Reddux - instructions for use, dose, side effects, contraindications

Active substanceRituximabRituximab

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Redtux®

concentrate d / infusion

Dr. Reddy's Laboratories Ltd. India

Dosage form: & nbspTOoncentrat for solution for infusion.

Composition:

1 ml of the preparation contains:

active substance: 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.

Description:Popaque or slightly opalescent, colorless or slightly yellowish liquid.

Pharmacotherapeutic group:antitumor and immunomodulating agent - antibodies monoclonal

ATX: & nbsp

L.01.X.C Monoclonal antibodies

L.01.X.C.02 Rituximab

Pharmacodynamics:

Rituximab is a chimeric mouse / human monoclonal antibody that specifically binds to the transmembrane antigen Cd20. This antigen is located on pre-B lymphocytes and mature B lymphocytes, but is absent on stem hemopoietic cells, pre-B cells, normal plasma cells, cells of other tissues and is expressed in more than 95% of cases with B-cell non-Hodgkin's lymphomas. Expressed on a cell Cd20 after binding to the antibody is not internalized and ceases to flow from the cell membrane into the extracellular space. Cd20 does not circulate in plasma as a free antigen and therefore does not compete for binding to antibodies.

Rituximab binds to the antigen Cd20 on B-lymphocytes and initiates immunological reactions mediating lysis of B-cells. Possible mechanisms of 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 the peripheral blood after the first administration of the drug is lower than normal and begins to recover in patients with hematologic malignancies after 6 months, reaching normal values 9-12 months after completion of therapy.

Antibodies to rituximab in 67 examined patients in treatment Cd20-positive B-cell non-Hodgkin's lymphoma was not detected by the Redditux® preparation.

Pharmacokinetics:

Non-Hodgkin's Lymphoma

In patients with recurrent B-cell lymphoma, serum rituximab concentration and its half-life (T_1/2) increase with increasing dose. After the first intravenous infusion, 375 mg / m²T_1/2 rituximab - 76.3 h, after the fourth infusion - 205.8 h, the maximum concentration (FROM_mOh) after the first infusion, 205.6 μg / ml, after the fourth infusion - 464.7 μg / ml, plasma clearance - 0.0382 l / h and 0.0092 l / h, respectively. Individual differences in serum drug concentration are quite pronounced. With effective treatment, serum concentrations of rituximab are significantly higher. The concentration of the drug negatively correlates with the value of the tumor load. Traces of rituximab can be found in the body for 3-6 months after the last infusion.

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

Pharmacokinetics in selected patient groups

Floor. The volume of distribution and clearance of rituximab, corrected for the body surface area in men is slightly higher 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:

- relapsing or chemically resistant B-cell, Cd20-positive non-Hodgkin's lymphoma of low degree of malignancy or follicular;

- follicular lymphoma III-IV stages in combination with chemotherapy in previously untreated patients;

- follicular lymphoma as maintenance therapy after responding to induction therapy;

- Cd20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with chemotherapy according to the scheme CHOP.

Chronic lymphocytic leukemia:

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

Recurrent or chemostatic 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;

- severe primary or secondary immunodeficiency;

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

- pregnancy and the period of breastfeeding.

Carefully:

Respiratory failure in history or tumor pulmonary infiltration; number of circulating malignant cells> 25 x 10⁹/ l or high tumor load; neutropenia (less than 1.5 x 10⁹/ l); thrombocytopenia (less than 75 x 10⁹/ l), chronic infections.

Pregnancy and lactation:

Corresponding data obtained in controlled studies in pregnant women are not available, however, in some newborns whose mothers received rituximab during pregnancy, there was a temporary depletion of the B-cell pool and lymphocytopenia. Concerning rituximab Do not prescribe to pregnant women, unless the possible benefits of therapy do not exceed the potential risk.

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

IgG can penetrate through the placental barrier. The level of B-cells in newborns in 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.

Dosing and Administration:

Rules for the preparation and storage of a solution for infusions

The necessary amount of the drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg / ml) in an infusion bottle (package) with 0.9% sodium chloride solution for injection or 5% dextrose solution (solutions must be sterile and pyrogen-free). For mixing, gently invert the vial (packet) to avoid foaming. Before administration, it is necessary to inspect the solution for any foreign matter or discoloration.

The doctor is responsible for the preparation, conditions and time of storage of the prepared solution prior to its use.

Since the Redditux® preparation does not contain any preservatives, the prepared solution must be used immediately.

The prepared infusion solution of the Redditux® is stable for 24 hours at room temperature (up to 25 ° C) or for 48 hours at a temperature of 2 to 8 ° C. The drug Redduitus ® is administered intravenously, by drop, through a separate catheter. Enter the drug intravenously struyno or bolusno not!

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

Before each infusion of the drug Redduitus ® it is necessary to carry out premedication (analgesic / antipyretics, for example, paracetamol; antihistamine, for example, diphenhydramine). If the drug Reddituks ® is not used in combination with chemotherapy containing glucocorticosteroids, then the composition of the premedication also includes glucocorticosteroids.

Correction of dose during therapy

It is not recommended to reduce the dose of rituximab. If the drug Reddituks® is administered in combination with chemotherapy, a reduction in the dose of chemotherapeutic drugs is carried out in accordance with standard recommendations.

Standard dosing regimen

Non-Hodgkin's lymphoma of low grade or follicular

Initial therapy:

- monotherapy of adult patients: 375 mg / m² Once a week, for 4 weeks;

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

Repeated use in case of relapse (in patients who responded 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 of the first course of therapy.

Supportive therapy (after responding to induction therapy) in previously untreated patients is 375 mg / m² 1 time in 2 months, no more than 2 years (12 infusions) or until the disease progresses; with relapsing or chemo-resistant lymphoma at 375 mg / m² 1 every 3 months, no more than 2 years or until the disease progresses.

Diffuse B-large-cell non-Hodgkin's lymphoma

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

Chronic lymphatic leukemia

In combination with chemotherapy, the drug is administered 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 the introduction of the drug Reddituks®.

To reduce the risk of developing tumor lysis syndrome, preventive maintenance of adequate hydration and the introduction of uricostatics 48 hours before the start of therapy are recommended.In patients with chronic lymphocytic leukemia and lymphocyte count> 25 x 10⁹/ l intravenously administered prednisolone at a dose of 100 mg per hour prior to the infusion of the Redditux® preparation to reduce the incidence and severity of acute infusion reactions and / or cytokine release syndrome.

Dosing in special cases

Elderly age

In patients older than 65 years, no dose adjustment is required.

Side effects:

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

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

On the part of the blood and lymphatic system: leukopenia, neutropenia, thrombocytopenia, anemia, febrile neutropenia,lymphadenopathy, clotting disorder, pancytopenia (4 weeks or more after the last administration of rituximab), transient increase in the level IgM in patients with Waldenstrom's macroglobulinemia, with a subsequent return to its initial value at 4 months; transient partial aplastic anemia, hemolytic anemia.

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

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

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

From the side of the cardiovascular system: lowering and / or lowering blood pressure (including a response to the introduction), orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular and supraventricular tachycardia, atrial fibrillation), unstable angina, vasodilation, venous thrombosis, in Vol. h. deep vein thrombosis limbs, cardiac failure, reduced ejection fraction, pulmonary edema, myocardial infarction, vasculitis, predominantly cutaneous (leukocytoclastic), ischemic cerebrovascular disease.

From the nervous system: dizziness, headache, paraesthesias, gipestezii, migraine, neuropathy, cranial nerves, in combination with a peripheral neuropathy or without (expressed as decrease in visual acuity, hearing loss of other sensory organs, facial paralysis) at different periods of treatment - up to several months after completion of the course of treatment with rituximab, sleep disturbance, agitation.

From the psychic sphere: confusion, nervousness, depression, feelings of anxiety, perversion of taste.

From the musculoskeletal system: myalgia, arthralgia, muscle hypertonus, muscle spasms, osteoarthritis.

From the endocrine system: hyperglycemia, decompensation of diabetes mellitus.

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

From the sense organs: disturbances of lacrimation, conjunctivitis, pain and noise in the ears.

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

Special categories of patients

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

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

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

Overdose:

No cases of overdose were observed in humans. Single doses of rituximab more than 1000 mg have not been studied. The maximum dose of 5000 mg was given to patients with chronic lymphocytic leukemia, no additional safety data was obtained. In connection with the increased risk of infectious complications when the B-lymphocyte pool is depleted, it is necessary to cancel the drug or reduce the rate of its infusion; it is recommended to conduct a detailed general blood test.

Interaction:

When used with other monoclonal antibodies for diagnostic or therapeutic purposes, the risk of allergic reactions increases in patients with antibodies to mouse proteins or anti-chimeric antibodies.

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

Drugs that inhibit bone marrow hematopoies increase the risk of myelosuppression.

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

Special instructions:

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

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-marketing application of rituximab. In most patients within 30 minutes -2 hour after the onset of the first infusion of rituximab, a fever with chills or tremors occurs. Severe reactions include symptoms on the part of the lungs, lowering or elevating blood pressure, hives, 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 fast tumor lysis syndrome. Infusion reactions disappear after the 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 complete disappearance of the symptomatology, the infusion can be resumed at a rate of 50% of the preceding (eg 50 mg / h instead of 100 mg / h). In most patients with life-threatening infusion reactions, the course of treatment with rituximab was completely completed. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions.

In connection with the potential for the development of anaphylactic reactions and other hypersensitivity reactions with intravenous administration of protein preparations, it is necessary to have the means to stop them: epinephrine, antihistamine and glucocorticosteroid preparations.

For 30-60 minutes before each infusion it is recommended to perform premedication (analgesics and antihistamines). The prepared infusion solution can not be injected.

Side effect from the side of the lungs

Perhaps the increase in symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully observed until the 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 reactions from the lungs, infusion of rituximab 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 before resolution of pulmonary symptoms.

Syndrome of rapid tumor lysis

Rituximab mediates 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 LDH activity. Patients at risk (patients with high tumor burden or a large number of circulating malignant cells (> 25 x 10⁹/ l), for example with chronic lymphocytic leukemia or lymphoma from the cells of the mantle zone) require careful medical supervision and regular laboratory examination.With the development of symptoms of rapid lysis of the tumor, appropriate therapy is carried out. After complete relief of symptoms in a limited number of cases, rituximab is continued in combination with the prevention of rapid tumor lysis syndrome. Features of prescribing the patient with a large number of circulating malignant cells (> 25 x 10⁹/ l) or high tumor load (for example, with chronic lymphocytic leukemia or mantle cell lymphoma), in which the risk of extremely severe infusion reactions can be particularly high, Redtux® should be administered with extreme caution, under close supervision. The first infusion of the drug in such patients should be administered at a slower rate or divided the dose of Redtux® for two days during the first cycle of therapy and every 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 in connection with the possibility of lowering blood pressure, angina, or arrhythmia (flutter and atrial fibrillation).Because of the possibility of developing hypotension at least 12 hours before the infusion of the drug Redduitus ® should be canceled antihypertensive drugs.

Control of blood elements

Although monotherapy with rituximab does not have a myelosuppressive effect, caution should be exercised in administering the Redtuks® preparation for neutropenia of less than 1.5 x 10⁹/ l and / or thrombocytopenia less than 75 x 10⁹/ l, since the experience of its clinical use in such patients is limited. Rituximab was used in patients after autologous bone marrow transplantation and in other risk groups with a possible violation of bone marrow function without causing the phenomena of myelotoxicity. During the treatment, it is necessary to regularly determine the detailed analysis of peripheral blood, including counting the number of platelets in accordance with routine practice.

Infections

The drug Redduitus ® should not be administered to patients with severe acute infection.

Hepatitis B

With the appointment of 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 the drug Redtux®, patients at risk should be excluded from hepatitis B. When administering Redtitux® to patients with hepatitis B virus and patients with hepatitis B, a history of clinical and laboratory signs of active hepatitis B should be carefully monitored, both during therapy and within a few months after its end.

Progressive multifocal leukoencephalopathy (PML)

When rituximab was used in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia, cases PML. Most patients received rituximab in combination with chemotherapy or in combination with transplantation of hematopoietic stem cells. If neurologic symptoms occur in these patients, differential diagnosis should be made to exclude PML and a neurologist's consultation.

Immunization

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

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

Does the preparation Redduitus ® on the ability to manage and work with machines and mechanisms is unknown, but given the safety profile of the drug and the presence of side effects from the nervous system, you should pay attention to the possible effects of the drug on the above functions.

Form release / dosage:

Concentrate for solution for infusion, 10 mg / ml.

Packaging:

A bottle of colorless glass class 1 (USP) with a capacity of 10 ml, corked with a rubber stopper, crimped with an aluminum cap with a plastic safety lid of orange color. 1 bottle with instructions for use in a pack of cardboard.

A bottle of colorless glass class 1 (USP) with a capacity of 50 ml, corked with a rubber stopper, crimped with an aluminum cap with a plastic safety lid of orange color. 1 bottle with instructions for use in a pack of cardboard.

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.

Shelf life:

2 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003584

Date of registration:25.04.2016 / 09.06.2016

Expiration Date:25.04.2021

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDr. Reddy`c Laboratoris Ltd.Dr. Reddy`c Laboratoris Ltd.

Information update date: & nbsp04.07.2016

Illustrated instructions

Instructions

Redtux® (Reddytux®)