Ocrewus® (Ocrevus®)

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Active substanceOkrelizumabOkrelizumab
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  • Ocrewus®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 bottle contains:

    active substance: okrelizumab - 300 mg;

    Excipients: sodium acetate trihydrate 21,4 mg, acetic acid ice 2.5 mg, α, α-trehalose dihydrate 400.0 mg, polysorbate 20 2.0 mg, water for injection up to 10 ml.

    1 ml of concentrate contains 30 mg of ocrelizumab.

    Description:

    Transparent or slightly opalescent liquid from colorless to slightly brownish in color.

    Pharmacotherapeutic group:Multiple sclerosis treatment
    ATX: & nbsp

    L.04.A.A.36   Okrelizumab

    Pharmacodynamics:

    Mechanism of action

    Ocrelizumab is a recombinant humanized monoclonal antibody that selectively acts on B-cells expressing Cd20.

    Cd20 is a surface antigen located on pre-B cells, mature B cells and B memory cells. Cd20 It is not expressed on stem lymphoid cells and plasma cells.

    The precise mechanism by which the therapeutic clinical effect of ocrelizumab is achieved in multiple sclerosis (PC), not fully installed. It is assumed that this mechanism involves the process of immunomodulation by reducing the number and suppressing the function of B-cells expressing Cd20. After binding on the surface of B-cells expressing Cd20, ocrelizumab selectively reduces their number through antibody-dependent cellular phagocytosis, antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, and apoptosis. The ability to restore B cells and the existing humoral immunity persist. Besides, okrelizumab does not affect innate immunity and the total number of T cells.

    Pharmacodynamic effects

    By the 14th day of Ocurtus®, there was rapid depletion of the pool Cd 19+ B cells in the blood, which persisted throughout the treatment period and was the expected pharmacological effect. To calculate the number of B cells, Cd 19, since okrelizumab prevents recognition Cd20 during the analysis (see subsection "Mechanism of action" above).

    In the periods between the injections of the Ocrewus® drug, the B-cell pool was restored (to the original value or above the lower limit of the norm (NGN)) at least once in approximately 5% of patients.

    The degree and duration of depletion of the B-cell pool in studies with primary progressive multiple sclerosis (PIRS) and recurrent forms of multiple sclerosis were similar.

    Based on the results of the longest observation period since the last infusion of the Ocrewus® drug (Phase II study, N=51) the median of the recovery period of the B-cell pool (return of NGN or to the baseline, if it is less than NGN) was 72 weeks (27-175 weeks). In 90% of patients, the B-cell pool was restored to

    NGN or baseline value approximately two and a half years after the last infusion of the drug.

    Clinical studies in relapsing forms of multiple sclerosis

    The efficacy and safety profile of Ocrewus® was evaluated in patients with relapsing forms of multiple sclerosis (according to McDonald's 2010 diagnostic criteria) in two randomized, double-blind clinical trials with identical design, double imitation, and using an active comparator (interferon beta-1a).

    Océlizumab at a dose of 600 mg every 24 weeks compared with interferon beta-1a therapy at a dose of 44 μg subcutaneously 3 times a week significantly reduced the average annual relapse rate (mean annual relapse rates were 0.155-0.156 and 0.290-0.292, respectively) patients with progression of disability after 12 weeks after initiation of therapy (9.8% and 15.2%, respectively).

    Clinical trials with primary progressive multiple sclerosis (PPRC)

    The efficacy and safety profile of Ocrewus ® was evaluated in a randomized, double-blind, placebo-controlled clinical trial involving patients with primary progressive PC. The results of this study showed that okrelizumab at a dose of 600 mg every 6 months significantly slows the progression of the disease and reduces the worsening of walking speed in comparison with placebo.

    Immunogenicity

    In patients participating in the study of multiple sclerosis (PC), tested for the presence of antitherapeutic antibodies (ATT) at several time points (before the first administration and every 6 months throughout the study). Of the 1311 patients treated with ocrelizumab, a positive ATT was observed in 12 patients (~ 1%), of whom 2 positive patients were positive for neutralizing antibodies. Assess the impact of treatment ATT on the safety profile and the effectiveness of therapy is not possible because of the low incidence ATT to Ocrewus ®.

    The immunogenicity data largely depend on the sensitivity and specificity of the assay methods used. In addition, the actual frequency of occurrence of positive results with the method of analysis used can be influenced by several factors, including the handling of the sample, sampling time, drug interactions, the administration of concomitant medications, and basic disease. Thus, the comparison of the incidence of antibodies to Ocrewus ® and the frequency of antibodies to other drugs may not be correct.

    Impact on fertility

    Ocrelizumab had no effect on the reproductive system of males and the estrous cycle of female Javanese macaques.

    Pharmacokinetics:

    Patients with relapsing forms of multiple sclerosis received the Ocrewus ® preparation at a dose of 600 mg every 6 months (the first dose was administered as two separate intravenous (IV) infusions: 300 mg of the drug, then 2 more weeks later, another 300 mg of the drug, and subsequent doses were administered in the form of a single IV infusion of 600 mg of the drug).

    Patients with PPR received Ocervus® at a dose of 600 mg (the first and all subsequent doses were administered as two separate IV infusions: 300 mg of the drug, then after 2 weeks another 300 mg of the drug).

    Pharmacokinetic (PK) properties of ocrelizumab in studies with multiple sclerosis (PC) are described with the help of a two-chamber model with time-dependent clearance and with the use of PK parameters characteristic for a monoclonal antibody of class IgGl. The total values ​​of the area under the "concentration-time" curve (AUC) for 24-week dosing intervals were identical with a double administration (300 mg, then after 2 weeks another 300 mg) and with a single administration (600 mg) of the drug. The value of the area under the "concentration-time" curve for the dosing period (AUCt) after the 4th injection of ocrelizumab in a dose of 600 mg was 3510 μg / ml * day. Average maximum concentration (FROMmOh) was 212 μg / ml with relapsing forms of multiple sclerosis (infusion of 600 mg) and 141 μg / ml with PPR (two separate intravenous infusions of 300 mg with a 2-week interval).

    Suction

    Okrelizumab is administered intravenously. Other ways of drug administration have not been studied.

    Distribution

    The calculated value of the central volume of the distribution was 2.78 liters. The calculated values ​​of the peripheral volume of distribution and the intercamera clearance were 2.68 liters and 0.294 liters / day, respectively.

    Metabolism

    There were no separate studies of the metabolism of ocrelizumab. Like other antibodies, okrelizumab predominantly subjected to catabolism.

    Excretion

    The calculated constant clearance was 0.17 l / day. The initial time-dependent clearance was 0.0489 l / day with a further decrease with a half-life of 33 weeks. The terminal elimination half-life was 26 days.

    Pharmacokinetics in specific patient groups

    Children

    Studies of the pharmacokinetics of ocrelizumab in children and adolescents <18 years of age have not been conducted.

    Elderly patients

    Studies of the pharmacokinetics of ocrelizumab in patients aged ≥65 years were not conducted.

    Patients with impaired renal function

    No separate studies of pharmacokinetics have been performed. Patients with impaired renal function of mild severity (creatinine clearance> 45 mL / min) were included in the clinical research program. Changes in pharmacokinetic parameters of ocrelizumab in such patients were not observed.

    Patients with impaired hepatic function

    No separate studies of pharmacokinetics have been performed. Patients with impaired liver function of mild severity were included in theclinical researches. Changes in pharmacokinetic parameters of ocrelizumab in such patients were not observed.

    Indications:

    Ocrewus ® is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis or with primary progressive multiple sclerosis.

    Contraindications:

    Hypersensitivity to ocrelizumab or any component of the drug in the history.

    Active hepatitis B.

    Pregnancy.

    Breastfeeding period.

    Children under 18 years of age (efficacy and safety of Ocrewus ® in children and adolescents <18 years old have not been studied).

    Life-threatening infusion reactions with the use of the drug Oakrevus® in history (see sections "Special instructions", "Method of administration and dose").

    Carefully:

    Patients with congestive heart failure (Class III and IV according to the classification of the New York Heart Association).

    Immunization by live and live attenuated viral vaccines.

    Patients aged ≥65 years.

    Violation of the function of the kidneys of medium and severe severity (efficacy and safety of the Ocrewus ® drug have not been studied).

    When using Ocrewus®, the risk of malignancy may be increased, including the risk of developing breast cancer.

    Pregnancy and lactation:

    Contraception

    Women with a safe reproductive function should use effective contraceptive methods during Ocravus® treatment and within 6 months after the last infusion of the drug.

    Pregnancy

    Océlizumab allegedly penetrates the placental barrier, since it refers to immunoglobulins of the subtype G1.

    Do not use okrelizumab during pregnancy.

    The change in the number of B cells in newborns whose mothers received okrelizumab, has not been studied in clinical studies. No controlled studies of okecrezumab with pregnant women are available.

    In some newborns, whose mothers received other antibodies to Cd20 during pregnancy, there was a temporary depletion of the peripheral B-cell pool and lymphocytopenia.

    Breastfeeding period

    It is not known whether okrelizumab with breast milk and whether it has an effect on its production. Potential harm to a child who is breastfed is not established.

    Okrelizumab penetrates into the milk of animals.

    It is not recommended to breast-feed during Orakus® therapy, because human IgG penetrates into breast milk, and the possibility of absorption of okrelizumab and subsequent depletion of the B-cell pool is unknown.

    Dosing and Administration:

    General recommendations

    Infusion of Ocrewus® should be carefully monitored by an experienced medical professional and with access to emergency care in case of severe reactions such as severe infusion reactions. It is necessary to observe the patient for at least one hour after completion of the infusion for the development of infusion reactions (see section "Special instructions", subsection "Infusion reactions").

    The drug Ocrewus ® is administered only intravenously (intravenously) via a separate catheter. Introduce the drug Ocrewus® stream or bolusno it is impossible.

    Premedication for prevention of infusion reactions

    Before each injection of Ocrewus ®, premedication with methylprednisolone (or equivalent drug) at a dose of 100 mg intravenously (iv) approximately 30 minutes before infusion should be performed to reduce the incidence and severity of infusion reactions (see section "Special instructions").

    In order to further reduce the frequency and severity of infusion reactions, it is recommended to perform additional premedication with an antihistamine drug (for example, diphenhydramine) approximately 30-60 minutes before each infusion of Ocrewus®. In case of clinical necessity, it is recommended to include premedication with an antipyretics (for example, acetaminophen / paracetamol) approximately 30-60 minutes before each infusion of the Ocrewus® preparation.

    Dosing regimen

    The recommended dose of Ocrewus® is 600 mg every 6 months in the form of an IV infusion.

    Initial dose

    The initial dose should be administered in the form of two separate IV infusions: with the first infusion, 300 mg of the drug are administered, then after another 2 weeks another 300 mg of the drug are administered.

    Subsequent doses

    All subsequent doses of Ocrewus ® are subsequently administered as a single IV infusion at a dose of 600 mg every 6 months (see Table 1). The first of the subsequent doses should be carried out 6 months after the Noah infusion of the initial dose.

    The minimum interval between each injection of Ocrewus ® should be 5 months.

    Table 1. Dosage regimen of Ocrewus ®.

    The amount of Ocrewus ® that is to be administered

    Instructions for administering the infusion
    The initial dose (600 mg), divided into 2 infusions

    1st infusion

    300 in 250 ml

    		 - Start the infusion at a rate of 30 ml / h.
    - Then the speed can be increased in 30 ml / h increments every 30 minutes to a maximum speed of 180 ml / h.
    - Each infusion should be carried out for approximately 2.5 hours.

    2nd infusion (2 weeks after the first)

    300 mg in 250 ml

    Subsequent doses (600 mg) every 6 months

    Single infusion

    600 mg in 500 ml

    		 - Start the infusion at a rate of 40 ml / h.
    - Then the speed can be increased in increments of 40 ml / h every 30 minutes to a maximum speed of 200 ml / h.
    - Each infusion should be carried out for about 3.5 hours.

    Skipping in the planned introduction

    If Ocrewus® is given in a scheduled dose, it is necessary to administer the drug at the recommended dose in the shortest possible time, without waiting for the next planned introduction. The schedule for the introduction of Ocrewus® should be adjusted to maintain a 6-month interval between administrations.

    Correction of dose

    Reducing the dose of Ocrewus ® is not recommended.

    When an infusion reaction occurs during any infusion of the drug, it is necessary to follow the recommendations for correcting the infusion,(see also "Special instructions", subsection "Infusion reactions").

    Life-threatening infusion reactions

    If symptoms of life-threatening or disabling infusion reactions such as acute hypersensitivity or acute respiratory distress syndrome occur during the infusion, discontinue the drug immediately Ocrewus®. The patient should receive appropriate supportive treatment. In such patients, the use of Ocrewus® should be discontinued and not resumed in the future.

    Severe Infusion Reactions

    With the development of a severe infusion reaction or with the simultaneous appearance of reddening of the face, fever and sore throat, the infusion should be immediately interrupted. The patient needs to undergo symptomatic treatment. Infusion can be resumed only after all symptoms have been resolved. The initial rate with the resumption of infusion should be two times lower than the infusion rate at the time of the onset of the reaction.

    Light and moderate infusion reactions

    With the development of mild or moderate infusion reaction (for example, headache), the infusion rate should be reduced to half the speed at the time of onset of the phenomenon.Continue introduction at this reduced rate for a minimum of 30 minutes. If the infusion is well tolerated, the rate of administration can be increased in accordance with the original schedule.

    For a detailed description of the symptoms associated with infusion reactions, see "Special instructions", subsection "Infusion reactions".

    Special instructions for dosing

    Children

    The efficacy and safety of Ocrewus® in children and adolescents (<18 years) have not been studied.

    Elderly and old age

    The efficacy and safety of Ocrewus® in patients aged ≥65 years have not been studied.

    Impaired renal function

    The efficacy and safety of Ocrewus® in patients with impaired renal function have not been studied separately. As okrelizumab is derived by catabolism (and not by urine), it is assumed that dose changes in patients with impaired renal function are not required (see the section "Pharmacological properties", subsection "Pharmacokinetics in special patient groups / Patients with impaired renal function").

    Impaired liver function

    The efficacy and safety of Ocrewus® in patients with impaired hepatic function have not been studied separately. As okrelizumab is displayed by catabolism (and not by liver metabolism), it is suggested that dose changes in patients with impaired liver function are not required (see the section "Pharmacological properties", subsection "Pharmacokinetics in special patient groups / Patients with hepatic impairment").

    Rules for the preparation and storage of a solution for infusion

    Dilution of Ocrewus® should be performed by medical personnel in aseptic conditions. The drug does not contain preservatives and is intended for single use only.

    In the concentrate of the Ocrewus ® preparation, the content of fine-dispersed transparent and / or light-reflecting particles is allowed, which is accompanied by increased opalescence. Concentrate can not be used for discoloration or in the presence of discrete foreign impurities.

    The solution should be administered using an infusion system with a built-in filter with a pore diameter of 0.2 or 0.22 microns.

    To prepare the solution for intravenous administration, the concentrate of Ocrewus ® should be diluted in an infusion bag containing 0.9% sodium chloride solution in the ratio 300 mg / 250 ml or 600 mg / 500 ml.The concentration of the finished solution should be approximately 1.2 mg / ml.

    Immediately before infusion, the contents of the infusion bag must be at room temperature to avoid the development of an infusion reaction associated with the administration of a low-temperature solution.

    From the point of view of microbiological purity, the infusion solution should be used immediately after preparation. In exceptional cases, the finished solution can be stored for no longer than 24 hours at a temperature of 2-8 ° C and 8 hours at room temperature. If the infusion can not be completed within the indicated period, the solution remaining in the infusion package should be discarded (see section "Special instructions", section "Instructions for the destruction of an unused drug or an expired product").

    The preparation does not contain preservatives, and therefore the preparation of the solution should be carried out under aseptic conditions.

    Compatibility

    A solution of Ocrewus ® is compatible with infusion bags of polyvinyl chloride or polyolefin and systems for intravenous administration.

    To dilute Ocrewus ®, only 0.9% sodium chloride solution should be used.The dilution of the preparation in other solvents was not investigated.

    Side effects:

    Table 2 summarizes the combined data on adverse reactions (HP) in patients with recurrent forms PC and with primary-progressive PC, which were observed in the clinical trials of Ocrewus ® Most frequent HP there were infusion reactions and respiratory tract infections.

    To describe the frequency of unwanted reactions, the following classification is used: very frequent (≥1 / 10), frequent (≥1 / 100 and <1/10), infrequent (≥1 / 1000 and <1/100), rare (≥1 / 10000 and <1/1000) and very rare (<1/10000), including isolated cases. Undesirable reactions are presented in order of decreasing incidence.

    Table 2. HP in patients with relapsing forms of multiple sclerosis or PPRC, observed with a greater frequency (difference ≥2%) against the background of the Ocrewus ® treatment as compared to the reference drug or placebo1.

    Class of organ systems

    Often

    Often

    Infectious and parasitic diseases

    Infections of the upper respiratory tract, nasopharyngitis, influenza.

    Sinusitis, bronchitis, herpes mucosa of the oral cavity, respiratory tract infection, viral infection, shingles (Herpes zoster).

    Disturbances on the part of the organ of sight


    Conjunctivitis.

    Disturbances from the respiratory system, chest and mediastinal organs


    Cough, catarrhal phenomena.

    Disturbances from the skin and subcutaneous tissues


    Inflammation of subcutaneous fat.

    Trauma, intoxication and complications of manipulation

    Infusion reactions2.


    1 Interferon beta-1 a in studies with recurrent forms of multiple sclerosis or placebo in studies with PPR.

    2 Symptoms reported as infusion reactions within 24 hours after infusion are described below under Infusion reactions.

    Infusion reactions

    The following symptoms associated with infusion reactions were observed: itching, rash, urticaria, erythema, hot flashes, lowering of arterial pressure, fever, increased fatigue, headache, dizziness, throat irritation, oropharyngeal pain, shortness of breath, swollen pharynx or larynx, nausea , tachycardia. In controlled clinical trials, there were no fatal infusion reactions.

    In clinical studies with relapsing forms of multiple sclerosis, infusion reactions were the most frequent adverse events against the background of the Ocrewus ® drug at a dose of 600 mg.The total incidence of infusion reactions was 34.3% and 9.9% when treated with Ocrewus ® and interferon beta-1a, respectively. The incidence of infusion reactions was maximal during the 1st infusion of the 1st dose of Ocrewus ® (27.5%) and decreased with time to <10% during the administration of the 4th dose. Most infusion reactions in both treatment groups were of mild or moderate severity (see section "Special instructions", subsection "Infusion reactions").

    In the clinical study with PPR, the frequency of infusion reactions was maximal during the 1st infusion of the 1st dose of Ocrewus ® (27.4%) and decreased with subsequent doses up to <10% during the administration of the 4th dose. In most patients, infusion reactions often developed during the first infusion of each dose compared with the second infusion of this dose. Most infusion reactions were of mild or moderate severity (see section "Special instructions", subsection "Infusion reactions").

    Infections

    An increase in the incidence of serious infections in patients treated with Ocrewus ® was not observed in comparison with patients in the control groups. The incidence of serious infections in patients with relapsing forms of multiple sclerosis in patients with Ocrewus ® was lower,than in the treatment with interferon beta-1a, and in patients with PPR - similar to that in the placebo group.

    In controlled clinical trials, respiratory infections and herpes infections of predominantly mild to moderate severity were more likely to occur with Ocrewus® than in control groups.

    Respiratory tract infections

    Respiratory tract infections were more common in patients receiving Ocrus® than in patients who received interferon beta-1a or placebo, and were predominantly mild and moderate in severity. In most cases, upper respiratory tract infections (including nasopharyngitis) and bronchitis were observed (see Table 2).

    Herpes

    The frequency of herpetic infection in patients with relapsing forms of multiple sclerosis was higher on the background of Ocrewus ® therapy compared to interferon beta-1a therapy. In the groups of Ocrewus ® and interferon runa-1a, the frequencies of the following undesired reactions were: shingles (Herpes Zoster) 2.1% and 1.0%, herpes simplex 0.7% and 0.1%, oral herpes 3.0% and 2.2%, genital herpes 0.1% and 0% and herpesvirus infection 0 , 1% and 0%, respectively.Infections were predominantly mild and moderate in severity, and patients recovered after standard treatment. Cases of disseminated herpes were not observed.

    In a clinical study in patients with PPR, herpes mucosa of the oral mucosa appeared with a frequency of 2.7% and 0.8% against the background of treatment with the drug Ocrewus ® and in the placebo group, respectively.

    Data on cases of serious infection in clinical studies of autoimmune disease, not related to PC

    Clinical studies of Ocrewus ® are available in combination with immunosuppressive therapy (long-term use of glucocorticosteroids, synthetic and biological disease-modifying anti-rheumatic drugs (BMARP), mycophenolate mofetil, cyclophosphamide, azathioprine) in rheumatoid arthritis and other autoimmune diseases.

    According to the results of studies with patients with rheumatoid arthritis (RA), there was an imbalance of serious infections in the group of Ocrewus ® and immunosuppressants, in particular, atypical pneumonia and pneumonia caused by Pneumocystis jirovecii, pneumonia caused by the virus of varicella, tuberculosis and histoplasmosis. In rare cases, the above infectious complications have a lethal outcome.Serious infections were more common with the use of the Ocravus® 1000 mg dose together with immunosuppressants compared with its similar use at a dose of 400 mg or with the use of immunosuppressants in combination with placebo.

    The risk factors for the development of serious infections included the presence of concomitant diseases, long-term therapy with immunosuppressants / glucocorticosteroids, as well as the patient's affiliation to the Asian region.

    Changes in laboratory indicators

    Immunoglobulins

    During treatment with Ocrewus ®, the overall concentration of immunoglobulins was reduced, mainly due to a decrease in the level of immunoglobulin M (IgM). At the same time, there were no correlations with the development of serious infections.

    Before starting treatment with Ocrewus ® as part of a clinical trial, baseline concentrations IgG, IgA and IgM were less than the lower limit of norm (NGN) in 0.5%, 1.5% and 0.1% of patients with relapsing forms of multiple sclerosis, respectively. At 96 weeks after the start of treatment, concentrations IgG, IgA and IgM were lower than NGN in 1.5%, 2.4% and 16.5% of patients, respectively.

    In a placebo-controlled study (with PPRC), the proportions of patients in the Ocrewus® group of therapy in whom baseline levels IgG, IgA and IgM were less than NGN, were 0%, 0.2%, and 0.2%, respectively. After therapy, the proportion of Ocrewus® patients receiving patients at week 120 IgG, IgA and IgM were less than NGN, were 1.1%, 0.5% and 15.5%, respectively.

    Neutrophils

    In patients with relapsing forms of multiple sclerosis treated with Ocrewus ®, the decrease in the number of neutrophils was observed less frequently (14.7%), compared with patients receiving interferon beta-1a (40.9%). In patients with OCD who were treated with Ocrewus ®, the decrease in the number of neutrophils was observed slightly more often (12.9%), compared to patients receiving placebo (10.0%).

    In most cases, a decrease in the number of neutrophils on the background of therapy with the Ocrewus ® preparation was transient, it was noted one day during therapy, was no longer repeated and had a 1st or 2nd degree of severity. Neutropenia of the third or fourth degree of severity was observed in approximately 1% of patients, with no correlation with the development of infection.

    Overdose:

    The experience of exceeding the recommended dose of Ocrewus ® is limited. The maximum dose studied was 2000 mg in the form of two intravenous infusions of 1000 mg at intervals of 2 weeks,while the observed adverse reactions corresponded to the established safety profile of the Ocrewus ® preparation.

    There is no specific antidote. If the dose of Ocrewus® is accidentally exceeded, the infusion should be stopped immediately and the patient is monitored for the development of infusion reactions (see section "Special instructions", subsection "Infusion reactions").

    Interaction:

    Immunosuppressive and immunomodulatory therapy

    With the simultaneous use of Ocrewus® and immunosuppressive and immunomodulatory therapies, including glucocorticosteroids in immunosuppressive doses, an increased risk of immunosuppression is expected. Thus, it is necessary to consider the risk of developing an additive effect on the immune system.

    When transferring a patient from therapy to drugs that have a prolonged effect on the immune system (daclizumab, phingolimod, natalizumab, teriflunomide or mitoxantrone), for therapy with Ocrewus®, the duration and mechanism of action of these drugs must be taken into account because of the possibility of an additive effect on the immune system.

    Separate studies of interaction with other drugs have not been carried out, since interactions related to the activity of cytochrome P450 isoenzymes and other metabolizing enzymes or transports are not expected.

    Special instructions:

    To ensure the monitoring of the quality and safety of the biological preparation, the trade name of the preparation (Ocrewus®) and serial number should be indicated in the patient's medical records.

    Infusion reactions

    The development of infusion reactions in patients receiving the Ocrewus ® preparation may be associated with the release of cytokines and / or chemical mediators.

    Symptoms of MI can develop during any infusion, but most often they were noted during the first injection of Ocrewus®.

    MI can also develop within 24 hours after infusion.

    Symptoms of IR may be itching, rash, hives, erythema, throat irritation, oropharyngeal pain, dyspnea, swelling of the pharynx or larynx, hot flashes, lowering of the arterial pressure, increased body temperature, fatigue, headache, dizziness, nausea and tachycardia (see section "Side effect").

    Patients should be carefully monitored for symptoms of ID at least one hour after the infusion is complete. The doctor should warn the patient that the development of IR is possible within 24 hours after the infusion.

    On the background of therapy with the drug Ocrewus ®, a hypersensitivity reaction may develop (an acute allergic reaction to the drug). MI can be clinically indistinguishable from acute type I hypersensitivity reactions (mediated IgE) (see subsection "Hypersensitivity Reactions" below). Recommendations for premedication to reduce the frequency and severity of MI are given in the section "Method of administration and dose".

    Control of infusion reactions

    Recommendations for correcting infusion of the drug to patients who have developed life-threatening, severe, moderate or mild IR are listed in the section "Dosage and Administration", subsection "Dose Correction".

    With the development of severe symptoms from the respiratory system (such as bronchospasm or an episode of exacerbation of bronchial asthma), the infusion should be stopped immediately. Continue therapy in the future can not.

    After performing symptomatic treatment, the patient should be monitored until the symptoms of the respiratory system are fully resolved,Since the initial improvement in symptoms may be followed by their worsening. During the infusion of the Ocrewus ® drug, it is possible to lower blood pressure, which may refer to symptoms of MI. In this regard, the possibility of suspending treatment with antihypertensive drugs should be considered for 12 hours before and during each infusion of Ocrewus®. In patients with congestive heart failure (class III and IV on the classification of the New York Heart Association) in the history of the use of Ocrewus ® has not been studied.

    Hypersensitivity reactions

    In controlled clinical trials, the development of hypersensitivity reactions with the use of Ocrewus ® was not reported.

    Possible difficulties in the differential diagnosis of hypersensitivity and MI. Hypersensitivity reactions may occur during any infusion, however, as a rule, they are absent during the first infusion. If in the course of subsequent infusions the previously observed symptoms are aggravated or there are new severe symptoms, it is necessary to immediately consider the likelihood of developing a hypersensitivity reaction.If you suspect a hypersensitivity reaction during infusion, you should stop the infusion immediately and do not resume later. Patients with established IgE-mediated hypersensitivity to Ocrewus® is contraindicated in therapy with this drug (see section "Contraindications").

    Infections

    In patients with active infection, the use of Ocrewus ® should be postponed until the infection is stopped.

    Progressive multifocal leukoencephalopathy (PML)

    PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JC), and usually occurs in patients with immunodeficiency. As a rule, the development of PML leads to death or severe disability.

    During the clinical trials of Ocrewus ® there were no cases of PML, however, JC-associated PML was observed in patients receiving therapy with other antibodies to Cd20, as well as other drugs for treatment PC. Development JC- associated PML was associated with risk factors such as immunodeficiency and multiple immunosuppressant therapy.

    If PML is suspected, the Ocrewus® therapy should be suspended and the necessary diagnostic evaluation performed. In this case, signs of PML can be detected during MRI before the onset of clinical symptoms.

    The characteristic symptoms of PML are diverse, can worsen over a period of several days to several weeks, and include progressive weakness on one side of the body or "awkwardness" of the limbs, impaired vision, changes in thinking, memory and orientation, leading to confusion and personality changes . These signs and symptoms may be similar to manifestations of relapse PC. When confirming the diagnosis of PML, it is necessary to completely stop treatment. Reactivation of hepatitis B

    In patients with PC, who received therapy with Ocrewus ®, did not report cases of reactivation of hepatitis B. In patients treated with antibodies to Cd20, reported on the reactivation of the hepatitis B virus (HBV), in some cases, leading to the development of fulminant hepatitis, hepatic insufficiency, lethal outcome. Before prescribing Ocrewus®, all patients should be screened for HBV in accordance with local guidelines.Ocrewus ® should not be used in patients with active hepatitis B virus (HBV) (active infection should be confirmed by positive results of determining the surface antigen (HBsAg) and antibodies to antigens of the hepatitis B virus (HBcAb)).

    Patients with positive serological markers of hepatitis B (negative HBsAg and a positive result on HBcAb), as well as carriers of HBV (positive result in HBsAg), should consult with a physician hepatologist before prescribing Ocrewus®.

    For such patients, it is necessary to conduct appropriate monitoring and take measures to prevent the reactivation of the hepatitis B virus in accordance with local standards.

    Treatment with immunosuppressants before, during and after therapy with Ocrewus ®

    Prescribe therapy with Ocrewus ® after immunosuppressive therapy or immunosuppressive therapy after Ocurtus ® therapy should be taken into account that it is possible to overlap their pharmacodynamic effects (see the section "Pharmacological properties", subsection "Mechanism of action").

    With the appointment of Ocrewus ® caution should be taken, taking into account the pharmacodynamics of other disease-modifying drugs (BMPs) for treatment PC, since there are no data from the Ocrewus ® preparation in combination with other BMNs for treatment PC.

    Vaccination

    The safety of immunization with live or live attenuated viral vaccines following OCR therapy has not been studied. During therapy with Ocrewus®, and before the B-cell pool is restored, vaccination with live or live attenuated vaccines is not recommended (see section "Pharmacological properties", subsection "Mechanism of action").

    The number of patients with positive tigers of antibodies to S. pneumoniae, causative agents of mumps, rubella and chickenpox after Ocurtus® for 2 years was generally similar to that at the baseline level.

    Data on the effects of vaccination in patients receiving Ocrewus ® are not available. Before prescribing Ocrewus ® the doctor should examine the status of the patient's immunization. In the case of vaccination, it must be completed at least 6 weeks before the start of treatment with Ocrewus ®.

    Malignization

    The risk of malignancy may be increased with the use of Ocrewus ®. In controlled clinical trials, malignancy, including breast cancer, was more common in patients receiving Ocrewus® than in patients receiving interferon beta-1a or placebo (breast cancer diagnosed in 6/781 patients and 0/668 patients, respectively). Patients should follow standard guidelines for screening breast cancer.

    Instructions for the destruction of an unused preparation or product with expired shelf life

    The release of the drug Ocrewus® into the environment should be minimized. Do not dispose of the product with sewage or with household waste. Destruction of an unused preparation or product with expired shelf life should be carried out in accordance with the requirements of the medical institution.

    The following points should be strictly observed regarding the use and disposal of syringes and other acute medical items:

    - never reuse needles and syringes;

    - all used needles and syringes should be placed in the sharps container (disposable container,resistant to piercing).

    Effect on the ability to drive transp. cf. and fur:

    The effect of Ocrewus® on the ability to drive and work with machinery has not been studied.

    Form release / dosage:Concentrate for the preparation of a solution for infusions of 30 mg / ml.
    Packaging:

    For 10 ml (300 mg / 10 ml) of the drug in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a plug of butyl rubber laminated with fluoropolymer, crimped with an aluminum cap and closed with a plastic lid.

    1 bottle with the drug, along with instructions for use, is placed in a cardboard box.

    Storage conditions:

    Store at 2-8 ° C in a cardboard box for protection from light.

    Keep out of the reach of children.

    Shelf life:

    2 of the year.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004503
    Date of registration:20.10.2017
    Expiration Date:20.10.2022
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspROSH-MOSCOW, CJSCROSH-MOSCOW, CJSCRussia
    Information update date: & nbsp24.10.2017
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