MabThera

MabThera – immunobiological drug on the basis of monoclones, an antineoplastic and immunodepressive effect.

Form of release and structure

Dosage forms of MabThera:

• Concentrate for preparation of solution for infusions: slightly opalescent, transparent, colourless or light yellow liquid (on 10 ml / 100 mg or 50 ml / 500 mg in the bottles from glass of a hydrolytic class 1 EF corked by traffic jams from the butyl rubber laminated by a ftorpolimer, which are pressed out by an aluminum cap and closed by a plastic cover, 1 bottle on 50 ml or 2 bottles on 10 ml in a pack cardboard);
• Solution for hypodermic (п / to) introductions: slightly opalescent, transparent, colourless or light yellow liquid (on 11,7 ml in bottles of colourless glass, 1 bottle in a pack cardboard).

Structure of 1 ml of a concentrate for solution preparation:

• Active ingredient: ритуксимаб – 10 mg;
• Auxiliary components: polysorbate 80, citrate sodium a dihydrate, sodium chloride, sodium hydroxide or Acidum hydrochloricum, water for and.

Structure of 1 ml of solution for п / to introduction:

• Active ingredient: ритуксимаб – 120 mg;
• Auxiliary components: recombinant human hyaluronidase (rHuPH20), L-methionine, a hydrochloride L-histidine monohydrate, α,α-трегалозы a dihydrate, a L-histidine, polysorbate 80, water for and.

Indications to use

MabThera is applied to therapy of such types of a nekhodzhkinsky lymphoma (NHL):

• Himioustoychivy or recurrent V-cellular, CD20-positive zlokachestvennost of low degree or follicular;
• Follicular (for the supporting treatment after reaction to induction therapy), and also follicular the III-IV stages (in combination with chemotherapy at patients not treated earlier);
• Diffusion CD20 - positive V-macrocellular (according to the scheme CHOP, in combination with chemotherapy).

In addition the concentrate for preparation of solution for infusions is applied to therapy of the following diseases:

• Chronic lymphocytic leukosis: at the patients who were not receiving earlier standard therapy (in combination with chemotherapy); himioustoychivy or recurrent (in combination with chemotherapy);
• Pseudorheumatism: heavy and moderately severe (an active form) at adult patients in a complex with a methotrexate in case of intolerance or inadequate reaction to the current modes of treatment including FNOα inhibitors (one and more) including for the purpose of braking of the destruction of joints proved radiological;
• Wegener's syndrome (a granulomatosis with a polyangiitis) and a microscopic polyarteritis: severe active forms (as a part of complex therapy with glucocorticosteroids (GKS)).

Contraindications

Absolute:

• Acute infectious diseases;
• The expressed immunodeficiency (primary or secondary);
• Final stage of damage of heart (the IV class on NYHA classification) in combination with a pseudorheumatism;
• Children's and teenage age up to 18 years (safety and efficiency of use are not established);
• Pregnancy period;
• Lactation (breastfeeding);
• The increased individual sensitivity to means components, a rituksimab or mouse protein.

Relative (drug is used with care in a type of the increased probability of complications):

• Respiratory insufficiency in the anamnesis or tumoral infiltration of lungs;
• High tumoral loading (number of the circulating tumor cells more than 25 000/mkl);
• Neutropenia (less 1500/mkl), thrombocytopenia (less than 75 000/mkl);
• Persistent infections.

Route of administration and dosage

Before therapy it is necessary to study attentively the instruction, to be convinced that the dosage form of MabThera corresponds to appointed: solution for п / to introductions or a concentrate for preparation of solution for infusions.

The solution prepared from a concentrate is intended for intravenous (in/in) infusional slow introduction with obligatory use of a separate catheter. It is not allowed in/in bolyusny or in/in injection administration of the solution prepared from a concentrate.

For the first infusion the initial speed of 50 mg/h with increase at 50 mg/h everyone half an hour to maximum – 400 mg/h is recommended further. For the subsequent infusions the initial speed of 100 mg/h with increase by 100 mg/h everyone half an hour to maximum – 400 mg/h is allowed.

Before each infusional introduction carrying out premedication is required: analgetic/antipyretic (paracetamol) with antihistaminic drug (дифенгидрамин). If MabThera is not a part of complex therapy with CVP (cyclophosphamide, Vincristinum, Prednisolonum) or CHOP (cyclophosphamide, doxorubicine, Vincristinum, Prednisolonum) chemotherapy, in premedication there have to be corticosteroids.

Solution for п / to introduction is entered under skin only in the field of a front abdominal wall, time of introduction about 5 minutes. There are no data on administration of drug to other areas. Solution for п / to introduction is not intended for in/in introductions.

Solution cannot be entered into places with reddenings, hypersensitivity, into hematomas, fabrics of hems, birthmarks, places with consolidations. Whenever possible it is necessary to avoid administration of solution MabThera with other drugs for п / to introduction to the same sites of skin. If the injection had to be interrupted, it can be renewed on the same place or, in case of need, to change an injection site. Patients who received a full dose of MabThera in the form of a concentrate for preparation of solution for infusions as well as patients who could not receive a full dose of MabThera, in the following cycles can receive drug to a solution form for п / to introduction.

The standard recommended dosing mode: 375 ^mg/sq.m once a week.

For dose adjustment in the course of therapy it is not recommended to reduce a dose of a rituksimab. At MabThera injections in combination with chemotherapy according to the scheme CVP or SNOR reduction of a dose of chemotherapeutic means is carried out according to standard recommendations.

Treatment of a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular:

• Initial monotherapy of adult patients: 375 ^mg/sq.m once a week for 4 weeks;
• The initial therapy combined with CVP: every first day of a cycle of chemotherapy later in/in introductions of a corticosteroid as a scheme CVP component – 375 ^mg/sq.m, course duration – 8 cycles (each cycle – 3 weeks);
• Repeated course at a recurrence (at patients with the favorable answer to the first course): 375 ^mg/sq.m once a week for 4 weeks;
• The supporting course: (after positive reaction to induction therapy) 375 ^mg/sq.m of 1 times in 3 months, duration – up to 2 years or before progressing of a disease.

Treatment of a diffusion V-macrocellular nekhodzhkinsky lymphoma (in a complex with chemotherapy according to the scheme SNOR): in the first day of each of 8 cycles of chemotherapy later in/in introductions of a corticosteroid – 375 ^mg/sq.m, administer other drugs of the scheme SNOR after MabThera.

Treatment of a pseudorheumatism:

• Initial therapy: 1000 mg in/in kapelno, slowly (half an hour later later in/in introductions of Methylprednisolonum in a dose of 100 mg), 1 time in 2 weeks, a course – 1 month (only 2 infusions);
• Repeated course (it is allowed later half a year-year after the first treatment): 1000 mg of 1 times in 2 weeks for a month (only 2 infusions).

Rules of preparation and storage of solution for infusions:

1. The required amount of drug in aseptic conditions is gained and parted to settlement concentration (1-4 mg/ml) in an infusional package (bottle) from 5% with solution of a dextrose or 0,9% chloride sodium solution for injections (solutions have to be sterile and apirogenna);
2. Accurately, that foam was not formed, overturn a package (bottle) before full hashing of contents;
3. Before introduction check solution for lack of foreign impurity and preservation of coloring;
4. As MabThera does not contain preservatives, freshly cooked solution is recommended to be used immediately (chemically and physically at the room temperature solution is stable 12 hours, at a temperature of 2-8 °C – no more than 24 hours);
5. The doctor is responsible for preparation, time and storage conditions of ready solution before its use.

Rules of set and storage in the solution syringe for п / to introduction:

1. The solution intake for hypodermic introduction (1400 mg / 11,7 ml) from a bottle in the syringe is made in aseptic conditions;
2. In the syringe solution chemically is also physically stable for 8 hours at a temperature of 30 °C and scattered daylight, or 48 hours at a temperature from 2-8 °C;
3. Taking into account microbiological safety solution is recommended to be used immediately;
4. At impossibility of use of drug right after a fence from a bottle, the user has to control conditions and storage time.

Side effects

Scale of assessment of frequency of side effects: ≥10% – are very frequent, ≥1%-<10% – are frequent, ≥0, l %-<1% – infrequently.

Therapy of a nekhodzhkinsky lymphoma of follicular or low degree of a zlokachestvennost (monotherapy / supporting):

• Infections and invasions: very often – viral and bacterial infections; often – pneumonia, the sepsis, respiratory infections surrounding the herpes, infections which are followed by a hyperthermia, mycoses, infections of the obscure etiology;
• Lymphatic system and blood: very often – a neutropenia, a leukopenia; often – anemia, thrombocytopenia; infrequently – disturbance of hemocoagulation, a lymphadenopathy, hemolitic anemia, partial tranzitorny aplastic anemia;
• Respiratory system, bodies of a thorax and mediastinum: often – a bronchospasm, rhinitis, cough, thorax pains, short wind, respiratory diseases; infrequently – an obliterating bronchiolitis, dysfunction of lungs, a hypoxia, bronchial asthma;
• Immune system: very often – a Quincke's edema; often – hypersensitivity reactions;
• Metabolism and food: often – decrease in body weight, a hyperglycemia, face edemas, peripheral hypostases, a hypocalcemia, increase in activity of a lactate dehydrogenase (LDG);
• System and local disturbances: very often – fever, an adynamy, a fever, a headache; often – a grippopodobny syndrome, pains in the tumor centers, weakness, inflows; infrequently – pains in an injection site;
• Digestive Tract (DT): very often – nausea; often – diarrhea or a lock, vomiting, dyspepsia, a dysphagy, lack of appetite, stomatitis, irritation in a throat, an abdominal pain; infrequently – increase in a stomach;
• Cardiovascular system (CCC): often – increase or lowering of arterial pressure (ABP), tachycardia, orthostatic hypotension, atrial fibrillation, arrhythmia, cardial pathology, a myocardial infarction; infrequently – ventricular and supraventricular tachycardia, left ventricular heart failure, bradycardia, stenocardia, myocardium ischemia;
• Nervous system: often – paresthesias, a hypesthesia, a vazodilatation, dizziness, a sleep disorder, excitement, feeling of alarm; infrequently – a food faddism;
• Mentality: infrequently – a depression, nervousness;
• Skeletal and muscular and connecting fabric: often – an arthralgia, a mialgiya, a muscle hyper tone, pains in a back and a neck;
• Skin and hypodermic fabrics: very often – rash, an itch; often – a hyperhidrosis, the increased night sweating, a small tortoiseshell, an alopecia;
• Organ of sight: often – conjunctivitis, disturbances of a slezootdeleniye;
• Acoustic organ and labyrinth disturbances: often – a sonitus, ear pain;
• Tool and laboratory results: very often – reduction of concentration of G(IgG) immunoglobulins.

The heavy side effects and/or effects meeting with higher frequency in addition to those which were observed at monotherapy / a maintenance therapy, caused rituksimaby in a complex with chemotherapy (R-CHOP, R-FC, R-CVP) at treatment of a chronic lymphoid leukosis and lymphosarcoma:

• Infections and invasions: very often – an inflammation of bronchial tubes; often – an acute bronchitis, sinusitis, hepatitis B (a repeated exacerbation of hepatitis B, primary infection);
• Limfosistema and blood: very often – thrombocytopenia, a neutropenia, a febrile neutropenia; often – a granulocytopenia, a pancytopenia;
• Skin and hypodermic fabrics: very often – a pathological hair loss; often – skin diseases;
• System and local disturbances: often – a fever, fatigue.

Side reactions from use of drug at a pseudorheumatism with a frequency more than 2% and a minimum from 2% a difference in comparison with control group:

• Immune system, the general frustration, disturbances in the place of an injection: very often – infusional reactions: increase and decrease in the ABP, inflows, rash, urticaria, an itch, a fever, fever, nausea, rhinitis, feeling of irritation in a throat, tachycardia, weakness, mouth and drink pain, peripheral hypostases, an erythema; infrequently – clinically significant infusional reactions: bronchospasm, generalized hypostasis, throat hypostasis, Quincke's disease, goose breathing, generalized itch, anaphylactoid reaction, anaphylaxis;
• Infections and invasions: very often – an upper respiratory tract infection and urinary tract; often – sinusitis, a gastroenteritis, bronchitis, a dermatofitiya of feet;
• Musculoskeletal system and connecting fabric: often – an arthralgia, an osteoarthritis, a bursitis, musculoskeletal pain;
• Disturbances of mentality: often – uneasiness, a depression;
• Nervous system: very often – a headache; often – paresthesias, a sciatica, dizziness, migraine;
• Alimentary system: often – diarrhea, dyspepsia, a gastroesophageal reflux, an ulceration of a mucous oral cavity, pain in the right upper quadrant of a stomach;
• Skin and hypodermic fabrics: often – an alopecia;
• Data of laboratory and tool researches: often – a hypercholesterolemia.

At repeated use the profile of side reactions does not differ from that at primary therapy and is characterized by decrease (with each following course) frequencies of infusional reactions, exacerbations of a disease and infections which are often observed in the first half a year of treatment.

The side effects observed at use of the drug MabThera at Wegener's granulomatosis and a microscopic polyangiitis (frequency of 10%):

• Infections and invasions: the surrounding herpes, infections (the most frequent – upper respiratory and urinary tract);
• Data of laboratory and tool researches: increase in activity of alaninaminotranspherase (ALT);
• Respiratory system, bodies of a thorax and mediastinum: cough, nasal bleeding, диспноэ;
• Disturbances of mentality: sleeplessness;
• Nervous system: headache;
• Cardiovascular system: increase in the ABP;
• Digestive tract: nausea, diarrhea;
• Immune system: infusional reactions, including the most often meeting, a syndrome of release of cytokines, reddening, irritation of a throat, a tremor;
• Skin and hypodermic fabrics: rash;
• Musculoskeletal system and connecting fabric: muscular spasms, arthralgia;
• Lymphatic system and blood: anemia, leukopenia;
• Disturbances in an injection site, the general frustration: peripheral hypostases, weakness.

Cross replacement of drug or replacement by other therapy on the basis of the weighed clinical decision is allowed.

Special instructions

It is required to specify a trademark (the name of medicine) in the medical record of the patient – MabThera. The drug needs to be administered under careful control of the oncologist, rheumatologist or hematologist, in the presence of the conditions demanded for performing resuscitation.

The side reactions arising when performing infusion, or soon after it can be caused by release of cytokines and/or other mediators. Heavy infusional answers are similar to reaction of hypersensitivity or a syndrome of release of cytokines. There are authentic data on infusional reactions with a lethal outcome in the post-registration period of use of drug. The most part of patients in the range of ^1/2-2 h from the beginning of the first infusion has a fever which is followed by a shiver or a fever. Symptoms of heavy reactions are decrease in the ABP, answers from lungs, a small tortoiseshell, a Quincke's disease, nausea, vomiting, weakness, a headache, rhinitis, an itch, hypostasis of a throat or irritation of language (vascular hypostasis), inflows, pain in the disease centers, and also, in some episodes, symptoms of a syndrome of a bystry lysis of a tumor.

Infusional reactions take place after the termination of administration of drug and interruption of medicamentous therapy (including in administration of acetaminophen and a difengidramin, 0,9% of solution of sodium of chloride, GKS, bronchodilators, etc.). After full removal of symptoms, most often, infusion is allowed to be resumed, but speed has to make 50% from previous, treatment continuation in that case seldom is followed by resuming of heavy infusional reactions. At the most part of patients with infusional reactions which do not threaten life the therapy course MabThera managed to be completed completely.

Considering potentiality of development of anaphylactic effects and other reactions of hypersensitivity owing to in/in administrations of proteinaceous drugs, medicines are necessary for their stopping: antihistaminic drugs, adrenaline and GKS.

Medicinal interaction

Data on interaction of MabThera with other medicinal substances / drugs are limited.

Pharmacokinetic indicators at a concomitant use of a rituksimab with cyclophosphamide do not change and fludarabiny at therapy of a chronic lymphoid leukosis.

At patients at a pseudorheumatism the concomitant use of a methotrexate with MabThera does not change its pharmacokinetics.

Purpose of drug with other monoclones for diagnosis or therapy to the patients having anti-chimeric antibodies or antibodies against mouse proteins leads to increase in risk of allergic reactions.

For infusional administration of MabThera it is possible to use plastic or polyvinyl chloride bags or systems as they are compatible with rituksimaby.

Terms and storage conditions

To store in the place protected from light, at a temperature of 2-8 °C. To protect from children.

Period of validity – 2,5 years.