Rituximab

When ATH:
L01XC02

Rituximab – Characteristic

Is a synthetic (genetic engineering) himernye monoclonal mouse antibody/person, possessing specificity to the CD20 Antigen, obnaruživaemomu on the surface of normal and malignant b-lymphocytes. On the structure of rituximab refers to class G Antisera₁ (IgG₁ Kappa), its molecule contains murine variable fragments of light and heavy chains and human standing segment. Rituximab consists of 2 heavy chains of 451 amino acids and 2 light chains of 213 amino acids and has a molecular mass of about 145 kd. Affinity of rituximab to the CD20 Antigen approximately 8 nM. Himernye anti-CD20 antibodies are produced by those in nutritious Wednesday cells of mammals (culture cells of Chinese hamster), that was introduced by genetic engineering of chimerical gene.

Rituximab – Pharmacological action

Antitumor.

Rituximab – Application

B-cell non-Hodgkin Lymphoma (recurrent or himioustoichive, low-grade or Follicular) adult.

Rituximab – Contraindications

Rituximab – Restrictions apply

High tumour load (the sizes of the pockets of more 10 cm), tumoral infiltration of the lung, pulmonary insufficiency in history, cardiovascular diseases (angina, arrhythmia), neutropenia (less 1500 cells /), thrombocytopenia (less 75000 cells /), childhood (safety and effectiveness in children have not been established).

Rituximab – Pregnancy and breast-feeding

Can be given to pregnant women only if, if the benefits of treatment outweigh the potential risk to the fetus. There had been no long-term animal studies to establish the potential carcinogenicity of, mutagenicity, the impact on fertility, not studied the toxic effect of rituximab on the reproductive system of animals. Rituximab can exert deleterious effect on the fetus when assigning pregnant women and whether the ability to procreate, unknown. Known, IgG class immunoglobulins that pass through placental barrier, Therefore, rituximab can cause depletion of the pool of B-cells in the fetus. During and for 12 months after the end of treatment to women of childbearing age should be rituksimabom to use effective methods of contraception.

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Unknown, whether allocated rituximab with breast milk in women. However, since the, that immunoglobulins IgG class, circulating in maternal blood, breast milk fall, rituximab should not appoint nursing mothers.

Rituximab – Side effects

Fatal infusion reactions. There have been reports of fatal outcomes for 24 h after infusions of rituximab. These fatal cases were the result of complex development of infusion reactions, including hypoxia, infiltration of the lungs, acute respiratory distress syndrome, myocardial infarction, Ventricular fibrillation or cardiogenic shock. About 80% fatal infusion reactions have been observed during the first infusion (cm. "Infusion Reactions» and «precautions»).

Tumor Lysis syndrome. It was reported about acute renal failure, established in the treatment of rituksimabom and requiring dialysis, There are lethal cases (cm. "Kidney complications» and «precautions»).

Rituximab is causing rapid lysis of benign and malignant CD20-positive cells. Describes the appearance of symptoms, tumor Lysis syndrome characteristic (acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, giperfosfatazemiâ), within 12-24 hours after the first infusions of rituximab.

Kidney complications. Introduction of rituximab, sometimes accompanied by severe kidney toxicity, including acute kidney failure with need for dialysis and in several cases resulted in death. The incidence of renal toxicity was greater in patients with a large number of circulating lymphocytes and malignant tumor with high load (cm. Tumor Lysis syndrome), and in patients, that conduct clinical trials simultaneously appointed cisplatin. Combination of cisplatin with rituksimabom is not recommended. In the case of the use of such combinations need emergency care and closely monitor patients for early detection of increasing the level of serum creatinine or oliguria.

Severe reactions by the mucous membranes and skin . Describes expressed reaction, sometimes accompanied by death, in connection with the treatment of rituksimabom (cm. Precautions). These reactions include paraneoplastičeskuû puzyrčatku (rarely occurring disease, that manifests itself in patients with malignant neoplasms), Stevens-Johnson syndrome, lihenoidnyj Dermatitis, vezikulobulleznyj Dermatitis, toxic epidermal necrolysis. Onset of these reactions in cases ranged from 1 to 13 weeks after the introduction of rituximab. Patients with severe skin reactions should not be ever further infusions of rituximab (security of the re-introduction of rituximab this group of patients not evaluated).

Most serious adverse reactions, caused by rituksimabom, includes: infusion reactions, tumor lysis syndrome, reaction from the mucous membranes and skin, hypersensitivity reactions, cardiac arrhythmias, stenokardiю, kidney failure. The most common infusion reactions and lymphopenia.

Monotherapy rituksimabom

In the table 1 presents data about side effects, were observed in patients, treated with rituximab as monotherapy (N = 356), When conducting non-randomized studies nesravnitel′nyh. The majority of patients receiving rituximab dose 375 mg / m² 1 once a week for 4 weeks. These patients have 39 There were large tumors (the value of ≥ 10 cm) and 60 patients, who got more 1 treatment rituksimabom. Most side effects symptoms grouped in box as "3 and 4 severity "in accordance with the National Cancer Institute Common Toxicity Criteria.

Data about side effects, obtained when conducting clinical trials, cannot be used directly for comparison with the results of other clinical research (tk. various studies have been conducted with a different set of conditions), as well as to predict the occurrence of side effects in ordinary medical practice, because the condition of patients and other factors may differ from those, that prevailed in the clinical trials. However, information on side effects, observed in clinical trials, can give an idea about the relative contribution of the substance itself, and other factors in the development of adverse effects when applying HP in a population.

The table shows the adverse effects, marked in conducting clinical trials, no less than 5% patients for the period 12 months after treatment rituksimabom.

Side effects, observed in clinical trials for the treatment of rituksimabom

Risk factors, having a relationship with increased frequency of side effects. Introduction 8 doses of rituximab 1 times per week resulted in an increase in the frequency of adverse reactions 3 and 4 the severity level to 70% (compared to 57% when administered 4 doses). The frequency of adverse reactions 3 and 4 the severity was similar in patients, again receiving rituximab, compared to initial treatment (58 and 57% respectively).

In patients with high tumour load (dimensions of single foci of ≥ 10 cm in diameter) (N = 39) compared with patients with size pockets <10 cm (N = 195) the frequency was increased following clinically expressed adverse reactions — abdominal pain, anemia, dyspnoea, gipotenziya, neutropenia.

Infusion Reactions (cm. also Fatal infusion reactions and «precautions»). In the majority of patients during the first infusion noted infusion symptom of mild to moderate severity, namely the emergence of fever and chill/shake. Other frequently observed infusion symptoms are nausea, itch, angioedema, asthenia, gipotenziya, headache, bronchospasm, irritation in the throat, rhinitis, hives, rash, vomiting, myalgia, dizziness, hypertension. Usually, These reactions occur within 30-120 min after the first infusion and disappear after slowing or interrupting the injection and holding support actions (incl. in/in the introductions of physiological solution, Diphenhydramine and paracetamol). When analyzing data introduction rituximab 356 patients, receiving downloads 1 infuziu during 4 (N = 319) or 8 (N = 37) weeks, the frequency of such responses was greatest during the first infusion and was 77%, and with each subsequent infusion it decreased: to 30% (4-I infusion) and 14% (8-I infusion).

Infectious complications . Rituximab has depleted the pool B-cells from 70-80% of patients and reduce levels of immunoglobulins in serum by a small number of patients; lymphopenia with the median duration of 14 days (range from 1 to 588 days). The frequency of infections was 31%: 19% - Bacterial infections, 10% -viral, 1% -fungal, 6% — unknown etiology (These percentages should not fold, tk. at the individual patient can be caught more than one type of infection). Serious cases of (3-ND and 4-th degree of gravity), including sepsis, were observed in 2% patients.

Hematologic adverse events. In clinical trials in patients, treated rituksimabom, in 48% the cases developed zitopenia, incl. lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), thrombocytopenia (2%). The median duration of lymphopenia amounted 14 days (range from 1 to 588 days), neutropenia- 13 days (range from 2 to 116 days). After treatment rituksimabom described 1 a case of transient aplastic anemia (Aplasia only èritrocitarnogo germ) and 2 the case of hemolytic anemia.

Besides, There are a limited number of postmarketingovyh messages about prolonged pancytopenia, bone marrow hypoplasia and neutropenia (defined as occurring after 40 days after the last injection of rituximab) in patients with hematological malignant diseases.

Cardiovascular adverse events. Cardiovascular reactions of 3-rd and 4-th degree of severity include hypotension. Describes the rare, fatal cases of congestive heart failure with the development of symptoms weeks after starting treatment rituksimabom.

The infusion should be stopped in case of serious, life-threatening arrhythmia. Patients, who developed clinically pronounced arrhythmia, cardiac monitoring should be undertaken during and after the following infusions of rituximab. In patients with previous heart disorders, including arrhythmia and cardiac angina, possible manifestation of the symptoms during therapy rituksimabom, Therefore, they should be monitored throughout the duration of the infusion and immediately thereafter.

Pulmonary symptoms. In clinical trials, pulmonary adverse events were observed in 135 patients (38%). The most common side effects of the respiratory system include: increased cough, rhinitis, bronchospasm, dyspnoea, sinusitis. As in clinical studies, and in postmarketingovyh there were a limited number of observations reported obliteriruuschem bronhiolite, naličestvuûŝem until 6 months after rituximab infusion, and the limited number of posts on pnevmonite (including interstitial Pneumonitis), up to the present 3 months after rituximab infusion (some of these pulmonary complications had fatal). Safety of recurrence or continuation of introduction of rituximab in patients with Pneumonitis or obliterating bronhiolitom unknown.

Hepatitis b reactivation. It was reported about a reactivation of hepatitis b virus with fulminant hepatitis development, liver failure and death in a few patients with hematological zlokačestvennost′û, treated with rituksimabom therapy. The majority of patients receiving rituximab in combination with chemotherapy. The median time to diagnoscirovaniâ hepatitis was approximately 4 months after the start of injection of rituximab and approximately 1 months after last dose.

Patients with a high risk of infection with hepatitis b virus should examine before starting treatment rituksimabom to detect virus. Hepatitis b virus carriers should be carefully examined for signs of active infection and symptoms of hepatitis during therapy, rituksimabom and a few months after it. In the case of patients with viral hepatitis rituximab and any concomitant chemotherapy should be abolished and assigned appropriate treatment, including initial antiviral therapy. Insufficient data, to demonstrate the safety of resumption of treatment of rituksimabom patients, who developed hepatitis due to reactivation of hepatitis b virus.

Immune/autoimmune unwanted reactions. Such reactions have been reported, How uveitis, optic neuritis in patients with systemic vaskulitom, pleural effusion in patients with volčanočnopodobnym syndrome, serum sickness with poliartikulârnym arthritis and Vasculitis with a rash.

Less common side effects observed. In clinical trials of less 5% and more 1% observed patients had the following side effects (a causal relationship with the appointment of rituximab is not installed) — psychomotor agitation, anorexia, arthritis, conjunctivitis, depression, dyspepsia, Eden, giperkineziya, hypertension, gipesteziya, gipoglikemiâ, pain at the injection site, insomnia, violation of lacrimation, malaise, irritability, neuritis, neuropathy, paraesthesia, drowsiness, vertigo, underweight.

Rituximab – Cooperation

With the introduction of other monoclonal antibody diagnostic purpose for patients, having antibodies against mouse proteins or antibodies antihimernye, they may develop an allergic reaction or hypersensitivity reactions.

In the appointment with cyclophosphamide, doxorubicin, Vincristine, prednisolone is the increasing incidence of toxic effects were observed. PM, suppress bone marrow hematopoiesis, increase the risk of myelosuppression.

Rituximab – Overdose

Cases of overdose in clinical studies in humans have been observed. However, one-time dose over 500 mg / m² We have not been studied.

Dosing and Administration

B /. Concentrate previously diluted in infuzionnom vial (package) sterile, non-pyrogenic 0,9% an aqueous solution of sodium chloride or 5% dextrose concentration to 1-4 mg/ml; introducing drip in the dose 375 mg / m² body surface 1 Once a week for 4 Sun; initial speed infusion the first introduction 50 mg/h, with a gradual increase of 50 mg/h every 30 m (maximum speed 400 mg / h); in the procedures to follow, you can start with speed 100 mg/h and increase it on the 100 mg/h every 30 min and Max (400 mg / h).

Rituximab – Precautions

Infusions are possible only in a hospital under close supervision of hematologist or oncologist, with experience of such treatment, While at the ready should be all that is necessary for the conduct of Resuscitation in full. In connection with the risk of hypotension recommended lifting antihypertensive drugs for 12 hours before the start of and throughout the time of infusion. Infusion regimes should be strictly observed, is invalid in/in a Jet or introduction in the form of bolusa.

To prevent the development of cytokine release syndrome "for 30-60 minutes before each procedure need premedication: analgesic/antipyretic (for example, paracetamol) and antigistaminnoe (Diphenhydramine etc.) means, and with an increased risk of allergic reactions-corticosteroids. Light or moderately expressed reaction can be eliminated by the reduction of the speed of, You can enlarge again after the disappearance of symptoms. In most cases, patients with adverse reactions, not life threatening, the course of treatment rituksimabom was able to complete.

Tumor Lysis syndrome. Isolated cases of fatal outcomes have been observed in connection with the development of this syndrome in patients, treated with rituximab. The risk of developing the syndrome is higher in patients with a large number of circulating malignant lymphocytes (≥ 25000 cells/mm²) or when high tumor load. Patients at risk for tumor Lysis syndrome it is necessary to carry out prevention activities (careful observation, the related laboratory monitoring, incl. monitoring of renal function and electrolyte balance, When developing symptoms of rapid lysis of tumor-related drug therapy, correction of electrolyte disturbances, dialysis). In a limited number of cases after full cupping therapy rituksimabom symptoms continued, coupled with rapid tumor Lysis syndrome prevention.

Caution must be exercised (the first introduction — lower speed infusion, careful observation) in patients with single-size tumor foci of more 10 cm in diameter or the number of circulating malignant cells is ≥ 25000 cells/mm³ due to the increased frequency of severe adverse reactions. Due to the high risk of cytokine release syndrome "patients with anamnestičeskimi guidance on pulmonary insufficiency and with neoplastic lung infiltration assignment is possible in conditions of careful observation and only the ineffectiveness of other treatment methods. With the development of cytokine release syndrome» infuziu should cease immediately and begin intensive symptomatic therapy.

Be wary appoint patients with neutropenia (less 1500 cells 1 l) and thrombocytopenia (less 75000 cells 1 l); over the course of a regular monitoring of the cells of peripheral blood.

Immunization. Any immunization vaccine safety, particularly live viral vaccines, After the treatment was not rituksimabom. Ability to provide primary or anamnestičeskuû humoral response to any vaccine is also not studied.