Ocrevus^® (Concentrate) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Roche Diagnostics GmbH (Germany)

Or

F. Hoffmann-La Roche, Ltd (Switzerland)

Packaging and Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

Or

ORTAT, JSC (Russia)

ATC Code

L04AG08 (Ocrelizumab)

Active Substance

Ocrelizumab (Rec.INN registered by WHO)

Dosage Form

Ocrevus®

Concentrate for solution for infusion 30 mg/1 ml: fl. 10 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear or slightly opalescent liquid from colorless to slightly brownish.

Excipients : sodium acetate trihydrate – 21.4 mg, glacial acetic acid – 2.5 mg, α,α-trehalose dihydrate – 400 mg, polysorbate 20 – 2 mg, water for injections – up to 10 ml.

10 ml – colorless glass vials (1) – cardboard packs with first opening control.

10 ml – colorless glass vials (1) – cardboard boxes

10 ml – colorless glass vials (1) – polypropylene boxes

Clinical-Pharmacological Group

Immunomodulator. A drug used for multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

A drug for the treatment of multiple sclerosis. Ocrelizumab is a recombinant humanized monoclonal antibody that selectively targets B-cells expressing CD20.

CD20 is a surface antigen located on pre-B-cells, mature B-cells, and memory B-cells. CD20 is not expressed on lymphoid stem cells and plasma cells.

The exact mechanism by which ocrelizumab achieves its therapeutic clinical effect in multiple sclerosis has not been fully established. It is assumed that this mechanism involves immunomodulation by reducing the number and suppressing the function of CD20-expressing B-cells.

After binding to the surface of CD20-expressing B-cells, Ocrelizumab selectively reduces their number through antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. The ability to recover B-cells and existing humoral immunity is preserved. Furthermore, Ocrelizumab does not affect innate immunity and the total number of T-cells.

Clinical studies have established that Ocrelizumab reduces the mean annual relapse rate, as well as the proportion of patients with disability progression at 12 weeks after the start of therapy, slows disease progression, and reduces the worsening of walking speed indicators compared to placebo.

In the analysis for immunogenicity, anti-therapeutic antibodies were detected in approximately 1% of patients, with neutralizing antibodies detected in isolated cases. It was not possible to assess the impact of anti-therapeutic antibodies that emerged during treatment on the safety and efficacy profile of the therapy due to the low frequency of occurrence of these antibodies to ocrelizumab.

Pharmacokinetics

The pharmacokinetic properties of ocrelizumab in multiple sclerosis studies were described using a two-compartment model with time-dependent clearance and using pharmacokinetic parameters characteristic of a monoclonal antibody of the IgG1 class. The total AUC values over 24-week dosing intervals were identical for the double administration (300 mg, then another 300 mg after 2 weeks) and the single administration (600 mg) of ocrelizumab.

The AUC value after the 4th administration of ocrelizumab at a dose of 600 mg was 3510 µg/ml×day. The mean C_max was 212 µg/ml for relapsing forms of multiple sclerosis (600 mg infusion) and 141 µg/ml for primary progressive multiple sclerosis (two separate IV infusions of 300 mg with a 2-week interval).

The calculated central V_d value was 2.78 L. The calculated peripheral V_d and intercompartmental clearance values were 2.68 L and 0.294 L/day, respectively.

No separate studies on the metabolism of ocrelizumab have been conducted. Like other antibodies, Ocrelizumab is predominantly catabolized.

The calculated constant clearance rate was 0.17 L/day. The initial time-dependent clearance was 0.0489 L/day with a subsequent decrease at T_1/2 33 weeks. The terminal T_1/2 was 26 days.

Indications

Relapsing forms of multiple sclerosis or primary progressive multiple sclerosis.

ICD codes

Dosage Regimen

Administered intravenously as an infusion.

Premedication is administered to prevent infusion reactions.

The initial dose is administered as two separate IV infusions: the first infusion administers 300 mg, then after 2 weeks another 300 mg is administered. All subsequent doses are administered as a single IV infusion at a dose of 600 mg every 6 months. The first of the subsequent doses should be administered 6 months after the first infusion of the initial dose.

Reduction of the ocrelizumab dose is not recommended.

If an infusion reaction occurs during any infusion of ocrelizumab, special recommendations for infusion adjustment should be followed.

Adverse Reactions

Infections and parasitic diseases very common – upper respiratory tract infections, nasopharyngitis, influenza; common – sinusitis, bronchitis, herpes of the oral mucosa, respiratory tract infections, viral infection, herpes zoster.

Eye disorders common – conjunctivitis.

Respiratory system disorders common – cough, catarrhal symptoms.

Skin and subcutaneous tissue disorders common – inflammation of the subcutaneous fat.

General disorders very common – infusion reactions

Laboratory parameters decrease in total immunoglobulin concentration, mainly due to a decrease in IgM levels (no correlation with the development of serious infections was noted); in most cases, the decrease in neutrophil count during therapy was transient, noted once during therapy, did not recur, and was characterized as grade 1 or 2 severity. Neutropenia of grade 3 or 4 severity was observed in approximately 1% of patients, with no correlation with the development of infection.

Contraindications

Active hepatitis B, pregnancy, breastfeeding period, age under 18 years, life-threatening infusion reactions with previous use of ocrelizumab, hypersensitivity to ocrelizumab.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Use with caution in patients with congestive heart failure (NYHA class III and IV), during immunization with live and live attenuated viral vaccines, in patients over 65 years of age, with moderate and severe renal impairment.

The use of ocrelizumab may increase the risk of malignancy, including the risk of breast cancer.

The development of infusion reactions in patients receiving Ocrelizumab may be associated with the release of cytokines and/or chemical mediators. Symptoms may develop during any infusion, but most often during the first administration of ocrelizumab. Infusion reactions may develop within 24 hours after the infusion.

Symptoms of infusion reactions may include itching, rash, urticaria, erythema, throat irritation, oropharyngeal pain, shortness of breath, pharyngeal or laryngeal edema, flushing, decreased blood pressure, increased body temperature, fatigue, headache, dizziness, nausea, and tachycardia. Due to the possible decrease in blood pressure, consideration should be given to suspending treatment with antihypertensive drugs for 12 hours before and during each infusion.

The patient’s condition must be carefully monitored for the occurrence of symptoms of infusion reactions for at least 1 hour after the completion of the infusion. The physician should warn the patient that the development of infusion reactions is possible within 24 hours after the infusion.

If severe respiratory symptoms develop (such as bronchospasm or an episode of asthma exacerbation), the infusion should be stopped immediately. Therapy should not be continued in the future.

After symptomatic treatment, the patient should be monitored until the respiratory symptoms have completely resolved, as an initial improvement in symptoms may be followed by their worsening.

In patients with an active infection, the use of ocrelizumab should be postponed until the infection is resolved.

Drug Interactions

With the simultaneous use of ocrelizumab and immunosuppressive and immunomodulatory therapy, including corticosteroids in immunosuppressive doses, an increased risk of immunosuppression is expected. Thus, the risk of an additive effect on the immune system must be considered.

When switching a patient from therapy with drugs that have a prolonged effect on the immune system (daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone) to therapy with ocrelizumab, the duration and mechanism of action of these drugs must be taken into account due to the possibility of an additive effect on the immune system.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.