Redditux conc. for preparation. solution for infusion 10 mg / ml 10 ml bottle 1 pc. (Rituximab)

Pharmacological action

Rituximab is a chimeric mouse / human monoclonal antibody that specifically binds to the CD20 transmembrane antigen. This antigen is located on pre-B lymphocytes and mature B-lymphocytes, but is absent on hematopoietic stem cells, pre-B cells, normal plasma cells, and other tissue cells and is expressed in more than 95% of cases with non-Hodgkin B-cell lymphomas. Expressed on a CD20 cell, after binding to the antibody, it does not internalize and ceases to enter the extracellular space from the cell membrane. CD20 does not circulate in plasma as a free antigen and therefore does not compete for binding to antibodies.

Rituximab binds to the CD20 antigen on B cells and initiates immunological responses that mediate B cell lysis. Possible mechanisms for cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. Rituximab increases the sensitivity of human B-cell lymphoma lines to the cytotoxic effect of certain chemotherapeutic drugs in vitro.

The number of B cells in peripheral blood after the first injection of the drug decreases below normal and begins to recover in patients with hematologic malignant diseases after 6 months, reaching normal values ​​9-12 months after completion of therapy.

Antibodies to rituximab in 67 patients examined in the treatment of CD20-positive B-cell non-Hodgkin lymphoma with ReddituxВ® were not detected.

Pharmacokinetics: Non-Hodgkin lymphoma

In patients with recurrent B-cell lymphoma, the concentration of serum rituximab and its half-life (T1 / 2) increase with increasing dose. After the first intravenous infusion of 375 mg / m2 T1 / 2 of rituximab - 76.3 h, after the fourth infusion - 205.8 h, the maximum concentration (Cmax) after the first infusion is 205.6 Ојg / ml, after the fourth infusion - 464.7 Ојg / ml, plasma clearance - 0.0382 l / h and 0.0092 l / h, respectively. Individual differences in serum concentration of the drug are quite pronounced. With effective treatment, serum rituximab concentrations are significantly higher. The concentration of the drug negatively correlates with the magnitude of the tumor load. Traces of rituximab can be detected in the body within 3-6 months after the last infusion.

In patients with diffuse B-large cell lymphoma, serum concentrations of rituximab are comparable to those in patients with non-Hodgkin's lymphoma of low malignancy or follicular, receiving the same doses of the drug.

Pharmacokinetics in selected patient groups

Gender. The volume of distribution and clearance of rituximab adjusted for body surface area in men is slightly larger than in women dose adjustment of rituximab is not required.

Patients with renal and hepatic insufficiency. Pharmacokinetic data in patients with renal and hepatic insufficiency are absent.

Indications

Non-Hodgkin's lymphoma: - recurrent or chemically resistant b-cell, CD20-positive non-Hodgkin's lymphoma of a low degree of malignancy or follicular

- follicular lymphoma of the III-IV stage in combination with chemotherapy in previously untreated patients

- follicular lymphoma as a supportive therapy after the response to induction therapy

- CD20-positive diffuse non-large B-large lymphoma in combination with chemotherapy according to the CHOP regimen.

Chronic lymphocytic leukemia: Chronic lymphocytic leukemia in combination with chemotherapy in patients who have not previously received standard therapy.

Recurrent or chemo-resistant chronic lymphocytic leukemia in combination with chemotherapy.

Contraindications

- Hypersensitivity to rituximab or other components that make up the drug, or mouse proteins

- acute infectious diseases

- pronounced primary or secondary immunodeficiency

- children under 18 years of age (efficacy and safety have not been proven)

- pregnancy and lactation.

Precautions: A history of respiratory failure or tumor lung infiltration, the number of circulating malignant cells> 25 x 109 / L or high tumor burden of neutropenia (less than 1.5 x 109 / L), thrombocytopenia (less than 75 x 109 / L), chronic infections.

Pregnancy and lactation

There are no relevant data from controlled trials in pregnant women, but some newborns whose mothers received rituximab during pregnancy experienced temporary depletion of B-cell pool and lymphocytopenia. In this regard, rituximab should not be prescribed to pregnant women, unless the possible benefits of therapy do not exceed the potential risk.

It is not known whether rituximab with breast milk is excreted. Given that class G immunoglobulins (IgG) circulating in the mother’s blood are excreted in breast milk, rituximab should not be used during breastfeeding.

IgG is able to cross the placental barrier. The level of B cells in newborns with the appointment of rituximab to women during pregnancy has not been studied.

During the treatment period and within 12 months after the end of treatment with the drug, women of childbearing age should use effective methods of contraception.

Special instructions

The drug ReddituxВ® is administered under the close supervision of an oncologist or hematologist, provided that the necessary conditions for resuscitation are available.

Infusion reactions

The development of infusion reactions may be due to the release of cytokines and / or other mediators. Severe infusion reactions are difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There are reports of lethal infusion reactions described during the post-registration use of rituximab. In most patients, within 30 minutes to 2 hours after the start of the first rituximab infusion, fever with chills or tremors develops. Severe reactions include symptoms from the lungs, lowering or increasing blood pressure, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, tongue irritation or swelling of the pharynx (vascular edema), rhinitis, hot flashes, pain in the foci of the disease and, in some cases, signs of rapid tumor lysis syndrome. Infusion reactions disappear after interruption of rituximab administration and drug therapy (intravenous administration of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, glucocorticosteroids, etc.). In most cases, after the symptoms disappear completely, the infusion can be resumed at a rate of 50% of the previous one (for example, 50 mg / h instead of 100 mg / h). In most patients with life-threatening infusion reactions, the treatment with rituximab was completely completed. Continuing therapy after symptoms have completely disappeared is rarely accompanied by a re-development of severe infusion reactions.

Due to the potential for the development of anaphylactic reactions and other hypersensitivity reactions with the intravenous administration of protein preparations, it is necessary to have funds for their relief: epinephrine, antihistamines and glucocorticosteroid drugs.

Premedication (analgesics and antihistamines) is recommended 30-60 minutes before each infusion. The prepared solution for infusion should not be administered jet.

Side effects from the lungs

Symptoms may increase over time or may worsen after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully monitored until symptoms are completely resolved. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often manifested in the first 1-2 hours after the start of the first infusion. With the development of severe pulmonary reactions, rituximab infusion should be stopped immediately and intensive symptomatic therapy should be prescribed. Since the initial improvement in clinical symptoms may be replaced by worsening, patients should be carefully monitored until pulmonary symptoms resolve.

Rapid tumor lysis syndrome

Rituximab mediates the rapid lysis of benign or malignant CD20-positive cells. Tumor lysis syndrome is possible after the first infusion of rituximab in patients with a large number of circulating malignant lymphocytes. Tumor lysis syndrome includes: hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased activity of LDH. Patients at risk (patients with a high tumor load or a large number of circulating malignant cells (> 25 x 109 / L), for example, with chronic lymphocytic leukemia or lymphoma from mantle cells) need careful medical supervision and regular laboratory examination. With the development of symptoms of rapid lysis of the tumor, appropriate therapy is performed. After the symptoms are completely relieved in a limited number of cases, rituximab therapy is continued in combination with the prevention of rapid tumor lysis syndrome. Features of prescribing the drug to patients with a large number of circulating malignant cells (> 25 x 109 / l) or high tumor burden (for example, with chronic lymphocytic leukemia or lymphoma from mantle cells), in which the risk of extremely severe infusion reactions may be particularly high, ReddituxВ® should be prescribed with extreme caution, under close supervision. The first infusion of the drug in such patients should be administered at a slower rate or the dose of ReddituxВ® should be divided into two days during the first cycle of therapy and in each subsequent cycle if the number of circulating malignant cells remains> 25 x 109 / L.

Side effect of the cardiovascular system

During the infusion, careful monitoring of patients with a history of cardiovascular disease is required due to the possibility of lowering blood pressure, angina pectoris or arrhythmia (atrial flutter and atrial fibrillation). Due to the possibility of developing hypotension at least 12 hours before the infusion of the drug ReddituxВ®, antihypertensive drugs should be discontinued.

Control of blood cells

Although rituximab monotherapy does not have a myelosuppressive effect, care should be taken when prescribing ReddituxВ® with neutropenia of less than 1.5 x 109 / l and / or thrombocytopenia of less than 75 x 109 / l, since experience of its clinical use in such patients are limited. Rituximab was used in patients after autologous bone marrow transplantation and in other risk groups with possible impaired bone marrow function without causing myelotoxicity. During treatment, it is necessary to regularly determine a detailed analysis of peripheral blood, including counting platelet counts in accordance with routine practice.

Infections

ReddituxВ® should not be prescribed to patients with severe acute infection.

Hepatitis B

When prescribing a combination of rituximab with chemotherapy, exacerbation of hepatitis B or fulminant hepatitis (including fatal outcome) was noted. Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy.

Before prescribing ReddituxВ® to patients at risk, hepatitis B should be excluded. When prescribing ReddituxВ® to patients with hepatitis B virus and patients with a history of hepatitis B, it is necessary to carefully monitor the occurrence of clinical and laboratory signs of active hepatitis B both during therapy and and for several months after its completion.

Progressive multifocal leukoencephalopathy (PML)

Cases of PML have been observed in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia with rituximab. Most patients received rituximab in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. If neurological symptoms occur in such patients, it is necessary to conduct differential diagnostics to exclude PML and consult a neurologist.

Immunization

The safety and efficacy of immunization with live viral vaccines after rituximab treatment have not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the frequency of response may decrease.

Impact on the ability to drive transp. Wed and fur .: It is not known whether ReddituxВ® affects the ability to control and work with machines and mechanisms, but, taking into account the safety profile of the drug and the presence of side effects from the nervous system, attention should be paid to the possible effect of the drug on the above functions.

Composition

1 ml of the preparation contains: active ingredient: rituximab - 10.00 mg

excipients: sodium citrate dihydrate - 7.35 mg, sodium chloride - 9 , 00 mg, polysorbate 80 - 0.70 mg, water for injection up to 1.00 ml.

Dosing and Administration

Rules for the preparation and storage of

infusion solution The required amount of drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg / ml) in an infusion vial (bag) with 0.9% sodium chloride solution for injection or 5% dextrose solution (solutions must be sterile and pyrogen-free). To mix, gently flip the bottle (bag) to avoid foaming. Before administration, it is necessary to inspect the solution for lack of impurities or discoloration.

The doctor is responsible for the preparation, conditions and storage time of the finished solution until it is used.

Since ReddituxВ® does not contain preservatives, the prepared solution must be used immediately.

The prepared solution for infusion of the ReddituxВ® preparation is stable for 24 hours at room temperature (up to 25 ° C) or for 48 hours at a temperature of 2 to 8 ° C. ReddituxВ® is administered intravenously, drip, through a separate catheter. It is impossible to administer the drug intravenously in a jet or bolus!

Recommended initial rate of the first infusion is 50 mg / h, in the future it can be increased by 50 mg / h every 30 minutes, bringing to a maximum speed of 400 mg / h. Subsequent infusions can be started at a speed of 100 mg / h and increased by 100 mg / h every 30 minutes to a maximum speed of 400 mg / h.

Before each infusion of ReddituxВ®, premedication (analgesic / antipyretic, for example, paracetamol antihistamine, such as diphenhydramine) should be performed. If ReddituxВ® is not used in combination with chemotherapy containing glucocorticosteroids, then premedication also includes glucocorticosteroids.

Dose adjustment during

therapy Reducing the dose of rituximab is not recommended. If ReddituxВ® is administered in combination with chemotherapy, the dose reduction of chemotherapeutic drugs is carried out in accordance with standard recommendations.

Standard dosing regimen

Non-Hodgkin low grade malignancy lymphoma or follicular

Initial therapy: - monotherapy for adult patients: 375 mg / m2 once a week, for 4 weeks

- in combination with chemotherapy according to any scheme: 375 mg / m2 in the first day of chemotherapy cycle after intravenous administration of glucocorticosteroid as a component of therapy.

Repeated use in case of relapse (in patients responding to the first course of therapy): 375 mg / m2 once a week for 4 weeks. The frequency of remission in re-treated patients is comparable to that in the first course of therapy.

Maintenance therapy (after responding to induction therapy) in previously untreated patients is 375 mg / m2 once every 2 months, no more than 2 years (12 infusions) or until the disease progresses with recurrent or chemically resistant lymphoma at 375 mg / m2 1 time per 3 months, no more than 2 years or until disease progression.

Diffuse B-large-cell non-Hodgkin lymphoma

The dose of ReddituxВ® is 375 mg / m2, on the first day of each chemotherapy cycle, 8 cycles, after intravenous administration of glucocorticosteroid. When combined with antitumor drugs, they are administered after the drug ReddituxВ®.

Chronic lymphoid leukemia

In combination with chemotherapy, the drug is prescribed at a dose of 375 mg / m2 on the first day of the first cycle, then 500 mg / m2 on the first day of each subsequent cycle, 6 cycles. Chemotherapy is carried out after administration of the drug ReddituxВ®.

To reduce the risk of tumor lysis syndrome, prophylactic provision of adequate hydration and administration of uricostatics 48 hours before the start of therapy is recommended. In patients with chronic lymphocytic leukemia and a lymphocyte count> 25 x 109 / L, intravenous administration of prednisone at a dose of 100 mg 1 hour before the ReddituxВ® infusion is recommended to reduce the frequency and severity of acute infusion reactions and / or cytokine release syndrome.

Dosage in special cases

Elderly

Dose adjustment is not required in patients over 65 years of age.

Side effects

Infusion reactions: chills, weakness, shortness of breath, dyspepsia, nausea, rash, hot flashes, fever, itching, urticaria, rhinitis, tachycardia, vomiting, pain, signs of tumor lysis syndrome. In some cases, during the R-CHOP regimen: myocardial infarction, atrial fibrillation, and pulmonary edema.

Infections: respiratory tract infections - nasopharyngitis, sinusitis bronchitis, pneumonia, superinfection of the lungs, urinary tract infections, sepsis, herpes zoster, septic shock, implant infection, staphylococcal septicemia, viral hepatitis B reactivation, fungal infections, infections of unknown etiology.

On the part of the blood and lymphatic systems: leukopenia, neutropenia, thrombocytopenia, anemia, febrile neutropenia, lymphadenopathy, bleeding disorders, pancytopenia (4 weeks or more after the last injection of rituximab), a transient increase in IgM levels in patients with macroglobulinemia B, subsequent return to its original value after 4 months of transient partial aplastic anemia, hemolytic anemia.

On the part of the respiratory system: rhinitis, mucous discharge from the nose, bronchospasm, cough or increased cough, respiratory disease, shortness of breath, acute respiratory failure, pulmonary infiltrates hypoxia, impaired lung function, bronchiolitis obliterans, bronchial asthma.

On the part of the body as a whole, reactions at the injection site: pharyngeal irritation, angioedema, back pain, chest pain, pain in the neck, pain in the foci of the tumor, flu-like syndrome, peripheral edema, mucositis, fainting, weight loss, multiple organ failure, rapid tumor lysis syndrome, serum sickness, increased abdomen, pain in injection site, anaphylactic reaction.

From the gastrointestinal tract: dyspepsia, nausea, vomiting, diarrhea, lack of appetite, dysphagia, stomatitis, constipation, perforation of the stomach and / or intestines (possibly fatal), abdominal pain.

From the cardiovascular system: lowering and / or lowering blood pressure (including in the form of a reaction to the injection), orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular and supraventricular tachycardia, atrial fibrillation), unstable angina pectoris, vasodilation venous thrombosis, including deep vein thrombosis of the extremities, heart failure, decreased ejection fraction, pulmonary edema, myocardial infarction, vasculitis, mainly cutaneous (leukocytoclastic), ischemic disturbance of cerebral circulation.

From the nervous system: dizziness, headache, paresthesia, hypesthesia, migraine, cranial nerve neuropathy, combined with or without peripheral neuropathy (marked decrease in visual acuity, hearing, damage to other senses, facial paralysis) to various periods of therapy - up to several months after completion of the course of treatment with rituximab, sleep disturbance, agitation.

From the mental side: confusion, nervousness, depression, anxiety, perversion of taste.

From the musculoskeletal system: myalgia, arthralgia, muscle hypertonicity, muscle cramps, osteoarthritis.

From the endocrine system: hyperglycemia, decompensation of diabetes.

On the part of the skin and its appendages: itching, rash, urticaria, increased sweating at night, sweating, alopecia, severe bullous reactions, toxic epidermal necrolysis with fatal outcome.

On the part of the sensory organs: tearing disorders, conjunctivitis, pain and tinnitus.

From the laboratory side: decreased concentration of immunoglobulins G (IgG), increased activity of lactate dehydrogenase (LDH), hypocalcemia, hyperglycemia, hypercholesterolemia, bacteremia.

Special categories of patients

High tumor burden (diameter of single foci more than 10 cm). Increased frequency of adverse reactions of 3-4 severity.

Old age (over 65): the frequency and severity of all side effects and side effects of severity 3 and 4 does not differ from that in younger patients.

Repeated therapy: the frequency and severity of all side effects does not differ from those during initial therapy.

Drug Interactions

When used with other monoclonal antibodies for diagnostic or therapeutic purposes, patients with antibodies to mouse proteins or antimeric antibodies increase the risk of allergic reactions.

When administered with cyclophosphamide, doxorubicin, vincristine, prednisolone - no increase in the frequency of toxic effects was noted.

Medications that inhibit bone marrow hematopoiesis increase the risk of myelosuppression.

Redditux® is compatible with polyvinyl chloride or polyethylene infusion systems or bags.

Storage conditions

At a temperature of 2 to 8 ° C. Do not freeze. Keep out of the reach of children.

Transportation conditions

At a temperature of 2 to 8 ° C in thermal containers. Do not freeze.

Expiration

2 years.

Deystvuyuschee substances

Rituximab

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Form of Treatment

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