus for intravenous injection.

It was later approved by Health Canada in August 2017, making the drug the first available treatment for PPMS in both the US and Canada.

In clinical trials of patients with relapsing forms of MS, treatment with ocrelizumab resulted in reduced relapse rates and reduced worsening of disability compared to interferon beta-1a.

In phase 3 clinical trials of patients with PPMS, treatment with ocrelizumab led to lower clinical and MRI progression rates compared to placebo.

In September 2024, a formulation of ocrelizumab containing hyaluronidase (human recombinant) was approved by the US FDA.

The addition of hyaluronidase allows for subcutaneous injection, which is a method often preferable for patients and provides an alternative means of administration for sites lacking Intravenous infrastructure, such as a doctor's office. 11, 12.

Ocrelizumab is a

CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

It is also indicated for the treatment of primary progressive MS in adults. 9,

Since ocrelizumab interferes with the

CD20 assay, CD19+B-cells are used to assess B-cell counts after treatment.

Fourteen days following infusion, a reduction in CD19+B-cell counts was observed.

In clinical studies, B-cell counts rose above the lower limit of normal (LLN) or baseline counts between infusions of ocrelizumab at least once in 0.3% to 4.1% of patients.

In a clinical study involving 51 patients, the time for B-cell counts to return to baseline or LLN ranged from 27-125 weeks, with a median time of 72 weeks after the last infusion.

Within 2.5 years after the last infusion, B-cell counts returned to either baseline or LNN in 90% of patients treated with ocrelizumab.

Since ocrelizumab is a recombinant humanized antibody, it is expected to be less immunogenic than rituximab, a chimeric antibody.

Compared to the ocrelizumab pivotal trial, a rituximab phase II trial had a higher proportion of anti-drug antibodies, suggesting greater immunogenicity.

However, caution should be exercised since these studies used different assay methods, and the association between anti-drug antibody development and infusion reactions has not been fully elucidated.

The use of ocrelizumab can cause infusion reactions, and lead to a higher risk of respiratory tract infections and viral infections.

Cases of progressive multifocal leukoencephalopathy (PML) and immune-mediated colitis have been reported in patients treated with ocrelizumab.

Also, an increased risk of malignancy may exist.

Ocrelizumab displays a two-compartment pharmacokinetic model with time-dependent clearance.

The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of ocrelizumab was 3,510 mcg/mL per day. Following the intravenous infusion of maintenance doses of 600 mg every 6 months in relapsing MS patients, the mean peak plasma concentration of ocrelizumab (C max ) was 212 mcg/mL.

Following intravenous infusion of two 300 mg doses separated by 14 days every 6 months in patients with PPMS, C max was 141 mcg/mL.

Ocrelizumab follows linear and dose proportional pharmacokinetics between 400 mg and 2000 mg.

In a population pharmacokinetic estimate, the central volume of distribution of ocrelizumab was 2.78 L.

As with other antibodies, ocrelizumab is expected to undergo nonspecific catabolism and broken into smaller peptides and amino acids.

Monoclonal antibodies (mAb) such as ocrelizumab are too large to be filtered by the kidneys, and therefore, not eliminated in urine under normal conditions.

If antibody fragments of low molecular weight are filtered, they are usually reabsorbed and metabolized in the proximal tubule.

The peptides and amino acids produced by catabolism are recycled or used as an energy source.

The terminal elimination half-life of ocrelizumab was 26 days.

The constant clearance of ocrelizumab was 0.17 L/day, while the initial time-dependent clearance was 0.05 L/day. Peripheral volume and inter-compartment clearance were 2.68 L and 0.29 L/day, respectively.

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information regarding ocrelizumab is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as immune-mediated colitis.

Symptomatic and supportive measures are recommended.

The carcinogenic and mutagenic potentials of ocrelizumab have not been evaluated.

In monkeys given three loading doses of 15 or 75 mg/kg Intravenous, followed by weekly doses of 20 or 100 mg/kg for 8 weeks (2-10 times the recommended human dose), ocrelizumab did not have effects on reproductive organs.

No reproductive effects were detected on the estrus cycle of female monkeys given the same ocrelizumab regimen.

is contraindicated in patients with: Active HBV infection A history of life-threatening infusion reaction to OCREVUS Active hepatitis B virus infection History of life-threatening infusion reaction to OCREVUS.

Before initiating

OCREVUS, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion Administer OCREVUS by intravenous infusion Adults and pediatric patients (10 years of age and older), who weigh 35 kg or more: Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion Subsequent doses: 600 mg intravenous infusion every 6 months Pediatric patients (10 years of age and older) who weigh 25 kg to less than 35 kg: Start dose: 150 mg intravenous infusion, followed two weeks later by a second 150 mg intravenous infusion Subsequent doses: 300 mg intravenous infusion every 6 months Must be diluted prior to administration Monitor patients closely during and for at least one hour after infusion 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.

Serum Immunoglobulins Prior to initiating

OCREVUS, perform testing for quantitative serum immunoglobulins.

For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with OCREVUS.

Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all age-appropriate 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.

Liver Function Tests Prior to initiating

OCREVUS, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels. 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.

To reduce the frequency and severity of infusion reactions, administer the following premedications: Methylprednisolone (or an equivalent corticosteroid) by intravenous infusion to be completed approximately 30 minutes prior to each OCREVUS infusion, as follows: Adults and pediatric patients who weigh 40 kg or more: 100 mg Pediatric patients who weigh less than 40 kg: 2 mg/kg An antihistamine (e.g., diphenhydramine) 30 to 60 minutes prior to each OCREVUS infusion.

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

Administer the antipyretic 30 minutes to 60 minutes prior to OCREVUS infusion. 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.

Observe the patient for at least one hour after the completion of the infusion.

OCREVUS is administered as an intravenous infusion.

The initial dose is split into two equal infusions administered two weeks apart.

Subsequent doses are administered every 6 months thereafter.

Dosing for pediatric patients (10 years of age and older) is according to body weight.

Table 1 Recommended Dose, Infusion Rate, and Infusion Duration for Adult Patients with 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 time may take longer if the infusion is interrupted or slowed.

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 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) .

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 Table 2 Recommended Dose, Infusion Rate, and Infusion Duration for Pediatric Patients 10 Years of Age and Older Infusion 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 for Injection.

Weight 25 kg to Less Than 35 kg Initial Dose (two infusions) Infusion 1 150 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) 150 mg in 250 mL Subsequent Doses (one infusion every 6 months) Single infusion once every 6 months 300 mg in 250 mL Body Weight 35 kg or More 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) Single infusion once every 6 months 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 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. 2.5 Dose Modifications Because of Infusion Reactions Dose modifications in response to infusion reactions depends on the severity.

Immediately stop and permanently discontinue OCREVUS if there are signs of a life-threatening or disabling infusion reaction.

Provide appropriate supportive treatment.

Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary.

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 and Table 2.

This change in rate will increase the total duration of the infusion but not the total dose.

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.

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 the required dose of

OCREVUS and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, as described in Table 3.

Table 3: Dilution of OCREVUS Dose of OCREVUS (mg) Volume of OCREVUS (mL) Volume of 0.9% Sodium Chloride Injection (mL) Final Drug Concentration (mg/mL) 150 mg 5 mL 250 mL 0.6 mg/mL 300 mg 10 mL 250 mL 1.2 mg/mL 600 mg 20 mL 500 mL 1.2 mg/mL Do not use other diluents to dilute OCREVUS because their use has not been tested.

The product contains no preservative and is intended for single use only.

Discard any unused portion left in the vial.

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.

Administer the diluted infusion solution through a dedicated line using an infusion set with a 0.2 or 0.22 micron in-line filter.

(ocrelizumab) injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01).

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.

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.

OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier.

There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women.

However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy.

B-cell levels in infants following maternal exposure to OCREVUS have not been studied in clinical trials.

The potential duration of

B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown.

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.

Data Animal Data Following intravenous administration of OCREVUS to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses.

Intravenous administration of

OCREVUS (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates.

The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections.

Reduced testicular weight was observed in neonates at the high dose.

A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are and 10 times the recommended human dose of 600 mg, on a mg/kg basis.

The safety and effectiveness of

OCREVUS for the treatment of relapsing-remitting MS have been established in pediatric patients 10 years of age and older who weigh 25 kg or more.

Use of

OCREVUS for this indication is supported by evidence from one randomized, double-blind clinical study in 187 pediatric patients (93 of whom received OCREVUS) and additional pharmacokinetic data in pediatric patients.

The overall safety profile in pediatric patients 10 years of age and older receiving OCREVUS was generally consistent with that observed in adult patients.

Safety and effectiveness of

OCREVUS have not been established in pediatric patients less than 10 years of age or who weigh less than 25 kg.

Clinical studies of

OCREVUS did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.