What Factors Affect a Sufficient Rituximab Dose?

Rituximab injection, indication for this product is suitable for: relapsed or resistant follicular central lymphoma (B-cell non-Hodgkin's lymphoma of subclasses B, C and D) treatment. Patients with previously untreated CD20-positive stage III-IV follicular non-Hodgkin's lymphoma should be treated with 8 cycles of standard CVP chemotherapy (cyclophosphamide, vincristine, and prednisone). CD20-positive diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) should be combined with 8 cycles of standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab injection, indication for this product is suitable for: relapsed or resistant follicular central lymphoma (B-cell non-Hodgkin's lymphoma of subclasses B, C and D) treatment. Patients with previously untreated CD20-positive stage III-IV follicular non-Hodgkin's lymphoma should be treated with 8 cycles of standard CVP chemotherapy (cyclophosphamide, vincristine, and prednisone). CD20-positive diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) should be combined with 8 cycles of standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone).

Drug Name

Rituximab injection

Drug type

prescription

Use classification

Antitumor gene therapy drugs

Rituximab injection ingredients

The main active ingredients of this product are recombinant rituximab excipients including sodium citrate, polysorbate 80, sodium chloride and water for injection.

Rituximab injection properties

Clear to slightly opalescent, colorless or light yellow liquid, no foreign matter, floc and precipitation.

Indications for rituximab injection

This product is suitable for:
Treatment of relapsed or resistant follicular central lymphoma (B-cell non-Hodgkin lymphoma of the International Working Classification B, C, and D subtypes).
Patients with previously untreated CD20-positive stage III-IV follicular non-Hodgkin's lymphoma should be treated with 8 cycles of standard CVP chemotherapy (cyclophosphamide, vincristine, and prednisone).
CD20-positive diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) should be combined with 8 cycles of standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab injection specifications

100 mg / 10 ml; 500 mg / 50 ml.

Dosage and Administration of Rituximab Injection

Directions and instructions for use Extract the required dose of rituximab under sterile conditions, place it in a sterile non-pyrogenic infusion bag containing 0.9% physiological saline or 5% glucose solution and dilute to rituximab The concentration is 1mg / ml. Gently invert the injection bag to mix the solution and avoid foaming. As this product does not contain antimicrobial preservatives or bacteriostatic agents, the sterility technique must be checked. Before intravenous use, observe the injection for particles or discoloration.
Rituximab is diluted for intravenous infusion through a separate infusion tube that is not mixed with other drugs, and is suitable for the treatment of ambulatory patients.
Rituximab treatment should be performed in a ward with a complete resuscitation facility 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 for cytokine release syndrome (see [Cautions]). For patients with severe reactions, especially those with severe breathing difficulties, bronchospasm and hypoxemia, the infusion should be stopped immediately. Patients should also be evaluated for tumor lysis syndrome, for example, by appropriate laboratory tests. Patients with pre-existing pulmonary insufficiency or tumor lung invasion must undergo chest X-rays. The drip should not be continued until all symptoms have disappeared and laboratory tests have returned to normal. At this time, the drip rate cannot exceed half of the original drip rate. If the same serious adverse reactions occur again, drug withdrawal should be considered.
Rituximab must not be injected intravenously without dilution, and the prepared injection solution cannot be used for intravenous bolus injection.
Follicular non-Hodgkin's lymphoma < br Before each infusion of rituximab, antipyretic analgesics (such as paracetamol) and antihistamines (such as diphenhydramine) should be used beforehand. Glucocorticoids should also be used beforehand, especially if the treatment regimen used does not include corticosteroids.
Initial treatment as a single treatment for adult patients, the recommended dose is 375 mg / m ² BSA (body surface area), intravenous administration, once a week, a total of 4 times in a 22-day course of treatment.
When combined with CVP chemotherapy, the recommended dose of rituximab is 375 mg / m ² BSA for 8 consecutive cycles (21 days / cycle). Corticosteroids are given orally each time and then on the first day of the chemotherapy cycle.
Retreatment after relapse In patients who relapse after the first treatment, the retreatment dose is 375 mg / m ² BSA, intravenous drip for 4 weeks, once a week (see [Clinical Trials], once a week for 4 weeks).

Diffuse large B-cell non-Hodgkin's lymphoma < br Antipyretic analgesics (such as paracetamol) and antihistamines (such as diphenhydramine) should be used before each infusion of rituximab. Glucocorticoids should also be used beforehand, especially if the treatment regimen used does not include corticosteroids.
Rituximab should be used in combination with CHOP chemotherapy. The recommended dose is 375 mg / m ² BSA and is used on the first day of each chemotherapy cycle. The other components of chemotherapy should be used after the application of rituximab.
It is recommended that the initial infusion rate be 50 mg / h for the first infusion; after the first 60 minutes, 50 mg / h can be increased every 30 minutes until the maximum rate is 400 mg / h.
The subsequent infusion of rituximab may start at a rate of 100 mg / h, increase by 100 mg / h every 30 minutes, and reach a maximum rate of 400 mg / h.
Dosage adjustments during treatment are not recommended for rituximab reduction. When rituximab is used in combination with standard chemotherapy, the standard chemotherapy dose can be reduced.

Adverse reactions of rituximab injection

[u] Adverse reactions abroad [/ u]

Hematological tumor clinical trial experience < br The incidence of adverse reactions (ADRs) of rituximab alone or in combination with chemotherapy is shown in the table below. The data comes from clinical trials. Include single-group studies of adverse reactions or adverse reactions that occurred in at least 2% of the experimental group compared to the control group in at least one major randomized clinical trial. They are reasonably classified according to the highest incidence of adverse reactions in any major clinical trial, as detailed in the table below. The adverse reactions of each group were ranked in descending order of severity. The incidence is defined as: very common, ³1 / 10; common, ³1 / 100-[1/10; uncommon, ³1 / 1000-[1/100.
Rituximab monotherapy / maintenance treatment < br The adverse reactions in Table 1 below are from multiple rituximab monotherapy studies, including 356 patients with low-grade malignant or follicular lymphoma, receiving each Rituximab monotherapy or retreatment once a week (see [Clinical Trials]). The table also includes data on 671 patients with follicular lymphoma who received maintenance therapy with rituximab. The patients received induction therapy with R-CHOP, R-CVP, or R-FCM, and continued for 2 years after remission. MAb maintenance therapy (see [Clinical Trials]). Adverse reactions were reported 12 months after monotherapy or 1 month after maintenance treatment with rituximab.
Table 1 Summary of adverse reactions in patients with low-grade or follicular lymphoma who received rituximab monotherapy (N = 356) or rituximab maintenance therapy (N = 671) in clinical trials

The incidence is calculated based on all grades of adverse reactions (from mild to severe), but the incidence of items marked with "+" includes only severe reactions (3 degree NCI common toxicity evaluation criteria). Only the highest incidence of adverse reactions was reported in each clinical trial.
Rituximab combined with chemotherapy for NHL and CLL
The adverse reactions listed in Table 2 below are from a controlled clinical trial of the rituximab treatment group, which occurred in addition to and / or higher than the adverse reactions observed with rituximab monotherapy / maintenance Rate of adverse reactions: 202 patients with DLBLC receiving R-CHOP, 234 and 162 patients with follicular lymphoma receiving R-CHOP and R-CVP, respectively, and 397 previously untreated CLL Patients and 274 patients with relapsed / refractory CLL who received rituximab combined with fludarabine and cyclophosphamide (R-FC) (see [Clinical Trials]).
Table 2 DLBCL patients (N = 202) and follicular lymphoma patients (N = 234) who received the R-CHOP regimen, follicular lymphoma patients (N = 162) who received the R-CVP regimen, and R Summary of severe adverse reactions in previously untreated CLL patients (N = 397) or relapsed / refractory CLL patients (N = 274) treated with the -FC regimen

* Including primary and recurrent infections, incidence rates are calculated from severe adverse reactions (defined as 3 degrees NCI common toxicity criteria) from relapsed / refractory CLL patients treated with the R-FC regimen
Only the adverse reactions with the highest incidence in each clinical trial are reported in the rituximab group compared with the control group. The incidence of adverse reactions is similar (the difference between groups is less than [2%) or lower. Reported adverse events: hematological toxicity, Infection due to neutropenia, urinary tract infection, septic shock, secondary lung infection, graft infection, staphylococcal septicemia, lung infection, rhinorrhea, pulmonary edema, heart failure, sensory disturbance , Venous thrombosis, mucosal inflammation, cold-like symptoms, lower extremity edema, abnormal ejection fraction, fever, deterioration of general physical condition, low mood, multiple organ failure, lower extremity deep vein thrombosis, positive blood culture, and poor control of diabetes.
The safety of rituximab combined with other chemotherapy regimens (such as: MCP, CHVP-IFN) is comparable to the safety of rituximab combined with CVP, CHOP, or FC in the same patient population.
Details of some serious adverse reactions < br Infusion- related reactions < br Signs and symptoms of infusion-related reactions were reported in more than 50% of patients in clinical trials with monotherapy-4 weeks of treatment, mainly in Occurs on the first infusion. Hypotension, fever, chills, chills, urticaria, bronchospasm, swelling of the tongue or throat (angioedema), nausea, fatigue, headache, itching, dyspnea, rhinitis, vomiting, facial flushing, and pain in the affected area, etc. It is related to rituximab infusion and belongs to infusion-related syndrome.
Combined therapy (NHL adopts R-CVP scheme; DLBCL adopts R-CHOP scheme; CLL adopts R-FC scheme)
During the treatment with rituximab combined with chemotherapy drugs, 12% of patients experienced severe infusion-related reactions during the first course, and the incidence of infusion-related reactions was significantly reduced in the subsequent courses. The rate is below 1%. Other reported reactions were indigestion, rash, hypertension, tachycardia, and tumor lysis syndrome. Individual cases have also reported myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia.
Infections < br Monotherapy-4 weeks of treatment with rituximab resulted in B-cell depletion in 70% -80% of patients, and only a few patients had a decrease in plasma immunoglobulin. Regardless of the causality, 30.3% of the 356 patients developed bacterial, viral, fungal, and unknown infections. Serious infections (3/4 degree) occurred in 3.9% of patients, including sepsis.
2 years of maintenance treatment (NHL)
Meriva / rituximab treatment observed higher overall infections, including grade 3-4 infections. No accumulated infectious toxicity during 2 years of maintenance treatment.
Data from clinical trials include fatal progressive multiple white matter disease in patients with non-Hodgkin's lymphoma, which occurs after disease progression and repeated treatments (see [Notes]).
No increase in the frequency of infection or infection was observed with the combination therapy (NH- RVP-CVP regimen; DLBCL R-CHOP regimen; CLL R-FC regimen). The most common infection is upper respiratory tract infection, with an incidence of 12.3% in the R-CVP group and 16.4% in the CVP group. The incidence of severe infections in the R-CVP treatment group was 4.3% and in the CVP group 4.4%. No life-threatening infections were reported.
In the R-CHOP study, the overall incidence of grade 2-4 infection was 45.5% in the R-CHOP treatment group and 42.3% in the CHOP group. R-CHOP group had a higher incidence of 2-4 degree fungal infections (4.5% of R-CHOP group vs 2.6% of CHOP group); this difference was due to a higher incidence of local Candida infections during treatment. The incidence of shingles of grade 2-4 in the R-CHOP group (4.5%) was higher than that in the CHOP group (1.5%). The proportion of patients with grade 2-4 infection and / or febrile neutropenia was 55.4% in the R-CHOP group and 51.5% in the CHOP group, respectively.
In CLL patients, the incidence of grade 3 or 4 hepatitis B (primary and recurrent) was 2% and 0% in patients on the R-FC regimen and FC regimen, respectively.
Hematological events < br Severe (3 and 4 degrees) neutropenia was observed in 4.2% of patients treated with monotherapy at 4 weeks, severe anemia was observed in 1.1% of patients, and 1.7% of patients Severe thrombocytopenia was observed.
2 years of maintenance treatment (NHL)
Grade 3-4 leukopenia in the rituximab group (2% Vs in the observation group, 5% in the rituximab group) and neutropenia (4% in the observation group, 10% in the rituximab group) The incidence was higher than that in the observation group. The incidence of grade 3-4 thrombocytopenia was lower in the rituximab group (1% Vs in the observation group [1%] in the rituximab group). It takes 12 months or more for B-cell levels to return to normal levels in nearly half of the patients with B-cell recovery after the end of melova / rituximab induction therapy.
Combination therapy (NH-RVP-CVP regimen; DLBCL R-CHOP regimen; CLL R-FC regimen) In the study of rituximab combined chemotherapy regimen, compared with the chemotherapy regimen alone, 3/4 degree leukopenia was reduced Disease (88% in R-CHOP group, 79% in CHOP group, 23% in R-FC group, 12% in FC group), neutropenia (R-CVP group in previously untreated chronic lymphocytic leukemia 24 %, CVP group 14%, R-CHOP group 97%, CHOP group 88%, R-FC group 30%, FC group 19)). However, the duration of neutropenia was not prolonged in patients receiving rituximab combined with chemotherapy, and its incidence was not related to the high incidence of infection and infection.
There was no correlation between 3-4 grade anemia and thrombocytopenia between the different treatment groups. In clinical studies of first-line treatment of CLL, 4% of patients in the R-FC group and 7% of patients in the FC group reported 3/4 degree anemia; 7% of patients in the R-FC group and 10% of the FC group. The patient reported 3/4 degree thrombocytopenia. In the clinical study of relapsed / refractory CLL, the incidence of adverse events of grade 3/4 grade anemia in the R-FC group was 12% and that of the FC group was 13%; the adverse events of grade 3/4 grade thrombocytopenia in the R-FC group The incidence was 11% and 9% in the FC group.
Cardiovascular events < br Cardiovascular events occurred in 18.8% of patients during monotherapy-4 weeks of treatment. Hypotension and hypertension are the most common events. During rituximab infusion, 3 or 4 degree arrhythmias (including ventricular and supraventricular tachycardia) and angina were reported.
2 years of maintenance treatment (NHL)
The incidence of 3-4 degree heart disease was basically the same in the two groups. [1% of patients in the observation group and 3% of patients in the rituximab group developed the following heart diseases reported as serious adverse events: atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure ([1 %), Myocardial ischemia ([1%).
Combination therapy (NH-L uses R-CVP; DLBCL uses R-CHOP; CLL uses R-FC)
In the R-CHOP trial, the incidence of 3-4 degree arrhythmias was higher in the R-CHOP group (6.9% of patients) than in the CHOP group (1.5% of patients), especially supraventricular arrhythmias (such as tachycardia and atrial Flutter / tremble). All of these arrhythmias occur during the infusion of rituximab 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]) . No other 3 and 4 degree cardiac adverse events (eg, heart failure, cardiomyopathy, and coronary artery disease manifestations) were observed between the R-CHOP and CHOP groups.
The overall incidence of 3 or 4 degree heart disease is low in CLL patients (first-line clinical studies: 4% in the R-FC group and 3% in the FC group; relapsed / refractory clinical studies: R-FC group 4%, FC group 4%).
IgG levels for 2 years of maintenance therapy (NHL)
After induction therapy, the median IgG levels in both the control and rituximab groups were below 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 rituximab treatment. Throughout the 2-year treatment period, the proportion of patients with IgG levels below the lower limit of the normal range was approximately 60% in the rituximab group and decreased in the control group (36% after 2 years).
Severe menstrual system adverse reactions <br /> Combination therapy (NH-RVP-CVP regimen; DLBCL R-CHOP regimen; CLL R-FC regimen) During the first course of treatment, the R-CHOP group is at risk for cardiovascular disease Factor 2% of patients developed thromboembolic cerebrovascular disease. The incidence of other thromboembolic diseases did not differ between the two treatment groups. Cerebrovascular events occurred in 1.5% of patients in the CHOP group, all of which occurred during follow-up.
In CLL patients, the overall incidence of 3rd or 4th degree meningeal systemic diseases is lower (first-line clinical studies: 4% in the R-FC group and 4% in the FC group; relapse / refractory clinical studies: R- FC group is 3%, FC group is 3%).
[u] Special population [/ u]
Monotherapy-4 weeks in elderly patients (65 years)
The incidence of any adverse reactions (88.3% and 92.0%) and grade 3 and 4 adverse reactions (16.0% and 18.1%) was similar between older patients and younger patients.
Combination therapy for elderly patients (65 years)
For previously untreated CLL patients and patients with relapsed / refractory CLL, older patients (³65 years) have a higher incidence of 3/4 degree blood and lymphatic adverse events than younger patients.
Patients with high tumor burden had a higher incidence of grade 3 and 4 adverse reactions (25.6% vs 15.4%) than those without high tumor burden. The incidence of any adverse reactions was similar in both groups (92.3% vs 89.2%).
Re-treatment after relapse is similar to the incidence of any adverse reaction (95.0% Vs 89.7%) and grade 3 and 4 adverse reactions (13.3% Vs 14.8%).
Experience from clinical trials of rheumatoid arthritis. <br /> The safety data of Romexil / Rituximab in patients with moderate to severe rheumatoid arthritis are as follows. In all exposed populations, more than 3,000 patients received at least one cycle of treatment and followed up for 6 months to 5 years. The total exposure level was equivalent to 7198 patient years, and about 2300 patients received during the follow-up period. 2 or more cycles of treatment.
The adverse reactions listed in Table 3 are based on data from four multicenter, amphibian-controlled clinical studies of rheumatoid arthritis. In the above studies, the patient population receiving melovahua / rituximab were different, including patients with early active rheumatoid arthritis who were not treated with methotrexate, patients with inadequate methotrexate, and anti-necrosis factor Ineffective patients.
Patients received 2´1000mg or 2´500mg rituximab (two weeks apart between doses) and methotrexate (10-25mg / week). Table 3 lists all adverse reactions with an incidence of more than 2% in all dose groups and a difference of more than 2% from the control group. The classification of incidence rates in Table 3 and its related footnotes are defined as: very common (incidence 1 / 10), common (1 / 100 to [1/10), and uncommon (³ 1 / 1,000 to [1 / 100).
Table 3 Summary of adverse reactions reported by patients with rheumatoid arthritis in the control phase of clinical trials

Safety data for all exposed populations were consistent with safety data during controlled clinical trials, and no new adverse reaction reports were found.
The characteristics of adverse reactions observed during multi-course treatment were similar to those observed after the first treatment. In subsequent treatment cycles, safety has improved due to the more common infusion-related reactions and exacerbations of rheumatoid arthritis and reduction of infections during the first 6 months.

Further information on adverse drug reactions:
Infusion-related reactions:
In clinical trials, the most common adverse reaction after receiving melovahua / rituximab was an infusion-related reaction. Of the 3,095 patients treated with melovahua / rituximab, 1077 (35%) patients had at least one infusion-related reaction. Most infusion-related reactions are CTC 1 or 2 events. In clinical studies, less than 1% of RA patients (14/3095 patients) experienced severe infusion-related reactions with each dose of melovahua / rituximab infusion. There were no CTC grade 4 infusion-related response events or infusion-related reaction-causing deaths in clinical studies (see post-marketing use experience). The percentage of CTC Grade 3 events and infusion-related response events that led to patient withdrawal decreases with increasing treatment cycles, and these events are less common after the third treatment cycle.
After the first use of rituximab in 3095 patients, 720 patients (23%) observed symptoms and signs of acute infusion reactions (nausea, pruritus, fever, rubella / rash, chills, fever, Chills, sneezing, angiosperm edema, throat irritation, cough, and bronchospasm, with or without hypotension or hypertension associated with medication). Intravenous administration of glucocorticoids before treatment significantly reduced the incidence and severity of these events (see [Contraindications] and [Cautions] for rheumatoid arthritis).
Infection In patients treated with merovawa / rituximab, the overall infection rate is approximately 97/100 person-years. Most infections are mild to moderate, and include upper respiratory and urinary tract infections. The incidence of severe infections is about 4/100 person-years, some of which are fatal. In addition to the adverse reactions listed in Table 3, medically serious adverse events include pneumonia, which has a incidence of 1.9%.
Malignant tumors In clinical studies, the incidence of malignant tumors was 0.8 / 100 person-years after treatment with merovawa / rituximab, which was within the expected range of age- and sex-matched populations.
ANCA-associated vasculitis (AAV) clinical trial experience < br In the AAV clinical study, 99 patients were treated with merovawa / rituximab (375 mg / m2, once a week, 4 weeks) and glucocorticoids ( (For more information, see [Clinical Trials]) Treatment. The adverse reactions listed in Table 4 are all adverse events with a incidence of 10% in the melovahua / rituximab treatment group. The frequency of occurrence 1 / 10 in Table 4 is defined as very common.
Table 4 Incidences of very common (10%) adverse reactions in patients with AAV treated with merovawa / rituximab in a 6-month clinical study *

* Study design allows patients to receive cross-treatment or choose a treatment option based on medical judgment. Thirteen patients in each treatment group received another treatment during the 6-month study period.
a The most common infections in the rituximab group include upper respiratory infections, urinary tract infections, and shingles.
b The most common infusion-related reactions reported in the rituximab group were cytokine release syndrome, facial flushing, throat irritation, and tremor.
Further information on adverse drug reactions < br Infusion- related reactions:
An infusion-related response in the AAV clinical study was defined as any adverse event that occurred within 24 hours of infusion in a safety population, and the investigator considered this event to be related to the infusion. Ninety-five patients were treated with merovawa / rituximab, of which 12% experienced at least one infusion-related response. All infusion-related reactions were Grade 1 or Grade 2 CTC. The most common infusion-related reactions include cytokine release syndrome, facial flushing, throat irritation, and tremor. Merova / Rituximab combined with intravenous glucocorticoids may reduce the incidence and severity of these events.
infection:
In 99 patients who received merovawa / rituximab, the overall infection rate was approximately 210 per 100 patient years (95% CI173-256). The infections are mainly mild and moderate, with the majority of upper respiratory tract infections, shingles and urinary tract infections. The incidence of severe infections is approximately 25 per 100 patient years. The most frequently reported severe infection in the melanovir / rituximab-treated group was pneumonia, with an incidence of 4%.
Malignant tumor:
In the clinical study of patients treated with melovahua / rituximab, the incidence of malignancy was 2.05 per 100 patient years. Based on the standard incidence, the incidence of this malignancy is similar to that reported in the previously reported AAV population.
[u] Domestic adverse reactions [/ u]
Diffuse large B-cell non-Hodgkin's lymphoma newly diagnosed <br A domestic multicenter, open, randomized, controlled clinical study of 63 cases of newly treated diffuse large B-cell non-Hodgkin's disease with CD20 positive Lymphoma patients were performed (32 patients in the test group and 31 patients in the control group). The test group was rituximab + standard CHOP chemotherapy, and the control group was standard CHOP chemotherapy. Both groups were treated for 6 courses. 21 days per course. In the test group, this product was used on the first day of the chemotherapy cycle with a dose of 375 mg / m2 BSA and intravenous drip. Safety analysis showed that the incidence of adverse reactions in the test group and the control group was 51.6% and 50.0%, respectively, and the difference was not statistically significant. Leukopenia was the most common adverse reaction in the test group, about 25%, followed by chills and fever, about 20%. Other adverse reactions include nausea, vomiting, elevated transaminase, hair loss, abdominal discomfort, abdominal pain, redness of the skin (allergies), viral hepatitis B, shortness of breath, dry mouth, tachycardia, chest tightness, dizziness, toothache, and injection site reactions. This included one severe adverse event, which resulted in death from liver failure. The patient had a history of hepatitis and the investigators believed that adverse events were related to chemotherapy and not to rituximab. After 4 courses of treatment, the severity of the abnormalities (NCIC CTC grade) of laboratory tests in the two groups was compared, and the difference was not statistically significant.
[u] Use experience after listing [/ u]
Non-Hodgkin's lymphoma and chronic lymphocytic leukemia < br The (rare, very rare) rates reported in this section are based on estimated market sales and spontaneous reporting data. During the post-marketing use of rituximab, other severe cases related to intravenous infusion have been reported (see [Precautions])
As part of the ongoing monitoring of rituximab safety after marketing, the following serious adverse reactions have been observed:
The cardiovascular system has observed severe cardiac events such as heart failure and myocardial infarction in patients with a previous history of heart disease and / or the use of cardiotoxic chemotherapy, most of which are associated with infusion-related reactions. Vasculitis, which is very rare, is mainly cutaneous vasculitis, such as leukocyte fragmenting vasculitis.
Rare respiratory failure / respiratory insufficiency and pulmonary infiltration in the respiratory system See infusion-related reactions (see [Cautions]). In addition to infusion-related lung disease, interstitial lung disease (with some fatal consequences) has also been reported.
Blood and lymphatic system:
Acute reversible thrombocytopenia related to infusion has been reported.
Case reports of severe severe bullous skin reactions in the skin and accessories, including fatal toxic epidermal necrolysis.
The central semen system has reported reversible posterior encephalopathy syndrome (PRES) and reversible posterior leukoencephalopathy syndrome (RPLS). Signs and symptoms include vision impairment with or without associated hypertension, headaches, epilepsy, and changes in spermatozoa. Diagnosis of PRES / RPLS requires confirmation by brain imaging. Reported cases have identified risk factors for PRES / RPLS, including patient underlying disease, hypertension, immunosuppressive therapy, and / or chemotherapy.
Cranial seminal menstrual lesions with or without peripheral seminal menstrual lesions are rare. Symptoms and signs of craniocerebral meningeal lesions occur at different times or even months after the end of rituximab treatment, such as severe vision loss, hearing loss, other sensory loss and facial paralysis. Overall serum disease-like reactions are rarely reported.
Infection and Infection In patients receiving chemotherapy with rituximab and cell proliferation inhibitors, cases of hepatitis B reactivation have been reported, including fulminant hepatitis (see [Precautions]). Other serious viral infections have been reported during treatment with rituximab, including new infections, reactivation, or exacerbations, some of which are fatal. Most patients are receiving chemotherapy with rituximab or as part of a hematopoietic stem cell transplant. These severe viral infections can be caused by herpes virus (cytomegalovirus CMV, varicella-zoster virus, and herpes simplex virus), JC virus (see [Precautions] for progressive multifocal leukoencephalopathy (PML)), and type C Caused by hepatitis virus.
Kaposi's tumor progression has been observed in patients with a history of Kaposi's tumors after using rituximab. These cases were observed in unapproved indications, and most patients were HIV positive.
Gastrointestinal tract In non-Hodgkin's lymphoma patients receiving rituximab combined with chemotherapy, gastrointestinal perforations have been observed, and in some cases even caused death.
Rheumatoid arthritis < br In addition to the adverse reactions seen in clinical trials of rituximab for 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. In post-market use, there have been reports of fatal severe infusion-related reactions (see [Clinical Trials]).
[u] Laboratory anomaly [/ u]
Non-Hodgkin's lymphoma < br Blood and lymphatic system:
Neutropenia: Four weeks after the last infusion of rituximab, neutropenia is rare.
Post-market research:
In a post-marketing study of rituximab in patients with Fahrenheit macroglobulinemia, transient increases in serum IgM levels were observed after treatment initiation, which may be related to high blood viscosity and related symptoms . Transiently elevated IgM levels usually return to baseline levels within 4 months.

Contraindications to rituximab injection

Patients with non-Hodgkin's lymphoma are not allowed to use rituximab in patients who are allergic to any component of the drug and murine protein.
Patients with rheumatoid arthritis who are allergic to the active ingredients or any excipients in the prescription are prohibited.
Patients with severe active infection or severely impaired immune response (such as hypoglycemia, severe decrease in CD4 or CD8 cell counts) should not be treated with rituximab (see [Cautions]).
Similarly, patients with severe heart failure (NYHA Class IV) should not be treated with rituximab.
The combination of rituximab and methotrexate is prohibited during pregnancy.

Precautions for rituximab injection

[u] Patients with non-Hodgkin's lymphoma and patients with chronic lymphocytic leukemia [/ u]
Infusion-Related Reactions <br /> Rituximab can cause infusion reactions, which may be related to the release of cytokines and / or other chemical mediators. Clinically, it may not be possible to distinguish severe infusion reactions from allergic reactions or cytokine release syndrome. In post-market use, fatal severe infusion reactions have been reported. Severe infusion reactions usually occur within 30 minutes to 2 hours after the start of rituximab infusion, and are characterized by the occurrence of pulmonary events. In some cases, in addition to fever, chills, chills, low In addition to blood pressure, rubella, angiospermic edema, and other symptoms, rapid tumor lysis and tumor lysis syndrome symptoms may occur (see [Adverse Reactions]). Patients with a high tumor burden or a high number of peripheral blood malignant cells (] 25 x 109 / L), such as those with CLL and mantle cell lymphoma, may be at greater risk for severe infusion reactions. These symptoms are generally reversible after the infusion is discontinued. Diphenhydramine and acetaminophen are recommended to treat infusion symptoms. In addition, bronchodilators or intravenous saline can be used for treatment. In most cases, after the symptoms have completely resolved, the infusion can be resumed at a slower rate of 50% (for example, from 100 mg / h to 50 mg / h). Most patients with non-fatal infusion reactions can complete the entire course of rituximab treatment. After the symptoms and signs have completely resolved, patients continue to receive treatment and rarely have serious infusion-related reactions. Allergic reactions and other hypersensitivity reactions have been reported after intravenous administration of protein to patients. When rituximab-related hypersensitivity occurs, epinephrine, antihistamines, and glucocorticoids should be used immediately.
Patients with high peripheral blood malignant tumor cells (> 25 x 10 ⁹ / L) or high tumor burden, such as patients with CLL and mantle cell lymphoma, have a relatively high risk of serious infusion-related reactions and should be treated with extreme caution. The patient should be closely observed when the first infusion is performed. When this type of patient is infused for the first time, it is necessary to consider whether to slow down the infusion rate, or to divide one dose into two in the first treatment cycle and complete the administration within two days. If the number of lymphocytes is still greater than 25 x 10 ⁹ / L, it should still be administered in this way in subsequent treatment cycles.
Pulmonary events < br 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, symptoms may worsen over time. In other cases, the initial improvement may be followed by a deterioration in clinical conditions. Therefore, patients with pulmonary events or other severe infusion symptoms should be closely monitored until their symptoms have completely resolved. Patients with a history of pulmonary insufficiency or lung tumor invasion are at greater risk of adverse outcomes, and physicians should exercise caution when treating them. It can be observed on chest X-rays that acute respiratory failure may be accompanied by pulmonary interstitial invasive lesions or edema. This symptom usually appears within 1 or 2 hours after the start of the first infusion. Patients with severe pulmonary events should immediately discontinue the infusion (see [Dosage and Administration]) and actively treat it symptomatically.
Rapid tumor lysis <br /> Rituximab can mediate rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms consistent with tumor lysis syndrome (TLS) (such as hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatase, etc.) have been reported in patients with high numbers of peripheral blood malignant lymphocytes Anemia, acute renal failure, elevated LDH levels). For patients at high risk (for example, patients with high tumor burden or high numbers of peripheral blood malignant cells (] 25 x 109 / L), such as those with CLL and mantle cell lymphoma), the prevention of TLS should be considered. With rituximab, these patients should be closely and appropriately monitored in the laboratory. Patients with rapid tumor lysis signs and symptoms should be given appropriate medical treatment. In some cases, after treatment of signs and symptoms and complete remission, rituximab treatment can be continued with concurrent TLS prophylaxis.
Patients should be treated with rituximab infusion in a fully equipped and readily available resuscitation environment and under the close supervision of an experienced oncologist / hematologist.
Cardiovascular < br Because hypotension may occur during rituximab infusion, antihypertensive drugs should be considered discontinued 12 hours before and during rituximab infusion . In patients treated with rituximab, events such as 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 test < br While rituximab is not myelosuppressive in a single treatment, rituximab is being considered for neutrophil counts [1.5 x 109 / L and / or platelets Care should be taken when treating patients with [75 x 109 / L] because of limited clinical experience accumulated in such patients. Rituximab has been used in autologous bone marrow transplantation and other populations who may be at risk of weakened bone marrow function, without causing bone marrow toxicity.
In adopting rituximab as a monotherapy, the need to regularly check the whole blood count, including the platelet count, should be considered. When combining rituximab with CHOP or CVP chemotherapy, a full blood count test should be performed on a regular basis in accordance with medical practice.
Infections < br Rituximab should not be used to treat patients who also have severe active infections.
Hepatitis B virus infection < br In patients taking rituximab, some cases reported reactivation of hepatitis B virus (HBV), including fulminant hepatitis (some cases are fatal), although Most subjects were also exposed to cytotoxic chemotherapy. Potential disease states and cytotoxic chemotherapy are mixed with reported events. For patients at high risk for hepatitis B, screening for hepatitis B virus (HBV) should be considered before commencing rituximab treatment. Carriers of hepatitis B virus and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory indicators of active HBV infection during and within months of treatment with rituximab.
Progressive multiple leukoencephalopathy < br In clinical applications, rituximab is used in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia to develop progressive multiple leukoencephalopathy (PML ) (See [Adverse Reactions]). Most patients are given rituximab in combination with chemotherapeutics or as a treatment during hematopoietic stem cell transplantation. Therefore, when treating patients with non-Hodgkin's lymphoma and patients with chronic lymphocytic leukemia, PML should be considered in the differential diagnosis of patients who report symptoms of meridian classics, and consult a doctor of seminal medicine according to clinical needs.
Immunization < br The safety of immunization with live virus vaccines after treatment with rituximab has not been studied. The use of live virus vaccines is not recommended.
Patients treated with rituximab can receive non-live vaccines, but the response rate to non-live vaccines may decline. In a non-randomized clinical study, patients with relapsed low-grade malignant NHL who received rituximab monotherapy compared with healthy volunteers in the untreated control group with tetanus recall antigen and keyhole limpet blue The response rate of immunization with KLH neoantigen was lower, which was 16% vs 81% and 4% vs 69% (evaluated by a 2-fold increase in antibody titer).
Prior to treatment, patients' average antibody titers to multiple antigens (streptococcus pneumoniae, influenza A, mumps, rubella, and chicken pox) were maintained for at least 6 months after treatment with rituximab.
[u] Patients with rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) [/ u]
With the exception of rheumatoid arthritis and ANCA-associated vasculitis, the effectiveness and safety of merovawa / rituximab for the treatment of autoimmune diseases is unknown.
Infusion-Related Responses <br /> The rituximab / melovarian-related infusion responses may be related to the release of cytokines and / or other chemical mediators. Antipyretic analgesics and antihistamines should be used before each infusion of rituximab. For patients with RA, to reduce the frequency and severity of infusion-related reactions, glucocorticoids should be used before each infusion of rituximab.
For patients with RA, most infusion-related reactions reported in most clinical trials were mild to moderate. In post-market use, lethal severe infusion-related reactions have been reported (see [Adverse Reactions]). Closely monitor patients with previous heart disease and previous cardiopulmonary adverse reactions. The most common symptoms include headache, itching, throat irritation, flushing, rash, urticaria, high blood pressure and fever. In general, the incidence of infusion-related reactions during the first infusion is higher in any treatment cycle than in the second infusion. Patients were better tolerated compared with the first infusion and subsequent administration of melovahua / rituximab. Serious infusion-related reactions occur in less than 1% of patients, most of which occur during the first infusion in the first treatment cycle (see [Adverse Reactions]). When the rituximab infusion is slowed or discontinued or antipyretics and antihistamines are reported, the response generally subsides, and for individual diseases such as oxygen inhalation, intravenous saline solution or bronchodilators, and Corticosteroids. Temporarily or permanently discontinue rituximab depending on the severity of the infusion-related response and the interventions required. In most cases, the infusion can be continued by reducing the infusion rate by 50% (eg, from 100 mg / h to 50 mg / h) when the symptoms and signs have completely subsided.
Allergic reactions and other hypersensitivity reactions have been reported in patients beginning, during and after intravenous administration of protein. Drugs used to treat hypersensitivity reactions (such as epinephrine, antihistamines, and corticosteroids) should be prepared for rapid use in allergic reaction events that occur during rituximab infusion.
Infusion-related reactions in patients with AAV in clinical trials were similar to those observed in patients with RA (see Adverse Reactions). For patients with AAV, rituximab combined with high-dose glucocorticoid therapy may reduce the incidence and severity of such events.
Cardiovascular < br Hypotension may occur during rituximab infusion, so antihypertensive drugs should not be used within 12 hours of rituximab infusion. Administration of rituximab in patients with non-Hodgkin's lymphoma can exacerbate 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 reactions before starting treatment with rituximab, and such patients should be closely monitored during rituximab administration.
Infections < br Treatment with rituximab may increase the risk of infection (see [Contraindications]). Patients with an active infection or severely impaired immune response, such as a severe decrease in CD4 or CD8 cell counts, should not use rituximab. Rituximab should be used with caution in patients with a history of recurrent or chronic infections, or in underlying diseases that are prone to severe infections (see [Adverse Reactions]). Patients who develop infections after treatment with rituximab should be studied immediately and treated appropriately.
Relapses of hepatitis B have been reported in RA and AAV patients treated with melovahua / rituximab.
Progressive multifocal leukoencephalopathy <br /> Severe progressive multifocal leukoencephalopathy (PML) has been reported when rituximab is used in autoimmune diseases, including rheumatoid arthritis. Several of the reported cases, but not all, have potential PML-related risk factors, including underlying disease and receiving long-term immunosuppressive therapy or chemotherapy. The occurrence of PML has also been reported in patients with autoimmune diseases not treated with rituximab. When treating patients with autoimmune diseases, doctors should consider PML in the differential diagnosis of patients with reports of menopausal symptoms, and consult a menopause doctor as needed.
Immunity < br The safety of immunizing live virus vaccines after rituximab treatment has not been studied. For patients receiving rituximab or peripheral B cell failure, a live virus vaccine is not recommended for vaccination. Patients treated with rituximab can receive non-live vaccines, but the response rate to non-live vaccines may decline.
For RA patients, physicians should review the patient's immune status before following rituximab treatment and follow the current version of the Immunization Guidelines. Immunizations should be performed at least 4 weeks before the first dose of rituximab.
In a randomized clinical study, patients with rheumatoid arthritis treated with rituximab combined with methotrexate compared to patients with rheumatoid arthritis treated with methotrexate only for tetanus recall antigen The response rate was similar (39% vs 42%), the response rate to the pneumococcal polysaccharide vaccine (the response rate to at least two pneumococcal antibody serotypes was 43% vs 82%), and the response rate to the KLH neoantigen (47% vs. 93%), patients were vaccinated for at least 6 months after receiving the first dose of rituximab. If a patient needs to receive a non-live vaccine while receiving rituximab, then the vaccination must be completed at least 4 weeks before the start of the next course of rituximab treatment.
Based on overall experience, the proportion of patients with RA who have positive antibody titers to Streptococcus pneumoniae, influenza, mumps, rubella, chicken pox and tetanus toxin after repeated treatment with rituximab for more than one year The proportion of patients at baseline was basically similar.
Patients with RA initially treated with methotrexate (MTX) <br /> Rituximab is not recommended for patients with initial methotrexate treatment because of a good benefit-risk relationship that has not been established.
[u] Incompatibility: [/ u]
No incompatibilities were observed between rituximab and polyvinyl chloride or polyethylene bags or infusion sets.
[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 aforementioned adverse effects have not been shown in pharmacological properties and adverse reactions reported to date. To avoid pre-administration of infusion reactions (antihistamines), treatment of these infusion reactions should be kept in mind. After the infusion reaction, the patient should not drive or operate the machine until the condition is stable.

Rituximab injection for pregnant and lactating women

Immunoglobulin IgG is known to pass through the placental barrier during pregnancy.
Developmental toxicity studies in cynomolgus monkeys have found no evidence of uterine embryo toxicity in rituximab treatment. In the study, it was observed that when the mother animal was exposed to rituximab, its newborn offspring showed a loss of B cell population in the postnatal period. In human clinical trials, the effect of maternal exposure to rituximab on neonatal B-cell levels has not been studied. Data from adequate, well-controlled studies in pregnant women are not yet available, but transient B-cell depletion and lymphopenia have been reported in newborns born to mothers who have used rituximab during pregnancy. For this reason, pregnant women should disable rituximab unless the possible benefits outweigh the risks.
Women of childbearing age should take effective contraception during the use of rituximab and 12 months after treatment.
Breastfeeding is unclear whether rituximab is excreted in milk. Maternal IgG is known to enter milk, so rituximab should not be used in nursing mothers.

Rituximab injection for children

The effectiveness and safety of rituximab in children has not been determined.

Rituximab injection for the elderly

Elderly patients have been included in foreign and domestic clinical studies. The results suggest that this product can be used in elderly patients without special contraindications. For details, please refer to the content under [Pharmacology and Toxicology].

Drug interactions of rituximab injection

Information on the possible interactions between rituximab and other drugs is limited.
Rituximab did not show an effect on the pharmacokinetics of fludarabine or cyclophosphamide in patients with chronic lymphocytic leukemia in combination with rituximab and fludarabine or cyclophosphamide; Rabin and cyclophosphamide did not significantly affect the pharmacokinetics of rituximab.
When rituximab and methotrexate are combined in patients with rheumatoid arthritis, the pharmacokinetics of rituximab will not be affected by methotrexate.
Patients with human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA) titers may develop allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
In the clinical trial of rheumatoid arthritis, 373 patients treated with rituximab were followed up with other disease-relieving antirheumatic drugs (DMARD), of which 240 were treated with biological DMARD. When patients received rituximab (before treatment with biological DMARD), the incidence of severe infection was 6.1 / 100 person-years, while the incidence of severe infection after receiving biological DMARD was 4.9 / 100 person-years.

Rituximab injection overdose

Clinical trials of rituximab overdose have not been performed in humans. Rituximab in a single dose of more than 1000 mg has not been studied in controlled clinical trials. To date, the highest test dose is 5 g for use in patients with chronic lymphocytic leukemia. No other safety signals were found. In the event of overdose, patients must be discontinued or dosed immediately and monitored closely. The need for regular monitoring of blood cell counts should be considered, and when the patient is in a state of B cell depletion, the risk of infection may be increased.

Pharmacology and toxicology of rituximab injection

Rituximab is a human-mouse chimeric monoclonal antibody that specifically binds to the transmembrane antigen CD20. CD20 antigen is located on the surface of pre-B and mature B lymphocytes, while hematopoietic stem cells, pre-pre-B cells, normal plasma cells, or other normal tissues do not express CD20. More than 95% of B-cell non-Hodgkin's lymphoma cells express CD20 . After antigen-antibody binding, CD20 will not internalize or fall off the cell membrane and enter the surrounding environment. CD20 does not circulate in the plasma as a free antigen, so it is not possible to compete with antibodies in a competitive manner.
After rituximab binds to the CD20 antigen on B cells, it initiates an immune response that mediates B cell lysis. Possible mechanisms of B cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC). After the first infusion of rituximab, peripheral B lymphocyte counts decreased significantly, lower than normal levels, and began to recover after 6 months, usually returning to normal within 12 months after completion of treatment, although some patients may require Longer (see [Clinical Trials]). In patients with rheumatoid arthritis, the duration of B cell depletion in peripheral blood varies. Most patients have received retreatment before the B cells have fully recovered.
Of the 67 patients evaluated with human anti-mouse antibodies (HAMA), all patients were negative. Of the 356 patients with non-Hodgkin's lymphoma who received human anti-chimeric antibody (HACA) evaluation, 4 patients (1.1%) were positive.
In vitro experiments have shown that rituximab can increase the sensitivity of resistant human B lymphoma cell lines to the cytotoxic effects of certain chemotherapeutic drugs.

Storage of rituximab injection

Bottled formulations are stored at 2-8 ° C. Undiluted bottle preparations should be protected from light. The prepared injection of this product is stable for 12 hours at room temperature. If the prepared solution cannot be applied immediately, it can be stored in a refrigerator (2-8 ° C) for 24 hours under the condition of no room temperature. Since this product does not contain antimicrobial preservatives, it is important that the formulated solution remains sterile.
Do not continue to use it after the expiry date on the medicine box.

Rituximab injection packaging

100 mg / 10 ml in glass bottle: 1 bottle / box, 2 bottles / box;
500 mg / 50 ml: 1 bottle / box.

Validity of rituximab injection

30 months.

Rituximab injection standard

JS20080031 ^[1]