Rituxsanbe

Rituximab.

Each vial contains: Rituximab (r-DNA origin) 100 mg and 500 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: Rituximab is a chimeric mouse/human monoclonal antibody that binds specifically to the transmembrane antigen, CD20. This antigen is located on pre-B- and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. The antigen is expressed on >95% of all B-cell non-Hodgkin's Lymphomas (NHLs). Following antibody binding, CD20 does not internalized or shed from the cell membrane into the environmen. CD20 does not circulate in the plasma as a free antigen and, thus, does not compete for antibody binding.
Rituximab binds to the CD20 antigen on B-lymphocytes and initiates immunologic reactions that mediate B-cell lysis. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis. Finally, in vitro studies have demonstrated that Rituximab sensitizes drug-resistant human B-cell lymphoma lines to the cytotoxic effects of some chemotherapeutic agents.
Peripheral B-cell counts declined to levels below normal following the first dose of Rituximab. In patients treated for hematological malignancies, B-cell recovery began within 6 months of treatment generally returning to normal levels within 12 months after completion of therapy, although in some patients this may take longer.
Rituximab Monotherapy: Initial treatment, weekly for 4 doses: In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B-cell NHL received 375 mg/m² of Rituximab as an IV infusion weekly for four doses. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48% (Cl95% 41%-56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months.
In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was < 5 cm versus > 7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration or response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% vs. 43% in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher's exact test) on response to Rituximab.
A statistically significant correlation was noted between response rates and bone marrow involvement. Forty percent of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a step-wise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.
Initial treatment, weekly for 8 doses: In a multi-centre, single-arm study, 37 patients with relapsed or chemoresistant, low grade or follicular B-cell NHL received 375 mg/m² of Rituximab as IV infusion weekly for eight doses. The ORR was 57% (Cl95% 41%-73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).
Initial treatment, bulky disease, weekly for 4 doses: In pooled data from three studies, 39 patients with relapsed or chemoresistant, bulky disease (single lesion ≥10 cm in diameter), low grade or follicular B-cell NHL received 375 mg/m² of Rituximab as IV infusion weekly for four doses. The ORR was 36% (Cl95% 21%-51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).
Re-treatment, weekly for 4 doses: In a multi-center, single-arm study, 58 patients with relapsed or chemorasistant low grade or follicular B-cell NHL, who had achieved an objective clinical response to a prior course of Rituximab were retreated with 375 mg/m² of Rituximab as IV infusion weekly for four doses.
Three of the patients had received two courses of Rituximab before enrollment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 retreatments on study, the ORR was 38% (Cl95% 26%-51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4-26.6). This compares favorably with the TTP achieved after the prior course of Rituximab (12.4 months).
Rituximb in Combination with Chemotherapy: Initial treatment: In an open-label randomized trial, a total of 322 previously untreated patients with follicular lymphoma were randomized to receive either CVP chemotherapy (Cyclophosphamide 750 mg/m², Vincristine 1.4 mg/m² up to a maximum of 2 mg on day 1, and Prednisolone 40 mg/m²/day on days 1-5) every 3 weeks for 8 cycles or Rituximab 375 mg/m² in combination with CVP (R-CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analyzed for efficacy.
The median follow-up of patients was 53 months. R-CVP led lo a significant benefit over CVP for the primary end-point, time to treatment failure (27 months vs 6.6 months, p< 0.0001, log-rank test). The proportion of patients with a tumor response (CR, CRu, PR) was significantly higher (p <0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test). The difference between the treatment groups with respect to overall survival showed a strong clinical benefit (p=0.029, log-rank test stratified by center): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group.
Results from three other randomized trials using Rituximab in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/lnterferon-α) also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key results from all four studies are summarized in Table 1 as follows. See Table 1.


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Rituximab Maintenance Therapy: Previously untreated follicular NHL: In a prospective, open label, international, multi-centre, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), RCVP (n=268) or R-FCM (n=44), according to the investigators choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomized to Rituximab IV maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. Rituximab maintenance treatment consisted of a single infusion of Rituximab at 375 mg/m² BSA given every 2 months until disease progression or for a maximum period of two years.
After a median observation time of 25 months for randomization, maintenance therapy with Rituximab resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to no maintenance therapy in patients with previously untreated follicular NHL (Table 2). This improvement in PFS was confirmed by an independent review committee IRC) (see Table 2 as follows).
Significant benefit from maintenance treatment with Rituximab was also seen for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy (TNCT) and overall response rate (ORR) (see Table 2 as follows). See Table 2.


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Rituximab maintenance treatment provided consistent benefit in all subgroups tested: gender (male, female), age (< 60 years, ≥60 years), FLIPI score (1, 2 or 3), induction therapy (R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR or PR).
Relapsed/Refractory follicular NHL: In a prospective, open label, international, multicenter, phase III trial, 465 patients with relapsed/refractory follicular NHL were randomized in a first step to induction therapy with either CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone; n=231) or Rituximab plus CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline characteristics and disease status. A total of 334 patients achieving a complete or partial remission.
Following induction therapy were randomized in a second step to Rituximab maintenance therapy (n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single infusion of Rituximab at 375 mg/m² BSA given every 3 months until disease progression or for a maximum period of two years.
The final efficacy analysis included all patients randomized to both parts of the study. After a median observation time of 31 months for patients randomized to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular NHL when compared to CHOP (see Table 3 as follows). See Table 3.


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For patients randomized to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomization. Maintenance treatment with Rituximab led to a clinically relevant and statistically significant improvement in the primary end-point, PFS, (time from maintenance randomization to relapse, disease progression or death) when compared to observation alone (p< 0.0001 log-rank test). The median PFS was 42.2 months in the Rituximab maintenance arm compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of experiencing progressive disease or death was reduced by 61% with Rituximab maintenance treatment when compared to observation (95% Cl; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78% in the Rituximab maintenance group vs. 57% in the observation group. An analysis of overall survival confirmed the significant benefit of Rituximab maintenance over observation (p = 0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by 56% (95% Cl; 22%-75%).
The median time to new anti-lymphoma treatment was significantly longer with Rituximab maintenance treatment than with observation (38.8 months vs. 20.1 months, p <0.0001 log-rank test). The risk of starting a new treatment was reduced by 50% (95% Cl; 30%-64%). In patients achieving a CR/CRu (complete response unconfirmed) as best response during induction treatment, Rituximab maintenance treatment significantly prolonged the median disease free survival (DFS) compared to the observation group (53. 7 vs. 16.5 months, p = 0.0003 log-rank test) (see Table 4 as follows). The risk of relapse in complete responders was reduced by 67% (95% Cl: 39%-82%). See Table 4.


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The benefit of Rituximab maintenance treatment was confirmed in all subgroups analyzed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (see Table 4). Rituximab maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p < 0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p = 0.0071). Rituximab maintenance treatment also provided a clinically meaningful benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP in the induction phase of the study.
Rituximab maintenance treatment provided consistent benefit in all subgroups tested: gender, age (60 years, >60 years), stage (III, IV), WHO performance status (0 vs. >0), B symptoms (absent, present), bone marrow involvement (no vs. yes), IPI (0-2 vs. 3-5), FLIPI score (0-1, vs. 3-5), number of extranodal sites (0-1 vs. >1), number of nodal sites (<5 vs. 5), number of previous regimens (1 vs. 2), best response to prior therapy (CR/PR vs. NC/PD), haemoglobin (<12 g/dL vs. 12 g/dL, β₂-microglobulin (< 3 mg/L vs. 3 mg/L), LDH (elevated, not elevated) except for the small subgroup of patients with bulky disease.
Diffuse Large B-cell Non-Hodgkin's Lymphoma: In a randomized, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B-cell lymphoma received standard CHOP chemotherapy (Cyclophosphamide 750 mg/m², Doxorubicin 50 mg/m², Vincristine 1.4 mg/m² up to a maximum of 2 mg on day 1, and Prednisolone 40 mg/m²/day on days 1-5) every 3 weeks for eight cycles, or Rituximab 375 mg/m² plus CHOP (R-CHOP), Rituximab was administered on the first day of the treatment cycle.
The final efficacy analysis included all randomized patients (197 CHOP, 202 R-CHOP), and had a median follow-up duration of approximately 31 months. The two treatment groups were well balanced in baseline characteristics and disease status. The final analysis confirmed that R-CHOP significantly increased the duration of event-free survival (the primary efficacy parameter, where events were death, relapse or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p =0.0071), representing a risk reduction of 32%.
The analysis of all secondary parameters (response rates, progression-free survival, disease-free survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The complete response rate after Cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group (p = 0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%.
In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, Beta 2 Microglobulin, LDH, Albumin, B-symptoms, Bulky disease, Extranodal sites, bone marrow involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95; respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk patients according to age adjusted IPI.
Pharmacokinetics: Absorption: Not applicable.
Distribution: Non-Hodgkin's Lymphoma: Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of Rituximab as a single agent or in combination with CHOP therapy, the typical population estimates of nonspecific clearance (CL1), specific clearance (CL2) likely contributed by B-cells or tumor burden, and central compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The estimated median terminal elimination half-life of Rituximab was 22 days (range, 6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumor lesions contributed to some of the variability in CL2 of Rituximab in data from 161 patients given 375 mg/m² as an IV infusion for 4 weekly doses. Patients with higher CD19-positive cell counts or tumor lesions had a higher CL2. However, a large component of inter-individual variability remained for CL2 after correction for CD19-positive cell counts and tumor lesion size. V1 varied by body surface area (BSA) and CHOP therapy. This variability in V1 (27.1% and 19.0%) contributed by the range in BSA (1.53 to 2.32 m²) and concurrent CHOP therapy, respectively, were relatively small. Age, gender, race, and WHO performance status had no effect on the pharmacokinetics of Rituximab. This analysis suggests that dose adjustment of Rituximab with any of the tested co-variates is not expected to result in a meaningful reduction in its pharmacokinetic variability.
Rituximab at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for 4 doses to 203 patients with NHL naive to Rituximab. The mean Cmax following the fourth infusion was 486 μg/mL (range, 77.5 to 996.6 μg/mL). The peak and trough serum levels of Rituximab were inversely correlated with baseline values for the number of circulating CD19-positive B-cells and measures of disease burden. Median steady-state serum levels were higher for responders compared with non-responders, Serum levels were higher in patients with International Working Formulation (IWF) sub-types B, C, and D as compared with those with sub-type A. Rituximab was detectable in the serum of patients 3-6 months after completion of last treatment.
Rituximab at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for 8 doses to 37 patients with NHL. The mean Cmax increased with each successive infusion, spanning from a mean of 243 μg/mL (range, 16-582 μg/mL) after the first infusion to 550 μg/mL (range, 171-1177 μg/mL) after the eighth infusion.
The pharmacokinetic profile of Rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with Rituximab alone.
Metabolism: No information available.
Elimination: See Distribution.
Pharmacokinetics In Special Populations: No pharmacokinetic data are available in patients with hepatic or renal impairment.
Usage In Special Populations: Pregnancy: There are no adequate and well-controlled studies of Rituximab in pregnant women. Women of child-bearing potential should use effective contraception while receiving Rituximab and for 12 months following treatment. Rituximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Human Data: Post-marketing data indicated that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to Rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.
Animal Data: In an embryo-fetal developmental toxicity study performed on pregnant cynomolgus monkeys, Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased B-cells and immunosuppression were noted in the offspring of Rituximab treated pregnant animals in subsequent pre- and post-natal reproductive toxicity studies and the B-cell counts returned to a normal levels, and immunologic function was restored within 6 months postpartum.
Nursing Mothers: It is not known whether Rituximab is secreted into human milk. However, Rituximab is secreted in the milk of lactating cynomolgus monkeys, and IgG is secreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risk to the infants from oral ingestion of Rituximab should be weighed against the known benefits of breastfeeding.
Pediatric Use: The safety and effectiveness of Rituximab in pediatric patients have not been established.
Geriatric Use: No information available.
Toxicology: Preclinical Safety: Carcinogenicity: No long-term animal studies have been performed to establish the carcinogenic potential of Rituximab, or to determine its effects on fertility in males or females. Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule. However, due to its character it is unlikely that Rituximab has any mutagenic potential.
Mutagenicity: No information available.
Impairment of Fertility: No information available.
Teratogenicity: No information available.
Other: Rituximab has shown to be highly specific to the CD20 antigen on B-cells. Toxicity studies in cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B-cells in peripheral blood and in lymphoid tissue.

RITUXSANBE is indicated for the treatment of Non-Hodgkin's lymphoma (NHL):
Relapsed or chemoresistant low-grade or follicular, CD20-positive, B-cell Non-Hodgkin's lymphoma.
Patients with stage III-IV follicular lymphoma in combination with CVP chemotherapy.
Patients with follicular lymphoma as maintenance treatment, after response to induction therapy.
Patients with CD20-positive diffuse large B-cell Non-Hodgkin's lymphoma in combination with CHOP chemotherapy.

Low-grade or Follicular Non-Hodgkin's Lymphoma: lnitial treatment: Intravenous Monotherapy: The recommended dosage of RITUXSANBE used as monotherapy for adult patients is 375 mg/m² body surface area (BSA), administered as an IV Infusion once weekly for four weeks.
Intravenous Combination therapy: The recommended dosage of RITUXSANBE in combination with any chemotherapy is 375 mg/m² BSA per cycle for a total of: a) 8 cycles with R-CVP (21 days/cycle); b) 8 cycles with R-MCP (28 days/cycle); c) 8 cycles with R-CHOP (21 days/cycle); 6 cycle if a complete remission is achieved after 4 cycles; d) 6 cycles with R-CHVP-interferon (21 days/cycle).
RJTUXSANBE should be administered on day 1 of each chemotherapy cycle after IV administration of the Glucocorticoid component of the chemotherapy, if applicable.
Retreatment following relapse in Non-Hodgkin's Lymphoma: Patients who have responded to RITUXSANBE initially have been treated again with RITUXSANBE at a dose of 375 mg/m² BSA, administered as an IV infusion once weekly for four weeks.
Maintenance treatment: Previously untreated patients after response to induction treatment may receive maintenance therapy with RITUXSANBE given at 375 mg/m² BSA once every 2 months until disease progression or for a maximum period two years (12 infusion) Relapsed/refractory patients after response to induction treatment may receive maintenance therapy with RITUXSANBE given at 375 mg/m² BSA once every 3 months until disease progression or for a maximum period two years.
Diffuse large B-cell Non-Hodgkin's Lymphoma: RITUXSANBE should be used in combination with CHOP chemotherapy. The recommended dosage of RITUXSANBE is 375 mg/m² BSA, administered on day1 of each chemotherapy cycle for 8 cycles after IV administration of the Glucocorticoid component of CHOP. Safety and efficacy of RITUXSANBE have not been established in combination with other chemotherapy.
Special Dosage Instruction: Children and adolescents: RITUXSANBE is not recommended for use in children due to lack of data on safety and efficacy.
Elderly: No dose adjustment is required in elderly patients (Age > 65 years).

Limited experience with doses higher than the approved intravenous doses of Rituximab is available from clinical trials in humans. The highest IV dose tested in humans to date is 5000 mg (2,250 mg/m²), tested in a dose escalation study in patients with chronic lymphocytic leukemia. No additional safety signals were identified. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.

Rituximab is contraindicated in patients with:
Hypersensitivity to the active substance or to murine proteins, or to any of the excipients.
Active, severe infections.
Patients in a severely immunocompromised state.
Patients who have or had Progressive Multifocal Leukoencephalopathy (PML).
Patients with severe heart failure (NYHA Class IV) or severe uncontrolled cardiac disease.

Non-Hodgkin's Lymphoma: Rituximab is associated with infusion/administration-related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.
Severe cytokine release syndrome is characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, In addition to fever, chills, rigors, urticaria, and angioedema. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see Dosage and Administration) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome. Infusion related adverse reactions including cytokine release syndrome accompanied by hypotension and bronchospasm have been observed in 10% of patients treated with Rituximab. These symptoms are usually reversible with interruption of Rituximab infusion and administration of an antipyretic, an antihistaminic, and, occasionally, oxygen, IV saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome previously for severe reactions.
Infusion-related reactions for Rituximab: Severe infusion-related reactions (IRRs) with fatal outcome have been reported during post-marketing use. Severe IRRs usually manifested within 30 minutes to 2 hours after starting the first Rituximab infusion, were characterized by pulmonary events and included, in some cases, rapid tumour lysis and features of tumor lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms. Patients with a high tumor burden or with a high number (> 25 x 10⁹/L) of circulating malignant cells such as patients with CLL and mantle cell lymphoma may be at higher risk of developing severe IRRs. Infusion reaction symptoms are usually reversible with interruption of the infusion.
Treatment of infusion-related symptoms with Diphenhydramine and Paracetamol/Acetaminophen is recommended. Additional treatment with bronchodilators or IV saline may be indicated. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/hour to 50 mg/hour) when symptoms have completely resolved. Most patients who have experienced non-life threatening IRRs have been able to complete the full course of Rituximab therapy. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe IRRs.
Patients with a high number (> 25x10⁹/L) of circulating malignant cells or high tumor burden such as patients with CLL and mantle cell lymphoma, who may be at higher risk of especially severe IRRs, should only be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25x10⁹/L.
Hypersensitivity reactions/anaphylaxis: Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins to patients. Epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.
Pulmonary Events: Pulmonary events have included hypoxia, lung infiltration, and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnea. In some cases, symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing pulmonary events or other severe infusion-related symptoms should be closely monitored until complete resolution of their symptoms occurs. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater rtsk of poor outcome and should be treated with increased caution. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or edema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients who experience severe pulmonary events should have their Rituximab administration interrupted immediately (see Dosage and Administration) and should receive aggressive symptomatic treatment.
Rapid Tumour Lysis: Rituximab mediates the rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms (e.g., hyperuricaemia, hyperkalemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated LDH) consistent with tumour lysis syndrome (TLS) have been reported to occur after the first Rituximab IV infusion in patients with high numbers of circulating malignant lymphocytes. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumor lysis (e.g., patients with a high tumor burden or with a high number [> 25x10⁹/L) of circulating malignant cells such as patients with CLL or mantle cell lymphoma). These patients should be followed closely and appropriate laboratory monitoring performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumor lysis. Following treatment for and complete resolution of signs and symptoms, subsequent Rituximab IV therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases.
Cardiovascular: Since hypotension may occur during Rituximab administration consideration should be given to with holding antihypertensive medications 12 hours prior to and throughout Rituximab IV/SC administration. Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with Rituximab IV/SC. Therefore patients with a history of cardiac disease should be monitored closely.
Monitoring of Blood Counts: Although Rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophil counts of < 1.5x10⁹ /L and/or platelet counts < 75x10⁹/L, as clinical experience with such patients is limited. Rituximab IV has been used in patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.
Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with Rituximab. When Rituximab is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.
Infections: Rituximab treatment should not be initiated in patients with severe active infections.
Hepatitis B Infections: Cases of hepatitis B reactivation, including reports of fulminant hepatitis, some of which were fatal, have been reported in subjects receiving Rituxirnab IV, although the majority of these subjects were also exposed to cytotoxic chemotherapy. The reports are confounded by both the underlying disease state and the cytotoxic chemotherapy.
Patients with a history of hepatitis B infection should be carefully monitored for signs of active hepatitis B infection when Rituximab is used in association with cytotoxic chemotherapy.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Rituximab. At minimum this should indude HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Rituximab. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Progressive multifocal leukoencephalopathy (PML): Cases of progressive multifocal leukoencephalopathy (PML) have been reported during use of Rituximab IV in NHL and CLL. The majority of patients had received Rituximab IV in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Physicians treating patients with NHL or CLL should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Skin reactions: Severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, some with fatal outcome, have been reported. In case of such an event with a suspected relationship to Rituximab, treatment should be discontinued. Re-administration must be carefully assessed based on the individual patient's benefit-risk profile.
Immunization: The safety of immunization with live viral vaccines following Rituximab IV/SC therapy has not been studied and vaccination with live virus vaccines is not recommended. The ability to generate a primary or anamnestic humoral response to any vaccine has also not been studied.
Patients treated with Rituximab may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced. In a non-randomized study, patients with relapsed low grade NHL who received Rituximab IV monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neo-antigen (4% vs. 76% when assessed for > 2-fold increase in antibody titer). Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with Rituximab IV.

Clinical Trials: Experience from Clinical Trials in Hemato-Oncology: The frequencies of adverse drug reactions (ADRs) reported with Rituximab alone or in combination with chemotherapy are summarized in the tables as follows and are based on data from clinical trials. These ADRs had either occurred in single arm studies or had occurred with at least 2% difference compared to the control arm in at least one of the major randomized clinical trials. ADRs are added to the appropriate category in the tables as follows according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping ADRs are listed in descending order of severity. Frequencies are defined as very common (≥1/10), common(≥1/100 to < 1/10), and uncommon (≥1/1,000 to <1/100).
Rituximab IV Monotherapy/Maintenance Therapy: The ADRs in Table 5, are based on data from single-arm studies including 356 patients with lowgrade or follicular lymphoma, treated with Rituximab weekly as single agent for the treatment or re-treatment of non-Hodgkin's lymphoma. The table also contains ADRs based on data from 671 patients with follicular lymphoma who received Rituximab as maintenance therapy for up to 2 years following response to initial induction with CHOP, R-CHOP, R-CVP or R-FCM. The ADRs ware reported up to 12 months after treatment with monotherapy and up to 1 month after treatment with Rituximab maintenance. See Table 5.


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Rituximab in Combination with Chemotherapy in NHL and CLL: The ADRs listed in Table 6 are based on Rituximab IV-arm data from controlled clinical trials that occurred in addition to those seen with monotherapy/maintenance therapy and/or at a higher frequency grouping: 202 patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, and from 234 and 162 patients with follicular lymphoma treated with R-CHOP or RCVP, respectively and from 397 previously untreated CLL patients and 274 relapsed/refractory CLL patients, treated with Rituximab in combination with Fludarabine and Cyclophosphamlde (R-FC). See Table 6.


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The following terms have been reported as adverse events, however, were reported at a similar (< 2% difference between the groups) or lower incidence in the Rituximab IV arms compared to control arms: Hematotoxicity, neutropenic infection, urinary tract infection, septic shock, superinfection lung, implant infection, septicemia staphylococcal, lung infection, rhinorrheoa, pulmonary edema, cardiac failure, sensory disturbance, venous thrombosis, mucosal inflammation nos, influenza-like illness, edema lower limb, abnormal ejection fraction, pyrexia, general physical health deterioration, fall, multi-organ failure, venous thrombosis deep limb, positive blood culture, diabetes mellitus inadequate control.
The safety profile for Rituximab in combination with other chemotherapies (e.g. MCP, CHVPIFN) is comparable to the safety profile as described for the combination of Rituximab and CVP, CHOP or FC in equivalent populations.
Further Information on Selected, Serious Adverse Drug Reaction: Administration-related reactions: Monotherapy-4 Weeks treatment: Signs and symptoms suggestive of an infusion-related reaction (IRR) were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion.
Hypotension, fever, chills, rigors, urticaria, bronchospasm, sensation of tongue or throat swelling (angioedema), nausea, fatigue, headache, pruritus, dyspnea, rhinitis, vomiting, flushing, and pain at disease sites have occurred in association with Rituximab infusion as part of an infusion related symptom complex. Some features of tumor lysis syndrome have also been observed.
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): Severe IRR occurred in up to 12% of all patients at the time of the first treatment cycle with Rituximab in combination with chemotherapy. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and in < 1% of patients by the eighth cycle. Additional reactions reported were: dyspepsia, rash, hypertension, tachycardia, and features of tumour lysis syndrome. Isolated cases of myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia were also reported.
Infections: Monotherapy 4 weeks treatment: Rituximab induced B-cell depletion in 70% to 80% of patients but was associated with decreased serum immunoglobulins in only a minority of patients. Bacterial, viral, fungal and unknown etiology infections, irrespective of causal assessment, occurred in 30.3% of 356 patients. Severe infectious events (Grade 3 or 4), including sepsis occurred in 3.9% of patients.
Maintenance Treatment (NHL) up to 2 years: Higher frequencies of infections overall, including Grade 3 and 4 infections, were observed during Rituximab treatment. There was no cumulative toxicity in terms of infections reported over the 2-year maintenance period.
Data from clinical trials included cases of fatal PML in NHL patients that occurred after disease progression and re-treatment (see Precautions).
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): No increase in the frequency of infections or infestations was observed. The most common infections were upper respiratory tract infections which were reported for 12.3% patients on RCVP and 16.4% patients receiving CVP. Serious infections were reported in 4.3% of the patients receiving R-CVP and 4.4% of the patients receiving CVP. No life-threatening infections were reported during this study.
In the R-CHOP study the overall incidence of Grade 2 to 4 infections was 45.5% in the R-CHOP group and 42.3% in the CHOP group. Grade 2 to 4 fungal infections were more frequent in the RCHOP group (4.5% vs. 2.6% in the CHOP group); this difference was due to a higher incidence of localized Candida infections during the treatment period. The incidence of Grade 2 to 4 herpes zoster was higher in the R-CHOP group (4.5%) than in the CHOP group (1.5%). The proportion of patients with Grade 2 to 4 infections and/or febrile neutropenia was 55.4% in the R-CHOP group and 51.5% in the CHOP group.
In patients with CLL, the incidence of Grade 3 or 4 hepatitis B infection (reactivation and primary infection) was 2% in the R-FC group vs. 0% in the FC group.
Haematologic events: Monotherapy 4 weeks treatment: Severe (Grade 3 and 4) neutropenia was reported in 4.2% of patients, severe anaemia was reported in 1.1% of patients and severe thrombocytopenia was reported in 1.7% of patients.
Maintenance Treatment (NHL) up to 2 years: There was a higher incidence of Grade 3 and 4 leucopenia (observation 2% vs. Rituximab 5%) and neutropenia (observation 4% vs. Rituximab 10%) in the Rituximab IV arm compared to the observation arm. The incidence of Grade 3and 4 thrombocytopenia (observation 1% vs. Rituximab <1%) was low. In approximately half of the patients with available data on B-cell recovery after end of Rituximab induction treatment, it took 12 months or more for their B-cell levels to return to normal values.
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): During treatment course in studies with Rituximab IV in combination with chemotherapy, Grade 3 and 4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), and neutropenia (RCVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with Rituximab and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established that in some cases neutropenia was prolonged or with a late onset following treatment in the Rituximab plus FC group.
No relevant difference between the treatment arms was observed with respect to Grade 3 and 4 anemia or thrombocytopenia. In the CLL first-line study, Grade 3 and 4 anemia was reported by 4% of patients treated with R-FC compared to 7% of patients receiving FC, and Grade 3 and 4 thrombocytopenla was reported by 7% of patients in the R-FC group compared to 10% of patients in the FC group. In the relapsed/refractory CLL study, adverse events of Grade 3 and 4 anemia were reported in 12% of patients treated with R-FC compared to 13% of patients receiving FC and Grade 3/4 thrombocytopenia was reported by 11 % of patients in the R-FC group compared to 9% of patients in the FC group.
Cardiovascular events: Monotherapy 4 weeks treatment: Cardiovascular events were reported in 18.8% of patients during the treatment period. The most frequently reported events were: hypotension and hypertension. Cases of Grade 3 and 4 arrhythmia (including ventricular and supraventriculer tachycardia) and angina pectoris during a Rituximab infusion were reported.
Maintenance Treatment (NHL) up to 2 years: The incidence of Grade 3 and 4 cardiac disorders was comparable between the two treatment groups. Cardiac events were reported as serious adverse event in < 1% of patients on observation and in 3% of patients on Rituximab: atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure (< 1%), myocardial ischemla (< 1%).
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): In the R-CHOP study the incidence of Grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the RCHOP group (6.9%) as compared to the CHOP group (1.5%). All arrhythmias either occurred in the context of a Rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease (see Precautions). No difference between the R-CHOP and CHOP group was observed in the incidence of other Grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease.
In CLL, the overall incidence of Grade 3 and 4 cardiac disorders was low both in the first-line study (4% R-FC vs. 3% FC) and in the relapsed/refractory study (4% R-FC vs. 4% FC).
IgG levels: Maintenance Treatment (NHL) up to 2 years: After induction treatment, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) in both the observation and the Rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during Rituximab treatment. The proportion of patients with IgG levels below the LLN was about 60% in the Rituximab group throughout the 2 years treatment period, while it decreased in the observation group (36% after 2 years).
Neurologic events: Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): During the treatment period, 2% of patients in the R-CHOP group, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents durtng the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, 1.5% of patients had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.
In CLL, the overall incidence of Grade 3 and 4 nervous system disorders was low both in the firstline study (4% R-FC vs. 4% FC) and in the relapsed/refractory study (3% R-FC vs. 3% FC).
Subpopulations: Monotherapy - 4 weeks treatment: Elderly patients (≥65 years): The incidence of any ADR and of Grade 3 and 4 ADR was similar in elderiy (65 years of age) and younger patients (88.3% vs. 92.0% for any ADR and 16.0% vs. 18.1% for Grade 3 and 4 ADRs).
Combination Therapy: Elderly patients (65 years): The incidence of Grade 3 and 4 blood and lymphatic adverse events was higher in elderly patients (≥65 years of age) compared to younger patients with previously untreated or relapsed/refractory CLL.
Bulky disease: Patients with bulky disease had a higher incidence of Grade 3 and 4 ADRs than patients without bulky disease (25.6% vs. 15.4%). The incidence of any ADR was similar in these two groups (92.3% in bulky disease vs. 89.2% in non-bulky disease).
Re-treatment with Monotherapy: The percentage of patients reporting any ADR and Grade 3 and 4 ADRs upon retreatment with further courses of Rituximab was similar to the percentage of patients reporting any ADR and Grade 3 and 4 ADRs upon initial exposure (95.0% vs. 89.7% for any ADR and 13.3% vs. 14.8% for Grade 3 and 4 ADRs).
Adverse Reactions Reported in Other Monotherapy Clinical Trials: One case of serum sickness has been reported in a clinical trial using Rituximab monotherapy for treatment of diffuse large B-cell lymphoma.
Post-Marketing: Non-Hodgkin's Lymphoma: The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and data largely derived from spontaneous reports.
Additional cases of severe IRRs have been reported during post-marketing use of Rituximab (see Precautions).
As part of the continuing post-marketing surveillance of Rituximab safety, the following serious adverse reactions have been observed:
Cardiovascular system: Severe cardiac events, including heart failure and myocardial infarction have bean observed, mainly in patients with prior cardiac condition and for cardiotoxic chemotherapy and mostly associated with IRRs. Vasculitis, predominantly cutaneous, such as leukocytoclastic vesculitis, has been reported very rare.
Respiratory system: Severe cardiac events, induding heart failure and myocardial infarction have been observed, mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with IRRs. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rare.
Blood and lymphatic system: Cases of infusion-related acute reversible thrombocytopenia have been reported.
Skin and appendages: Severe bullous skin reactions including fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported rarely.
Nervous system: Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms include visual disturbance, headache, seizures and altered mental status, with or without associated hypertension.
A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized risk factors for PRES/RPLS, including the patients underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.
Cases of cranial neuropathy with or without peripheral neuropathy have been reported rarely. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses and facial nerve palsy, occurred at various times up to several months after completion of Rituximab therapy.
Body as a whole: Serum sickness-like reactions have been reported rarely.
Infections and Infestations: Gases of hepatitis B reactivation have been reported, the majority of which were in subjects receiving Rituximab in combination with cytotoxic chemotherapy (see Precautions). Other serious viral infections, either new, reactivation or exacerbation, some of which were fatal, have been reported with Rituximab treatment. The majority of patients had received Rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus [CMV], varicella zoster virus and herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML]) see Precautions) and Hepatitis C virus.
Progression of Kaposi's sarcoma has been observed in Rituximab-exposed patients with preexisting Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Gastro-intestinal system: Gastrointestinal perforation, in some cases leading to death, has been observed in patients receiving Rituximab in combination with chemotherapy for non-Hodgkin's lymphoma.
Laboratory Abnormalities: Non-Hodgkin's Lymphoma: Blood and lymphatic system: Rarely the onset of neutropenia has occurred more than four weeks after the last infusion of Rituximab.
Post Marketing: In studies of Rituximab in patients with Waldenstrom's macroglobulinemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

At the present, there are limited data on possible drug interactions with Rituximab. In CLL patients, co administration with Rituximab did not appear to have an effect on the pharmacokinetics of Fludarabine or Cyclophosphamide, in addition; there was no apparent effect of Fludarabine and Cyclophosphamide on the pharmacokinetics of Rituximab.
Patients with human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA) titters may develop allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
The tolerability of simultaneous or sequential combination of Rituximab with agents, other than CHOP chemotherapy, which are liable to cause depletion of normal B-cells is not well defined.

Instruction For Use, Handling and Disposal: Intravenous Formulation: Withdraw the required amount of Rituximab under aseptic conditions and dilute to a calculated Rituximab concentration of 1 to 4 mg/mL in an infusion bag containing sterile, non-pyrogenic 0.9%, aqueous saline solution or 5% aqueous dextrose solution. To mix the solution, gently invert the bag in order to avoid foaming. Parenteral medications should be inspected visually for particulate matter and discoloration prior to administration.
The prepared infusion solution of Rituximab is physically and chemically stable for 24 hours at 2°C-8°C and subsequently 12 hours at room temperature.
Incompatibilities: No incompatibilities between Rituximab and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via waste-water and disposal through household waste should be avoided. Use established "collection systems", if available in your location.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused. Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

This medicine should not be used after the expiry date (EXP) shown on the pack.
Intravenous Formulation: Stability: Store vials at 2°C-8°C (in a refrigerator). Keep the container in the outer carton in order to protect from light.
From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Targeted Cancer Therapy

L01FA01 - rituximab ; Belongs to the class of CD20 (Clusters of Differentiation 20) inhibitors. Used in the treatment of cancer.

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