美罗华Mabthera

【 Function and Indication 】
Rituximab Mabthera can be used to treat diseases caused by excessive B lymphocytes, including lymphoma, leukemia, transplantation rejection and some autoimmune diseases.

“Model and specification”
100mg/10ml; 500 mg /50 ml.

【 Usage and dosage 】
The required dose of rituximab was extracted under aseptic conditions and placed in an infusion bag containing 0.9% normal saline or 5% glucose solution without pyrogen, and the concentration of rituximab was diluted to 1mg/ml. Gently invert the injection bag to mix the solutions and avoid foaming. Because this product does not contain antimicrobial preservatives or bacteriostatic agents, it is necessary to check the aseptic technology. Observe whether the injection has particles or discoloration before intravenous use.

Rituximab diluted by intravenous drip through an independent infusion tube that is not mixed with other drugs is suitable for the treatment of bedridden patients.

Rituximab should be treated in a ward with complete resuscitation equipment and under the direct supervision of an experienced oncologist or hematologist. Monitor patients with respiratory symptoms or hypotension for at least 24 hours. Each patient should be closely monitored to monitor whether cytokine release syndrome occurs (see [Precautions]). Patients with severe reactions, especially those with severe dyspnea, bronchospasm and hypoxemia, should stop dripping immediately. Patients should also be evaluated for tumor lysis syndrome, for example, appropriate laboratory tests can be performed. Patients with preexisting pulmonary insufficiency or tumor pulmonary infiltration must undergo chest X-ray examination. After all the symptoms disappear and the laboratory tests return to normal, the drip can not be continued. At this time, the drip speed should not exceed half of the original drip speed. If the same serious adverse reaction occurs again, you should consider stopping the drug.

Rituximab should never be given intravenously without dilution, and the prepared injection should not be used for intravenous injection.

Follicular non-Hodgkin’s lymphoma
Antipyretic and analgesic drugs (such as paracetamol) and antihistamines (such as diphenhydramine) should be used before each drip of rituximab. Glucocorticoids should also be used in advance, especially if the treatment regimen used does not include corticosteroids.

Initial treatment
As a single therapeutic drug for adult patients, the recommended dose is 375 mg/m[sup]2[/sup] BSA (body surface area), which is given intravenously once a week, and administered four times in 22 days.

When combined with CVP chemotherapy, the recommended dose of rituximab is 375 mg/m[sup]2[/sup] BSA for 8 cycles (21 days/cycle). Corticosteroids were given orally at first, and then on the first day of the chemotherapy cycle.

Re-treatment after recurrence
For patients with recurrence after the first treatment, the dose of retreatment is 375 mg/m[sup]2[/sup] BSA, which is given intravenously once a week for 4 weeks (see Clinical Trial, once a week for 4 weeks).

Diffuse large b-cell non-Hodgkin’s lymphoma
Antipyretic and analgesic drugs (such as paracetamol) and antihistamines (such as diphenhydramine) should be used before each drip of rituximab. Glucocorticoids should also be used in advance, especially if the treatment regimen used does not include corticosteroids.

Rituximab should be used in combination with CHOP chemotherapy. The recommended dose is 375mg/m[sup]2[/sup] BSA, which is used on the first day of each chemotherapy cycle. Other components of chemotherapy should be used after rituximab.

Initial drip
The recommended initial drip speed is 50 mg/h; After the first 60 minutes, 50 mg/h can be increased every 30 minutes until the maximum speed is 400 mg/h.

Subsequent drip
The initial speed of rituximab infusion can be 100 mg/h, and it can be increased by 100 mg/h every 30 minutes until the maximum speed is 400 mg/h.

Dose adjustment during treatment
Dosage reduction of rituximab is not recommended. When rituximab is combined with standard chemotherapy, the dose of standard chemotherapy can be reduced.

[Clinical research]
Moustache tumor has a highly specific combination with human CD20. CD20 is mainly expressed in pre-B to fully differentiated B lymphocytes, but the finally differentiated plasma cells do not express this molecule. At present, the function of CD20 is not fully understood, but this molecule can be used as a target to attack malignant B lymphocytes with melanoma.
The mechanism that moustache tumor can effectively kill cancer cells is mainly to trigger antibody-dependent cytotoxicity and complement cytotoxicity, and attack cancer cells identified by moustache tumor by using the immune system in vivo.
In addition, moustache tumor can also inhibit the cell growth cycle of malignant B lymphocytes and induce apoptosis.
Moustache tumor can also attack normal B lymphocytes, but new B lymphocytes can develop from lymphoid stem cells.

【 Precautions 】
Infusion-related reaction
Rituximab can cause infusion reaction, which may be related to the release of cytokines and/or other chemical mediators. Clinically, it may be impossible to distinguish severe infusion reaction from allergic reaction or cytokine release syndrome. In the post-marketing use, there have been reports of fatal serious infusion reactions. Severe infusion reactions usually occur within 30 minutes to 2 hours after the start of rituximab infusion, characterized by the occurrence of lung events. In some cases, besides fever, chills, hypotension, rubella, vascular edema and other symptoms, rapid tumor dissolution and tumor lysis syndrome may occur (see [Adverse Reaction]). Patients with high tumor load or high number of malignant cells in peripheral blood (]25 x 109/L), such as CLL and mantle cell lymphoma, may be at greater risk of serious infusion reaction. After stopping infusion, these symptoms are generally reversible. It is suggested that diphenhydramine and acetaminophen should be used to treat the symptoms of infusion. In addition, bronchodilators or intravenous saline can also be used for treatment. In most cases, when the symptoms are completely relieved, the infusion treatment can be restarted at a speed of 50% (for example, from 100 mg/h to 50 mg/h). Most patients with non-fatal infusion reactions can complete the whole course of rituximab treatment. After the symptoms and signs are completely relieved, patients continue to receive treatment and rarely have serious infusion-related reactions again. It has been reported that allergic reactions and other hypersensitivity reactions occurred after intravenous administration of protein to patients. Adrenaline, antihistamine and glucocorticoid should be used immediately when rituximab-related hypersensitivity occurs.

Patients with high number of malignant tumor cells in peripheral blood (]25 x 109/L) or high tumor load, such as CLL and mantle cell lymphoma, have a relatively high risk of serious infusion-related reactions and should be treated with special caution. Patients should be closely observed during the first infusion. This kind of patients should consider whether it is necessary to slow down the infusion speed for the first time, or divide the dosage into two parts in the first treatment cycle and finish the administration within two days. If the number of lymphocytes is still greater than 25 x 109/L, it should still be administered in this way in the subsequent treatment cycle.

Pulmonary events
Pulmonary events include tissue hypoxia, lung infiltration and acute respiratory failure. Some of these events may be secondary to severe bronchospasm and dyspnea. In some cases, the symptoms may get worse with the passage of time. In other cases, the initial improvement is followed by the deterioration of clinical conditions. Therefore, patients with pulmonary events or other severe infusion symptoms should be closely monitored until their symptoms are completely relieved. Patients with a history of pulmonary insufficiency or lung tumor infiltration are at greater risk of poor prognosis, and doctors should be more careful in treatment. It can be observed on the chest X- ray film that acute respiratory failure may be accompanied by pulmonary interstitial infiltrative lesions or edema. This symptom usually occurs within 1 or 2 hours after the first infusion. For patients with severe pulmonary events, infusion should be stopped immediately (see [Usage and Dosage]) and active symptomatic treatment should be given.

Rapid tumor dissolution
Rituximab can mediate rapid lysis of benign and malignant CD20 positive cells. It has been reported that signs and symptoms consistent with tumor lysis syndrome (TLS) have been observed in patients with a high number of malignant lymphocytes in peripheral blood (such as hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure and elevated LDH level). For high-risk patients (such as patients with high tumor load or high number of malignant cells in peripheral blood (]25 x 109/L), such as patients with CLL and mantle cell lymphoma), the prevention of TLS should be considered. After using rituximab, these patients should be closely and properly monitored in the laboratory. Patients with signs and symptoms of rapid tumor dissolution should be given appropriate medical treatment. In some cases, after the signs and symptoms are treated and completely relieved, rituximab can continue to be given under the condition of TLS preventive treatment.

Patients should be treated with rituximab infusion in an environment where resuscitation equipment is complete and immediately available, and under the close supervision of experienced oncologists/hematologists.

 

cardiovascular
Because hypotension may occur during rituximab infusion, antihypertensive drugs should be stopped 12 hours before and during rituximab infusion. In patients treated with rituximab, angina pectoris or arrhythmia have occurred, such as atrial flutter and fibrillation, heart failure or myocardial infarction. Therefore, patients with a history of heart disease should be closely monitored.

Blood cell count detection
Although rituximab is not myelosuppressive in monotherapy, we should be cautious when considering the use of rituximab in the treatment of patients with neutrophil count [1.5 x 109/L and/or platelet count [75 x 109/L], because the accumulated clinical experience in such patients is limited. Rituximab has been used in autologous bone marrow transplantation and other people who may be at risk of bone marrow dysfunction, and has not produced bone marrow toxicity.

In the process of using rituximab as monotherapy, the necessity of regular examination of whole blood cell count, including platelet count, should be considered. When rituximab is combined with CHOP or CVP chemotherapy, the whole blood cell count should be checked regularly according to the routine of medical practice.

infect
Rituximab should not be used to treat patients with severe active infection.

Hepatitis B virus infection
Among the subjects who took rituximab, some cases reported the reactivation of hepatitis B virus (HBV), including fulminant hepatitis (some cases were fatal), although most subjects were also exposed to cytotoxic chemotherapy. Potential disease states and cytotoxic chemotherapy are mixed with reported events. For high-risk patients with hepatitis B, screening for hepatitis B virus (HBV) should be considered before starting rituximab treatment. Hepatitis B virus carriers and patients with a history of hepatitis B should closely monitor the clinical signs and laboratory indicators of active HBV infection during the treatment with rituximab and within a few months after treatment.

Progressive leukoencephalopathy
In clinical application, when rituximab is used in the treatment of patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, progressive polyleukoencephalopathy (PML) occurs (see [Adverse Reaction]). Most patients use rituximab in combination with chemotherapy drugs or as a treatment during hematopoietic stem cell transplantation. Therefore, when doctors treat patients with non-Hodgkin’s lymphoma and patients with chronic lymphocytic leukemia, they should consider PML in differential diagnosis of patients who report symptoms of Jing Jing, and consult doctors of Jing Jing according to clinical needs.

immunization
The safety of immunization with live virus vaccine after rituximab treatment has not been studied. Vaccination with live virus vaccine is not recommended.

Patients treated with rituximab can be vaccinated with non-live vaccine, but the response rate to non-live vaccine may decrease. In a non-randomized clinical study, compared with untreated healthy volunteers in the control group, patients with relapsed low-grade malignant NHL who received rituximab monotherapy had lower response rates to immunization with tetanus memory antigen and new antigen of keyhole limpet hemocyanin (KLH), which were 16% vs 81％% and 4% vs 69%, respectively (as evaluated by the antibody titer increasing by more than 2 times).
The average antibody titers of patients to various antigens (streptococcus pneumoniae, influenza A, mumps, rubella and chickenpox) before treatment can be maintained for at least 6 months after treatment with rituximab.

[u] Patients with rheumatoid arthritis (RA) and ANCA-related vasculitis (AAV) [/u]
Except for rheumatoid arthritis and ANCA-associated vasculitis, the efficacy and safety of rituximab in the treatment of autoimmune diseases are not clear.

Infusion-related reactions
The infusion reaction related to rituximab/rituximab may be related to the release of cytokines and/or other chemical mediators. Antipyretic and analgesic drugs and antihistamines should be used in advance before each drip of rituximab. For RA patients, in order to reduce the frequency and severity of infusion-related reactions, glucocorticoid should be used in advance before each infusion of rituximab.

For patients with RA, the infusion-related reactions reported in most clinical trials are mild to moderate. In post-marketing use, fatal serious infusion-related reactions have been reported (see [Adverse Reactions]). Closely monitor patients with previous heart diseases and adverse cardiopulmonary reactions. The most common symptoms include headache, itching, throat irritation, flushing, rash, urticaria, hypertension and fever. Generally speaking, in any treatment cycle, the incidence of infusion-related reactions in the first infusion is higher than that in the second infusion. Compared with the first infusion, patients can tolerate rituximab later. Less than 1% of patients will have serious infusion-related reactions, most of which occur during the first infusion of the first treatment cycle (see [Adverse Reactions]). When the infusion of rituximab is slowed down or interrupted, the reactions reported by antipyretics and antihistamines can generally subside, and individual cases can be given oxygen inhalation, intravenous saline solution or bronchodilators and corticosteroids if necessary. According to the severity of infusion-related reactions and the required intervention treatment, the treatment of rituximab was temporarily or permanently stopped. In most cases, after the symptoms and signs have completely subsided, the infusion can be continued by reducing the infusion rate by 50% (for example, from 100 mg/h to 50 mg/h).

It has been reported that patients have allergic reactions and other hypersensitivity reactions before, during and after intravenous administration of protein. Drugs (such as epinephrine, antihistamines and corticosteroids) used to treat hypersensitivity should be prepared so as to be quickly used in allergic reaction events during rituximab infusion.

Infusion-related reactions of AAV patients in clinical trials are similar to those observed in RA patients (see [Adverse Reactions]). For AAV patients, rituximab combined with high-dose glucocorticoid therapy may reduce the incidence and severity of such events.

cardiovascular
Hypotension may occur during rituximab infusion, so antihypertensive drugs should not be used within 12 hours of rituximab infusion. Rituximab administration in patients with non-Hodgkin’s lymphoma can aggravate the original ischemic heart disease and cause symptoms such as angina pectoris, myocardial infarction, atrial fibrillation, ventricular fibrillation and atrial flutter. Therefore, patients with a history of heart disease should consider the risk of cardiovascular complications caused by infusion reaction before starting rituximab treatment, and closely monitor such patients during rituximab administration.

infect
Rituximab treatment may increase the risk of infection (see [contraindications]). Rituximab should not be used in patients with active infection or severely impaired immune response (such as a serious decrease in CD4 or CD8 cell count). Rituximab should be used with caution in patients with a history of recurrent or chronic infection, or with underlying diseases that are likely to cause serious infection (see [Adverse Reactions]). Patients with infection after treatment with rituximab should be studied immediately and treated appropriately.

Among RA and AAV patients treated with rituximab, cases of hepatitis B recurrence have been reported.

Progressive multifocal leukoencephalopathy
Severe progressive multifocal leukoencephalopathy (PML) was reported when rituximab was used in autoimmune diseases including rheumatoid arthritis. There are several reported cases, but not all of them have potential risk factors related to PML, including potential diseases and long-term immunosuppressive treatment or chemotherapy. PML has also been reported in patients with autoimmune diseases who were not treated with rituximab. When treating patients with autoimmune diseases, doctors should consider PML in differential diagnosis of patients who report symptoms of Jing Jing, and consult doctors of Jing Jing according to clinical needs.

immune
The safety of live virus vaccine immunization after rituximab treatment has not been studied. For patients who use rituximab or peripheral B cell failure, it is not recommended to use live virus vaccine for vaccination. Patients treated with rituximab can be vaccinated with non-live vaccine, but the response rate to non-live vaccine may decrease.

For RA patients, before using rituximab, doctors should review the patients’ immune status and follow the current immunization guidelines. Immunization should be carried out at least 4 weeks before the first dose of rituximab.

In a randomized clinical study, the response rates of rheumatoid arthritis patients treated with rituximab combined with methotrexate to tetanus memory antigen (39％ vs42％%), pneumococcal polysaccharide vaccine (43% vs82% to at least two serum subtypes of pneumococcal antibodies) and KLH new antigen (47% vs 93%) were similar to those of rheumatoid arthritis patients treated with methotrexate only. If the patient needs to be vaccinated with non-live vaccine when receiving rituximab treatment, the vaccination must be completed at least 4 weeks before the next course of rituximab treatment.

From the overall experience, the proportion of RA patients with positive antibody titers to streptococcus pneumoniae, influenza, mumps, rubella, chickenpox and tetanus toxin after repeated treatment with rituximab for more than one year is basically similar to that in the baseline period.

RA patients initially treated with methotrexate (MTX)
Because a good benefit-risk relationship has not been established, rituximab is not recommended for patients who are initially treated with methotrexate.

[u] incompatibility: [/u]
Incompatibility between rituximab and PVC or polyethylene bags or infusion sets was not observed.

[u] Impact on the ability to drive and operate machines: [/u]
It is unknown whether rituximab impairs the ability to drive and operate machines, although the pharmacological characteristics and adverse reactions reported so far do not show the above adverse effects. In order to avoid pre-administration of infusion reactions (antihistamines), the treatment of these infusion reactions should be kept in mind. After the infusion reaction, the patient can drive or operate the machine only after the state is stable.

[Adverse reactions and contraindications]
Experience in clinical trials of hematological tumors
The incidence of adverse reactions (ADRs) of rituximab alone or in combination with chemotherapy is shown in the table below, and the data are from clinical trials. Including the adverse reactions of a single group study or at least one major randomized clinical trial, the incidence of the experimental group is at least 2% worse than that of the control group. According to the adverse reactions with the highest incidence in any major clinical trial, they are reasonably classified, as shown in the table below. Adverse reactions in each group were arranged in descending order of severity. The incidence rate is defined as: very common, 1 in 10; Common, 1/100-[1/10; Unusual, 1 in 1000-[1 in 100.

Rituximab monotherapy/maintenance therapy
The adverse reactions in Table 1 below come from multiple single-group studies of rituximab, including 356 patients with low-grade malignant or follicular lymphoma who received rituximab monotherapy or retreatment once a week (see Clinical Trial). The table also includes the data of 671 patients with follicular lymphoma who received rituximab maintenance treatment. Patients received R-CHOP, R-CVP or R-FCM regimen induction treatment, and then continued to receive rituximab maintenance treatment for 2 years after remission (see [Clinical Trial]). Adverse reactions were reported 12 months after monotherapy or 1 month after rituximab maintenance treatment.

Table 1 Overview of adverse reactions of patients with low-grade or follicular lymphoma receiving rituximab monotherapy (N=356) or rituximab maintenance therapy (N=671) in clinical trials.

The calculation of each incidence is based on all levels of adverse reactions (from mild to severe), but the incidence of items marked with “+”only includes severe reactions (NCI common toxicity evaluation standard of ≥3 degrees). Only the adverse reactions with the highest incidence rate in all clinical trials are reported.

Rituximab combined with chemotherapy for NHL and CLL
The adverse reactions listed in Table 2 below come from the rituximab treatment group in the controlled clinical trial, which are in addition to the adverse reactions observed by rituximab monotherapy/maintenance therapy and/or have a higher incidence: 202 patients with DLBLC treated with R-CHOP regimen, 234 patients with follicular lymphoma treated with R-CHOP regimen and 162 patients with R-CVP regimen respectively. And 397 patients with previously untreated CLL and 274 patients with relapsed/refractory CLL who received rituximab combined with fludarabine and cyclophosphamide (R-FC) (see Clinical Trial).

Table 2 Patients with DLBCL (N=202) and follicular lymphoma (N=234) receiving R-CHOP regimen, patients with follicular lymphoma receiving R-CVP regimen (N=162) and patients with previously untreated CLL (n = 397) or relapsed/refractory CLL receiving R-FC regimen (n = 277)

* Including primary and recurrent infections, the incidence statistics are from patients with relapsed/refractory CLL treated with R-FC regimen.
Only serious adverse reactions (defined as NCI common toxicity standard of ≥3 degrees) were counted.
Only the adverse reactions with the highest incidence rate in all clinical trials are reported.

Compared with the control group, the incidence of adverse reactions in rituximab group is similar (the difference between groups is less than [2%) or lower: hematological toxicity, infection caused by neutropenia, urinary tract infection, septic shock, secondary infection of lung, graft infection, staphylococcal septicemia, pulmonary infection, rhinorrhea, pulmonary edema, heart failure, sensory disturbance, venous thrombosis, mucosal inflammation, and so on.

The safety of rituximab combined with other chemotherapy regimens (such as MCP and CHVP-IFN) is comparable to that of rituximab combined with CVP, CHOP or FC in the same patient population.

Details of some serious adverse reactions

Infusion-related reaction
Single drug therapy -4 weeks treatment
In clinical trials, more than 50% patients reported signs and symptoms of infusion-related reactions, which mainly occurred at the first infusion. Hypotension, fever, chills, urticaria, bronchospasm, swelling of tongue or throat (vascular edema), nausea, fatigue, headache, itching, dyspnea, rhinitis, vomiting, facial flushing and pain in the lesion are related to rituximab infusion, and belong to infusion-related syndrome.

Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; CLL adopts R-FC scheme)
During the treatment of rituximab combined with chemotherapy drugs, 12% patients had serious infusion-related reactions in the first course of treatment, and the incidence of infusion-related reactions decreased significantly in the subsequent courses, and the incidence was less than 1% in the eighth course of treatment. Other reported reactions include dyspepsia, rash, hypertension, tachycardia and tumor lysis syndrome. Individual cases also reported myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

infect
Single drug therapy -4 weeks treatment
Rituximab caused 70%-80% of patients with B cell depletion, and only a few patients were accompanied by the decrease of plasma immunoglobulin. Regardless of the causal relationship, 30.3% of 356 patients had bacterial infection, viral infection, fungal infection and infection with unknown etiology. 3.9% patients had serious infection events (3/4 degree), including septicemia.

Two years of maintenance treatment (NHL)
Rituximab/rituximab treatment observed a higher overall frequency of infection, including grade 3-4 infection. There was no accumulated infectious toxicity during the 2-year maintenance treatment.
Data from clinical trials include fatal progressive leukoencephalopathy in patients with non-Hodgkin’s lymphoma, which occurs after disease progression and repeated treatment (see [Precautions]).

Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; CLL adopts R-FC scheme), no increase in infection or infection frequency was observed. The most common infection was upper respiratory tract infection, the incidence rate was 12.3% in R-CVP group and 16.4% in CVP group. The incidence of severe infection was 4.3% in R-CVP treatment group and 4.4% in CVP group. No life-threatening infections were reported.

In the R-CHOP study, the total incidence of 2-4 degree infection in the R-CHOP treatment group was 45.5%, and that in the Chop group was 42.3%. The incidence of 2-4 degree fungal infection in R-CHOP group was higher (4.5% in R-CHOP group vs 2.6% in chop group). The difference is due to the higher incidence of local candida infection during treatment. The incidence of 2-4 degree herpes zoster in R-CHOP group (4.5%) was higher than that in CHOP group (1.5%). The proportion of patients with 2-4 degree infection and/or febrile neutropenia was 55.4% in R-CHOP group and 51.5% in CHOP group, respectively.

In patients with CLL, the incidence of degree 3 or 4 hepatitis B (primary and recurrent) is 2% and 0% in patients who adopt R-FC regimen and FC regimen respectively.

Hematological events
Single drug therapy -4 weeks treatment
Severe neutropenia (3 and 4 degrees) was observed in 4.2% patients, severe anemia was observed in 1.1% patients, and severe thrombocytopenia was observed in 1.7% patients.

Two years of maintenance treatment (NHL)
The incidence of 3-4 degree leukopenia (2% in the observation group vs 5% in the rituximab group) and neutropenia (4% in the observation group vs 10% in the rituximab group) was higher than that in the observation group. The incidence of 3-4 degree thrombocytopenia in rituximab group was lower (1% in observation group 1%Vs 1% in rituximab group). After receiving rituximab/rituximab induction therapy, it takes 12 months or more for nearly half of the patients with B cell recovery to return to normal level.

Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; CLL adopts R-FC regimen) In the study of rituximab combined with chemotherapy regimen, compared with chemotherapy regimen alone, 3/4 degree leukopenia (88% in R-CHOP group, 79% in CHOP group, 23% in R-FC group and 12% in FC group), neutropenia (24% in R-CVP group in previously untreated chronic lymphocytic leukemia). However, the duration of neutropenia in patients receiving rituximab combined with chemotherapy was not prolonged, and its incidence was not related to the high incidence of infection and infection.

There was no correlation between 3-4 degree anemia and thrombocytopenia in different treatment groups. In the clinical study of CLL first-line treatment, 4% patients in R-FC group and 7% patients in FC group reported 3/4 degree anemia respectively. 7% patients in R-FC group and 10% patients in FC group reported 3/4 degree thrombocytopenia respectively. In the clinical study of recurrent/refractory CLL, the incidence of 3/4 anemia in R-FC group was 12%, and that in FC group was 13%. The incidence of 3/4 degree thrombocytopenia in R-FC group was 11%, and that in FC group was 9%.

Cardiovascular event
Single drug therapy -4 weeks treatment
During the treatment, 18.8% patients had cardiovascular events. Hypotension and hypertension are the most common events. During the infusion of rituximab, 3 or 4 degree arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris were reported.

 

Two years of maintenance treatment (NHL)
The incidence of 3-4 degree heart disease in the two groups was basically the same. [1% of patients in the observation group and 3% of patients in the rituximab group suffered from the following heart diseases as reported by serious adverse events: atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure ([1%) and myocardial ischemia ([1%).

Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; CLL adopts R-FC scheme)
In R-CHOP test, the incidence of 3-4 degree arrhythmia in R-CHOP group (6.9% patients) was higher than that in Chop group (1.5% patients), especially supraventricular arrhythmia (such as tachycardia and atrial flutter/fibrillation). All these arrhythmias either occur when rituximab is instilled, or are related to the susceptible state of the body, such as fever, infection, acute myocardial infarction or previous respiratory and cardiovascular diseases (see [Precautions]). Other 3 and 4 degree adverse cardiac events (such as heart failure, myocardial lesions and coronary artery lesions) were not observed between R-CHOP and CHOP groups.

In CLL patients, the total incidence of degree 3 or 4 heart diseases is low (clinical study of first-line treatment: 4% in R-FC group and 3% in FC group; Recurrent/refractory clinical study: 4% in R-FC group and 4% in FC group).

IgG level
Two years of maintenance treatment (NHL)
After induction therapy, the median IgG levels in the control group and rituximab group were lower than the lower limit of the normal range ([7g/L]). After that, the median IgG level in the control group increased above the lower limit of the normal range, but remained unchanged during the treatment of rituximab. During the whole two-year treatment period, the proportion of patients whose IgG level was below the lower limit of the normal range was about 60% in the rituximab group, while it decreased in the control group (36% after two years).

Adverse reaction of Jing Jing system
Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; During the treatment of CLL with R-FC regimen, 2% patients with cardiovascular risk factors in R-CHOP group developed thromboembolic cerebrovascular disease in the first course of treatment. There was no difference in the incidence of other thromboembolic diseases between the two treatment groups. In CHOP group, 1.5% patients had cerebrovascular events, all of which occurred in the follow-up stage.

In CLL patients, the total incidence of third-degree or fourth-degree spermatic system diseases is low (first-line treatment clinical study: 4% in R-FC group and 4% in FC group; Recurrent/refractory clinical study: 3% in R-FC group and 3% in FC group).

[u] special population [/u]
Single drug therapy -4 weeks treatment
Elderly patients (≥65 years old)
The incidence of any adverse reactions (88.3% and 92.0%) and third-degree and fourth-degree adverse reactions (16.0% and 18.1%) were similar between elderly patients and younger patients.

Combined therapy
Elderly patients (≥65 years old)
For patients with previously untreated CLL and patients with relapsed/refractory CLL, the incidence of 3/4 degree blood and lymph adverse events in elderly patients (65 years old) is higher than that in younger patients.

High tumor load
Patients with high tumor load have higher incidence of 3 and 4 degree adverse reactions (25.6%Vs15.4%) than those without high tumor load. The incidence of any adverse reactions was similar in both groups (92.3% Vs89.2%).

Re-treatment after recurrence
The incidence of any adverse reactions (95.0% Vs 89.7%) and third and fourth degree adverse reactions (13.3% Vs 14.8%) in retreatment was similar to that in initial treatment.

Experience in clinical trials of rheumatoid arthritis
The safety data of rituximab/rituximab in the treatment of patients with moderate to severe rheumatoid arthritis are as follows. Among all exposed people, more than 3,000 patients received at least one cycle of treatment and were followed up for 6 months to more than 5 years. The total exposure level was equivalent to 7,198 patient years, and about 2,300 patients received two or more cycles of treatment during the follow-up period.

The adverse reactions listed in Table 3 are based on the data of four multicenter, analgesics-controlled clinical studies of rheumatoid arthritis. In the above study, the patients who received rituximab/rituximab were all different, including patients with early active rheumatoid disease who were not treated with methotrexate, patients with insufficient efficacy of methotrexate, and patients with insufficient efficacy against tumor necrosis factor.

Patients were treated with 21,000 mg or 2´500mg of rituximab (two weeks after administration) and methotrexate (10-25mg/ week). Table 3 lists all the adverse reactions in all dose groups, with the incidence exceeding 2% and the difference exceeding 2% from the control group. The incidence rates in Table 3 and its related footnotes are classified as very common (incidence ≥1/10), common (≥1/100 to [1/10] and uncommon (1/1,000 to [1/100]).

Table 3 Overview of Adverse Reactions Reported by Patients with Rheumatoid Arthritis in Clinical Trial Control Period

The safety data of all exposed people were consistent with the safety data during the control period of clinical trials, and no new adverse reactions were found.

Multi-treatment
The characteristics of adverse reactions observed during multi-course treatment are similar to those observed after the first medication. In the subsequent treatment cycle, the safety was improved due to the common infusion-related reactions and the aggravation of rheumatoid arthritis and the reduction of infection in the first 6 months.

Further information about adverse drug reactions:
Infusion-related reactions:
In clinical trials, the most common adverse reaction after rituximab/rituximab treatment is infusion-related reaction. Of the 3095 patients treated with rituximab, 1077 (35%) had at least one infusion-related reaction. Most infusion-related reactions are CTC1 or 2 events. In clinical research, less than 1%(14/3095 patients) of RA patients had serious infusion-related reactions when rituximab was infused at various doses. No CTC level 4 infusion-related reaction events or fatal infusion-related reaction events occurred in clinical research (see post-marketing experience). The percentage of CTC level 3 events and infusion-related reaction events that caused patients to quit decreased with the increase of treatment cycle, and these events were less common after the third treatment cycle.

After the first treatment with rituximab in 3095 patients, 720 patients (23%) observed the symptoms and symptoms of acute infusion reaction (nausea, pruritus, fever, rubella/rash, chills, sneezing, vascular seminal edema, throat irritation, cough and bronchospasm with or without hypotension or hypertension related to drug treatment). Intravenous administration of glucocorticoid before treatment significantly reduced the incidence and severity of these events (see contraindications and precautions of rheumatoid arthritis).

infect
In patients treated with rituximab, the total infection rate is about 97/100 person-years. Most infection events are mild to moderate, mainly including upper respiratory tract infection and urinary tract infection. The incidence of serious infection is about 4/100 person-years, some of which are fatal events. In addition to the adverse reactions listed in Table 3, serious medical adverse events include pneumonia, the incidence of which is 1.9%.

malignant tumor
In clinical research, the incidence of malignant tumor after rituximab/rituximab treatment is 0.8/100 person-years, which is within the expected range of age and gender-matched population.

Clinical trial experience of ANCA-associated vasculitis (AAV)
In the clinical study of AAV, 99 patients were treated with rituximab/rituximab (375 mg/m2 once a week for 4 weeks) and glucocorticoids (see Clinical Trial for more information). The adverse reactions listed in Table 4 are all adverse events with an incidence of ≥10% in the rituximab/rituximab treatment group. The frequency of occurrence in Table 4 ≥1/10 is defined as very common.

Table 4 Incidence rate of very common (≥10%) adverse reactions among AAV patients treated with rituximab in the 6-month clinical study *

* The study design allows patients to receive cross-treatment or choose a treatment plan according to medical judgment. Thirteen patients in each treatment group received another treatment during the 6-month study period.
A The most common infections in rituximab group include upper respiratory tract infection, urinary tract infection and herpes zoster.
B The most common infusion-related reactions reported by rituximab group were cytokine release syndrome, facial flushing, throat irritation and tremor.

Further information about adverse drug reactions

Infusion-related reactions:
Infusion-related reactions in AAV clinical research are defined as any adverse event that occurs within 24 hours of infusion in a safe population, and researchers believe that this event is related to infusion. Ninety-nine patients were treated with rituximab, and 12% of them experienced at least one infusion-related reaction. All infusion-related reactions were CTC grade 1 or 2. The most common infusion-related reactions include cytokine release syndrome, facial flushing, throat irritation and tremor. Rituximab/rituximab combined with intravenous glucocorticoid may reduce the incidence and severity of these events.

Infection:
In 99 patients who used rituximab/rituximab, the total infection rate was about 210 per 100 patient years (95% CI173-256). Infection is mainly mild and moderate, and most of them are upper respiratory tract infection, herpes zoster and urinary tract infection. The incidence of severe infection is about 25 per 100 patient years. In rituximab/rituximab treatment group, the most frequently reported serious infection was pneumonia, with an incidence of 4%.

Malignant tumor:
In clinical research, the incidence of malignant tumor in patients treated with rituximab and rituximab is 2.05 per 100 patient years. Based on the standard incidence rate, the incidence rate of this malignant tumor is similar to that of AAV population previously reported.

[u]Domestic adverse reactions[/u]
Initially treated diffuse large B-cell non-Hodgkin’s lymphoma
A multicenter, open, randomized, controlled clinical study was conducted in 63 patients with CD20-positive, initially treated diffuse large B-cell non-Hodgkin’s lymphoma (32 cases in the experimental group and 31 cases in the control group). The experimental group was treated with rituximab + standard CHOP chemotherapy, and the control group was treated with standard CHOP chemotherapy. Both groups received 6 courses of treatment. Each course lasted 21 days. In the experimental group, this product was used on the first day of the chemotherapy cycle, with a dose of 375mg/m2 BSA, by intravenous drip. Safety analysis showed that the incidence of adverse reactions in the experimental group and the control group were 51.6% and 50.0%, respectively, with no statistically significant difference. The most common adverse reaction in the experimental group was leukopenia, about 25%, followed by chills and fever, about 20%. Other adverse reactions included nausea, vomiting, elevated transaminases, alopecia, abdominal discomfort, abdominal pain, skin redness (allergy), viral hepatitis B, shortness of breath, dry mouth, tachycardia, chest tightness, dizziness, toothache, and injection site reactions. One serious adverse reaction was death due to liver failure. The patient had a history of hepatitis, and the investigators believed that the adverse event was related to chemotherapy and not to rituximab. After 4 courses of treatment, the severity of laboratory tests turning abnormal (NCIC CTC grade) in the two groups was compared, and there was no statistically significant difference.

[u] Post-marketing experience [/u]
Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
The (rare, very rare) incidences reported in this section are based on estimated market sales and spontaneous reporting data. During the post-marketing use of rituximab, additional serious cases related to intravenous administration have been reported (see [Precautions])

As part of the ongoing post-marketing monitoring of rituximab safety, the following serious adverse reactions have been observed:

Cardiovascular system
Serious cardiac events such as heart failure and myocardial infarction have been observed mainly in patients with a history of heart disease and/or receiving cardiotoxic chemotherapy, most of which were accompanied by infusion-related reactions. Vasculitis, very rare, mainly cutaneous vasculitis, such as leukocytoclastic vasculitis.

Respiratory system
Rare respiratory failure/respiratory insufficiency and pulmonary infiltration, see infusion-related reactions (see [Precautions]). In addition to infusion-related lung disease, interstitial lung disease (some with fatal consequences) has also been reported.

Blood and lymphatic system:
Acute reversible thrombocytopenia associated with infusion has been reported.

Skin and appendages
Rare severe bullous skin reactions, including fatal case reports of toxic epidermal necrolysis.

Central spermatic system
Reversible posterior encephalopathy syndrome (PRES) and reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms include visual impairment, headache, seizures, and altered spermatic status with or without associated hypertension. Diagnosis of PRES/RPLS requires confirmation by brain imaging. Reported cases have identified risk factors for PRES/RPLS, including underlying patient disease, hypertension, immunosuppressive therapy, and/or chemotherapy.

Rare cranial spermatic lesions with or without peripheral spermatic lesions. Signs and symptoms of cranial spermatic lesions, such as severe visual loss, hearing loss, other sensory loss, and facial paralysis, occur at varying times and up to several months after the end of rituximab treatment. Global serum sickness-like reactions have been rarely reported.

Infections and infestations
Cases of hepatitis B reactivation, including fulminant hepatitis, have been reported in patients receiving rituximab and cytostatic chemotherapy (see [Precautions]). Other serious viral infections have been reported with rituximab, including new infections, reactivation, or exacerbations, some of which were fatal. Most patients were treated with rituximab in combination with chemotherapy or as part of hematopoietic stem cell transplantation. These serious viral infections can be caused by herpes viruses (CMV, varicella-zoster virus, and herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML) see [Precautions]), and hepatitis C virus.

Kaposi’s tumor progression has been observed in patients with a history of Kaposi’s tumor after taking rituximab. These cases were observed in unapproved indications, and most patients were HIV positive.

Gastrointestinal tract
Gastrointestinal perforation, in some cases leading to death, has been observed in patients with non-Hodgkin lymphoma receiving rituximab in combination with chemotherapy.

Rheumatoid arthritis
In addition to adverse reactions seen in clinical trials of rituximab for the treatment of rheumatoid arthritis (see Adverse Reactions – Rheumatoid arthritis), progressive multifocal leukoencephalopathy (PML), serum sickness-like reactions, and hepatitis B recurrence have been reported in postmarketing experience. Serious infusion-related reactions resulting in fatalities have been reported in postmarketing use (see Clinical Trials).

[u]Laboratory Abnormalities[/u]
Non-Hodgkin’s Lymphoma
Hematologic and Lymphatic System:
Neutropenia: Neutropenia is rare four weeks after the last infusion of rituximab.

Post-Marketing Studies:
In post-marketing studies of rituximab in patients with Waldenstrom’s macroglobulinemia, transient increases in serum IgM levels were observed after the start of treatment, which may be related to hyperviscosity and related symptoms. Transiently elevated IgM levels usually return to baseline levels within 4 months.

[Contraindications]
Patients with Non-Hodgkin’s Lymphoma
Rituximab is contraindicated in patients with known hypersensitivity to any component of this drug and mouse protein.
Patients with Rheumatoid Arthritis
Rituximab is contraindicated in patients with hypersensitivity to the active ingredient or any excipients in the prescription.
Patients with severe active infection or severe impairment of immune response (such as hypoglycemia, severe decrease in CD4 or CD8 cell counts) should not be treated with rituximab (see [Precautions]).
Similarly, patients with severe heart failure (NYHA Class IV) should not be treated with rituximab.
Rituximab is contraindicated in combination with methotrexate during pregnancy.

[Use in Pregnant Women]
Pregnancy
IgG is known to cross the placental barrier.
Developmental toxicity studies in macaques did not find evidence of intrauterine embryotoxicity with rituximab treatment. In studies, it was observed that newborn offspring of maternal animals exposed to rituximab had a loss of B cell populations in the postnatal period. In human clinical trials, the effects of maternal exposure to rituximab on neonatal B cell levels have not been studied. There are no adequate, well-controlled data from pregnant women, but transient B cell depletion and lymphocytopenia have been reported in newborns born to mothers who have used rituximab during pregnancy. In view of this, rituximab should be contraindicated in pregnant women unless the possible benefits outweigh the risks.
Women of childbearing age should take effective contraceptive measures during and for 12 months after the use of rituximab.
Breastfeeding
It is not known whether rituximab is excreted in breast milk. It is known that maternal IgG can enter breast milk, so rituximab should not be used by breastfeeding mothers.

[Pediatric Use]
The efficacy and safety of rituximab in children have not been established.

[Drug Interactions]
Currently, there is very limited information on the possible interactions between rituximab and other drugs.

When rituximab is co-administered with fludarabine or cyclophosphamide in patients with chronic lymphocytic leukemia, rituximab has not been shown to affect the pharmacokinetics of fludarabine or cyclophosphamide; moreover, fludarabine and cyclophosphamide do not have a significant effect on the pharmacokinetics of rituximab.

When rituximab is co-administered with methotrexate in patients with rheumatoid arthritis, the pharmacokinetics of rituximab are not affected by methotrexate.

Patients with human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA) titers may experience allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

In clinical trials for rheumatoid arthritis, 373 patients treated with rituximab were subsequently treated with other disease-modifying antirheumatic drugs (DMARDs), of which 240 were treated with biological DMARDs. The incidence of serious infections in patients treated with rituximab (before treatment with biological DMARDs) was 6.1/100 person-years, while the incidence of serious infections after treatment with biological DMARDs was 4.9/100 person-years.

[Storage] Bottled preparations are stored at 2-8°C. Undiluted bottled preparations should be stored away from light. The prepared injection of this product remains stable at room temperature for 12 hours. If the prepared solution cannot be used immediately, it can be stored in a refrigerator (2-8°C) for 24 hours without being affected by room temperature. Since this product does not contain antimicrobial preservatives, it is very important to keep the prepared solution sterile.
Do not use after the expiration date on the drug packaging.

[Manufacturer]
Hofmeyer-La Roche GmbH