Rituxirel

Non–Hodgkin's Lymphoma (NHL)

Rituxirel® (Rituxirel) is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxirel in combination with chemotherapy, as single-agent maintenance therapy.
• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Chronic Lymphocytic Leukemia (CLL)

Rituxirel® (Rituxirel) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

Rheumatoid Arthritis (RA)

Rituxirel® (Rituxirel) in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Rituxirel® (Rituxirel), in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

Limitations of Use

Rituxirel is not recommended for use in patients with severe, active infections.

Rituxirel injection is used alone or with other medicines to treat a type of cancer called non-Hodgkin's lymphoma (NHL). It helps the immune system destroy cancer cells. Rituxirel injection is a monoclonal antibody.

Rituxirel is used together with fludarabine and cyclophosphamide to treat a type of cancer called chronic lymphocytic leukemia (CLL).

Rituxirel is used together with methotrexate to treat the symptoms of rheumatoid arthritis. It helps to keep joint damage from getting worse after at least one other medicine (eg, adalimumab, etanercept, or infliximab) has been used and did not work well.

Rituxirel is used together with steroids to treat granulomatosis with polyangiitis (GPA or Wegener's granulomatosis) and microscopic polyangiitis (MPA). These are immune disorders that cause blood vessels to be inflamed.

Rituxirel is to be administered only by or under the immediate supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Rituxirel is used in certain patients with the following medical conditions:

• Immune or idiopathic thrombocytopenic purpura (ITP) (a blood disease).
• Posttransplant lymphoproliferative disorder (blood disorder occurring after an organ transplant) in children.
• Waldenstrom's macroglobulinemia (cancer of the blood).

Standard

Dosage: Rituxirel should be administered as an IV infusion through a dedicated line.

Premedication consisting of an analgesic/antipyretic (eg, paracetamol) and an antihistaminic drug (eg, diphenhydramine) should always be administered before each infusion of Rituxirel. Premedication with corticosteroids should also be considered if Rituxirel is not given in combination with CHOP chemotherapy.

Low-Grade or Follicular Non-Hodgkin's Lymphoma: Initial Treatment: The recommended dosage of Rituxirel used as monotherapy for adult patients is 375 mg/m² body surface area, administered as an IV infusion once weekly for 4 weeks. The recommended dosage of Rituxirel in combination with any chemotherapy is 375 mg/m² body surface area per cycle, for a total of 8 cycles with R-CVP (21 days/cycle)/8 cycles with R-MCP (28 days/cycle)/8 cycles with R-CHOP (21 days/cycle); 6 cycles if a complete remission is achieved after 4 cycles/6 cycles with R-CHVP-Interferon (21 days/cycle). Rituxirel/Rituxirel 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: Patients who have responded to Rituxirel initially have been treated again with Rituxirel at a dose of 375 mg/m² body surface area, administered as an IV infusion once weekly for 4 weeks.

Maintenance Treatment: Previously untreated follicular lymphoma patients after response to induction treatment may receive maintenance therapy with Rituxirel given at 375 mg/m² body surface area once every 2 months until disease progression or for a maximum period of 2 years.

Relapsed/refractory patients after response to induction treatment may receive maintenance therapy with Rituxirel given at 375 mg/m² body surface area once every 3 months until disease progression or for a maximum period of 2 years.

Diffuse Large B-Cell Non-Hodgkin's Lymphoma: Rituxirel should be used in combination with CHOP chemotherapy. The recommended dosage of Rituxirel is 375 mg/m² body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after IV administration of the corticosteroid component of CHOP. The other components of CHOP (cyclophosphamide, doxorubicin, prednisone and vincristine) should be given after the administration of Rituxirel.

First Infusion: The recommended initial infusion rate is 50 mg/hr; subsequently, the rate can be escalated in 50-mg/hr increments every 30 min to a maximum of 400 mg/hr.

Subsequent Infusions: Subsequent infusions of Rituxirel can be started at a rate of 100 mg/hr and increased by 100-mg/hr increments every 30 min to a maximum of 400 mg/hr.

Dosage Adjustments During Treatment: No dose reductions of Rituxirel are recommended. When Rituxirel is given in combination with CHOP chemotherapy, standard dose reductions for the chemotherapeutic drugs should be applied.

Maintenance Treatment: Patients who have responded to induction treatment may receive maintenance therapy with Rituxirel given at 375 mg/m² body surface area once every 3 months until disease progression or for a maximum period of 2 years.

Chronic Lymphocytic Leukemia: Prophylaxis with adequate hydration and administration of uricostatics starting 48 hrs prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are >25 x 10⁹/L, it is recommended to administer prednisone/prednisolone 100-mg IV shortly before infusion with Rituxirel/Rituxirel to decrease the rate and severity of acute infusion reactions and/or cytokine-release syndrome. The recommended dosage of Rituxirel/Rituxirel in combination with chemotherapy is 375 mg/m² BSA administered on day 1 of the 1st treatment cycle followed by 500 mg/m² BSA administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rituxirel/Rituxirel infusion.

Rheumatoid Arthritis: A course of Rituxirel/Rituxirel consists of two 1000 mg IV infusions. The recommended dosage of Rituxirel/Rituxirel is 1000 mg by IV infusion followed 2 weeks later by the 2nd 1000 mg IV infusion. The need for further courses should be evaluated 24 weeks following the previous course with re-treatment given based on residual or disease activity returning to a level above a DAS28-ESR of 2.6 (treatment to remission). Patients may receive further courses no sooner than 16 weeks following the previous course. Rheumatoid arthritis patients should receive treatment with methylprednisolone 100 mg IV 30 min prior to Rituxirel/Rituxirel to decrease the rate and severity of acute infusion reactions.

First Infusion of Each Course: Recommended initial rate for infusion is 50 mg/hr; after the first 30 min, it can be escalated in 50 mg/hr increments every 30 min, to a maximum of 400 mg/hr.

Second Infusion of Each Course: Subsequent doses of Rituxirel can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 min intervals to a maximum of 400 mg/hr.

See also:
What is the most important information I should know about Rituxirel?

You should not receive this medication if you have ever had a severe allergic reaction to Rituxirel.

Some people receiving a Rituxirel injection have had a reaction to the infusion (within 24 hours after the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, weak, light-headed, short of breath, or if you have chest pain, wheezing, sudden cough, or pounding heartbeats or fluttering in your chest.

If you have hepatitis B you may develop liver symptoms after you stop using this medication, even months after stopping.

Call your doctor right away if you have symptoms of a serious viral infection of the brain, such as: confusion, trouble concentrating, problems with speech or walking, vision problems, or weakness on one side of your body.

Use Rituxirel as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Rituxirel comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Rituxirel refilled.
• Rituxirel must be administered in an appropriate medical setting under close medical supervision.
• Do not use Rituxirel if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• You may receive other medicines before your dose of Rituxirel. This is to decrease the chance of an infusion reaction. Discuss any questions with your doctor.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Rituxirel, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Rituxirel.

Use: Labeled Indications

Chronic lymphocytic leukemia (Rituxirel and Rituxirel biosimilars): Treatment of previously untreated or previously treated CD20-positive chronic lymphocytic leukemia (CLL) in adults (in combination with fludarabine and cyclophosphamide).

Note: Other medications have approval for use in combination with Rituxirel (eg, idelalisib, venetoclax, ibrutinib) for the treatment of relapsed or refractory CLL.

Granulomatosis with polyangiitis (Rituxirel and Rituxirel biosimilars): Treatment of granulomatosis with polyangiitis (Wegener granulomatosis) (in combination with glucocorticoids) in adults (Rituxirel and Rituxirel biosimilars) and pediatric patients ≥2 years of age (Rituxirel only).

Microscopic polyangiitis (Rituxirel and Rituxirel biosimilars): Treatment of microscopic polyangiitis (in combination with glucocorticoids) in adults (Rituxirel and Rituxirel biosimilars) and pediatric patients ≥2 years of age (Rituxirel only).

Non-Hodgkin lymphomas (Rituxirel and Rituxirel biosimilars): Treatment of CD20-positive non-Hodgkin lymphomas (NHL) in adults with:

Relapsed or refractory, low-grade or follicular B-cell NHL (as a single agent).

Follicular B-cell NHL, previously untreated (in combination with first-line chemotherapy, and as single-agent maintenance therapy if complete or partial response to Rituxirel with chemotherapy).

Nonprogressing (including stable disease), low-grade B-cell NHL (as a single agent after first-line cyclophosphamide, vincristine, and prednisone [CVP] treatment).

Diffuse large B-cell NHL, previously untreated (in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] chemotherapy, or other anthracycline-based regimen).

Pemphigus vulgaris (Rituxirel only): Treatment of moderate to severe pemphigus vulgaris in adults.

Rheumatoid arthritis (Rituxirel and Rituxirel [Rituxirel biosimilar] only): Treatment of moderately to severely active rheumatoid arthritis (in combination with methotrexate) in adults with inadequate response to one or more tumor necrosis factor-antagonist therapies.

Note: Ruxience (Rituxirel-pvvr) and Rituxirel (Rituxirel-abbs) have been approved as biosimilars to Rituxirel (Rituxirel).

Off Label Uses

Antibody-mediated rejection in cardiac transplantation (treatment)

Based on the American Heart Association's Scientific Statement for Antibody-Mediated Rejection in Cardiac Transplantation and the International Society of Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients, Rituxirel, usually in combination with other immune therapies, may be a reasonable option for the secondary treatment of patients with antibody-mediated rejection (AMR) of the cardiac allograft. ISHLT guidelines state Rituxirel may be added to the current regimen to reduce the risk of recurrent rejection. There are currently no large randomized trials evaluating treatments for AMR in cardiac transplantation; recommendations are based on consensus.

Autoimmune hemolytic anemia (refractory)

Data from a meta-analysis of 21 observational studies with a total of 409 patients support the use of Rituxirel in the management of refractory autoimmune hemolytic anemia (AIHA).

Based on recommendations from the Eighth International Workshop on Waldenström Macroglobulinemia (IWWM), Rituxirel either alone (avoid single-agent Rituxirel in patients with high IgM levels) or in combination with chemotherapy may be used for the treatment of Waldenström macroglobulinemia.

See also:
What other drugs will affect Rituxirel?

At present, limited data is available on possible drug interactions with Rituxirel.

In CLL patients, co-administration with Rituxirel 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 Rituxirel.

Co-administration with methotrexate had no effect on the pharmacokinetics of Rituxirel in rheumatoid arthritis patients.

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

In the rheumatic arthritis clinical trial program, 373 patients treated with Rituxirel received subsequent therapy with other DMARDs, of whom 240 received a biologic DMARD. In these patients, the rate of serious infection while on Rituxirel (prior to receiving a biologic DMARD) was 6.1 per 100 patient years compared to 4.9/100 patient years following subsequent treatment with the biologic DMARD.

Incompatibilities: No incompatibilities between Rituxirel and polyvinyl chloride or polyethylene bags or infusion sets have been observed.

See also:
What are the possible side effects of Rituxirel?

Non-Hodgkin's Lymphoma (NHL): Follicular NHL: Monotherapy: The following data are based on 356 patients treated in single-arm studies of Rituxirel administered as single agent. Most patients received Rituxirel 375 mg/m² weekly for 4 doses. These include 39 patients with bulky disease (lesions ≥10 cm) and 58 patients who received more than 1 course of Rituxirel (60 re-treatments). Thirty-seven (37) patients received 375 mg/m² for 8 doses and 25 patients received doses other than 375 mg/m² for 4 doses and up to 500 mg/m² single dose in the phase I setting.

The following adverse events were considered to be at least possibly related to Rituxirel during or up to 12 months after treatment. Adverse events were graded according to the 4-scale National Cancer Institute common toxicity criteria (NCI CTC).

Others reported <5% were body pain (4.2%), flushing (4.2%), chest pain (2.2%), malaise (2%), tumour pain (1.7%), cold syndrome (1.4%), neck pain (1.1 %), hypertension (4.5%), tachycardia (1.4%), arrhythmia (1.4%), orthostatic hypotension (1.1%), diarrhoea (4.2%), dyspepsia (2.8%), anorexia (2.8%), dysphagia (1.4%), stomatitis (1.4%), constipation (1.1%), anaemia (3.7%), peripheral oedema (4.8%), increased lactate dehydrogenase (2.2%), hypocalcaemia (2.2%), facial oedema (1.1%), decreased weight (1.1%), hypertonia (1.4%), musculoskeletal pain (1.1%), insomnia (2.2%), vasodilatation (1.7%), hypoaesthesia (1.4%), agitation (1.4%), dyspnoea (2.2%), chest pain (1.1%), respiratory disease (1.1%), night sweats (2.8%), sweating (2.8%), lacrimation disorder (3.1%), conjunctivitis (1.4%), ear pain (1.1%), tinnitus (1.1%).

The following adverse events were reported in <1%: Coagulation disorders, asthma, lung disorder, bronchiolitis obliterans, hypoxia, abdominal enlargement, pain at the infusion site, bradycardia, lymphadenopathy, nervousness, depression, dysgeusia.

Infusion-Related Reactions: Infusion-related reactions occurred in more than 50% of patients and were predominantly seen during the 1st infusion, usually during the first 1-2 hrs. These events mainly comprised of fever, chills and rigors. Other symptoms included flushing, angioedema, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, vomiting and tumour pain. These symptoms were accompanied by hypotension and bronchospasm in about 10% of the cases. Less frequently, patients experienced an exacerbation of preexisting cardiac conditions eg, angina pectoris or congestive heart failure. The incidence of infusion-related symptoms decreases substantially with subsequent infusions.

Infections: Rituxirel induced B-cell depletion in 70-80% of patients but was associated with decreased serum immunoglobulins only in a minority of patients. Infectious events, irrespective of causal assessment, occurred in 30.3% of 356 patients: 18.8% of patients had bacterial infections, 10.4% had viral infections, 1.4% had fungal infections and 5.9 % had infections of unknown aetiology. Severe infectious events (grade 3 or 4), including sepsis occurred in 3.9% of patients; in 1.4% during the treatment period and in 2.5% during the follow-up period. As these were single-arm trials, the contributory role of Rituxirel or of the underlying NHL and its previous treatment to the development of these infectious events cannot be determined.

Haematologic Adverse Reactions: Haematological abnormalities occurred in a minority of patients and are usually mild and reversible. Severe (grade 3 and 4) thrombocytopenia and neutropenia were reported in 1.7% and 4.2% of patients respectively, and severe anaemia was reported in 1.1% of patients. A single occurrence of transient aplastic anaemia (pure red cell aplasia) and infrequent occurrences of haemolytic anaemia following Rituxirel treatment were reported.

Cardiovascular Events: Cardiovascular events were reported in 18.8% of patients during the treatment period. The most frequently reported events were hypotension and hypertension. Two (2) patients (0.6%) experienced grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) during a Rituxirel infusion and 1 patient with a history of myocardial infarction experienced angina pectoris, evolving into myocardial infarction 4 days later.

Subpopulations: Elderly Patients (≥65 years): The incidence of any adverse event and of grade 3 and 4 adverse events was similar in elderly (N=94) and younger (N=237) patients (88.3% vs 92% for any adverse event and 16% vs 18.1% for grade 3 and 4 adverse events).

Bulky Disease: Patients with bulky disease (N=39) had a higher incidence of grade 3 and 4 adverse events than patients without bulky disease (N=195) (25.6% vs 15.4%). The incidence of any adverse event was similar in these 2 groups (92.3% in bulky disease vs 89.2% in non-bulky disease).

Re-Treatment: The percentage of patients reporting any adverse event and grade 3 and 4 adverse events upon retreatment (N=60) with further courses of Rituxirel was similar to the percentage of patients reporting any adverse event and grade 3 and 4 adverse events upon initial exposure (N=203) (95% vs 89.7% for any adverse event and 13.3% vs 14.8% for grade 3 and 4 adverse events).

Adverse Reactions Reported in Other Monotherapy Clinical Trials: One case of serum sickness has been reported in a clinical trial using Rituxirel monotherapy for treatment of diffuse large B-cell lymphoma.

In Combination with Cyclophosphamide, Vincristine, Prednisolone (CVP) Chemotherapy: The following data are based on 321 patients from a randomised phase III clinical trial comparing Rituxirel+CVP [Rituxirel-cyclophosphamide, vincristine, prednisolone (R-CVP)] to CVP alone (162 R-CVP, 159 CVP). Differences between the treatment groups with respect to the type and incidence of adverse event were mainly accounted for by typical adverse events associated with Rituxirel monotherapy. The following grade 3 to 4 clinical adverse events were reported in ≥2% higher incidence in patients receiving R-CVP compared to CVP treatment group and therefore may be attributable to R-CVP. Adverse events were graded according to the 4-scale NCI CTC: Fatigue: 3.7% (R-CVP), 1.3% (CVP); neutropenia: 3.1% (R-CVP), 0.6% (CVP).

Infusion-Related Reactions: The signs and symptoms of severe or life-threatening (NCI CTC grades 3 and 4) infusion-related reactions (defined as starting during or within 1 day of an infusion with Rituxirel) occurred in 9% of all patients who received R-CVP. These results are consistent with those observed during monotherapy : Follicular NHL: Monotherapy) and included rigors, fatigue, dyspnoea, dyspepsia, nausea, rash, flushing.

Infections: The overall proportion of patients with infections or infestations during treatment and for 28 days after trial treatment end was comparable between the treatment groups (33% R-CVP, 32% CVP). The most common infections were upper respiratory tract infections which were reported for 12.3% patients on R-CVP and 16.4% patients receiving CVP; most of these infections were nasopharyngitis. 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.

Haematologic Laboratory Abnormalities: Twenty-four percent (24%) of patients on R-CVP and 14% of patients on CVP experienced grade 3 or 4 neutropenia during treatment. The proportion of patients with grade 4 neutropenia was comparable between the treatment groups. These laboratory findings were reported as adverse events and resulted in medical intervention in 3.1% of patients on R-CVP and 0.6% of patients on CVP. All other laboratory abnormalities were not treated and resolved without any intervention. In addition, the higher incidence of neutropenia in the R-CVP group was not associated with a higher incidence of infections and infestations. No relevant difference between the 2 treatment arms was observed with respect to grade 3 and 4 anaemia (0.6% R-CVP and 1.9% CVP) and thrombocytopenia (1.2% in the R-CVP group and no events reported in the CVP group).

Cardiac Events: The overall incidence of cardiac disorders in the safety population was low (4% R-CVP, 5% CVP), with no relevant differences between the treatment groups.

Maintenance Therapy: The following data are from a phase III clinical trial where patients with relapsed or refractory follicular NHL were randomised in a 1st phase to induction treatment with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or Rituxirel+CHOP (R-CHOP).

Patients who responded to induction treatment with CHOP or R-CHOP were randomised in a 2nd phase to receive no further treatment (observation) or Rituxirel maintenance treatment. Rituxirel maintenance treatment consisted of a single infusion of Rituxirel at 375 mg/m² body surface area administered every 3 months for a maximum period of 2 years or until disease progression.

In the induction phase of the trial, a total of 462 patients (228 on CHOP, 234 on R-CHOP) contributed to the safety evaluation of the 2 induction regimens.

Events that had an incidence <5% were stomatitis, skin disorder, urinary tract infection and back pain.

A total of 332 patients (166 observations, 166 Rituxirel) were included in the safety evaluation of the maintenance phase of the study. Rituxirel was given at a dose of 375 mg/m² body surface area once every 3 months until disease progression or for a maximum period of 2 years. The grade 3 and 4 adverse events reported in >2% Rituxirel arm and hence can be attributed to be contributed by Rituxirel were respiratory tract infection, neutropenia, leucopenia, alpaca, cardiac disorder. Other adverse events reported in <2% of patients were asthenia, haematotoxicity, pneumonia, sensory disturbance and hypertension.

Infusion-Related Reactions: During maintenance treatment non-serious signs and symptoms suggestive of an infusion-related reaction were reported in 41% of patients for general disorders (mainly asthenia, pyrexia, influenza-like illness, pain) and in 7% of patients for immune system disorders (hypersensitivity). Serious infusion-related reactions (defined as serious adverse events starting during or within 1 day of a Rituxirel infusion) occurred in <1% of patients treated with Rituxirel maintenance.

Infections: The proportion of patients with grade 1 to 4 infections was 25% in the observation group and 45% in the Rituxirel group with grade 3 to 4 infections in 3% of patients on observation and 11% receiving Rituxirel maintenance treatment. Grade 3 to 4 infections reported in ≥1% of patients in the Rituxirel arm were pneumonia (2%), respiratory tract infection (2%), febrile infection (1%) and herpes zoster (1%). In a large proportion of infections (all grades), the infectious agent was not specified or isolated, however, where an infectious agent was specified, the most frequently reported underlying agents were bacterial (observation 2%, Rituxirel 10%), viruses (observation 7%, Rituxirel 11%) and fungi (observation 2%, Rituxirel 4%). There was no cumulative toxicity in terms of infections reported over the 2-year maintenance period.

Haematologic Events: Leucopenia (all grades) occurred in 21% of patients on observation versus 29% of patients in the Rituxirel arm, and neutropenia was reported in 12% of patients on observation and in 23% of patients on Rituxirel. There was a higher incidence of grade 3-4 neutropenia (observation 4%, Rituxirel 10%) and leucopenia (observation 2%, Rituxirel 5%) in the Rituxirel arm compared to the observation arm. The incidence of grade 3 to 4 thrombocytopenia (observation 1%, Rituxirel <1%) was low.

Cardiac Disorders: The incidence of grade 3 to 4 cardiac disorders was comparable between the 2 treatment groups (4% in observation, 5% in Rituxirel). Cardiac events were reported as serious adverse event in <1% of patients on observation and in 3% of patients on Rituxirel: Atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure (<1%) and myocardial ischemia (<1%).

Immunoglobulin G (IgG) Levels: After induction treatment, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) in both the observation and the Rituxirel groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during Rituxirel treatment. The proportion of patients with IgG levels below the LLN was about 60% in the Rituxirel group throughout the 2-year treatment period, while it decreased in the observation group (36% after 2 years).

Diffuse Large B-Cell Non-Hodgkin's Lymphoma: In combination with CHOP chemotherapy: See Table 3.

Other events with <5% incidence were herpes zoster (R-CHOP 4% and CHOP 1.5%), acute bronchitis (R-CHOP 2.5% and CHOP 0.5%), sinusitis (2.5% in R-CHOP alone), shivering (R-CHOP 3.5% and 1% in CHOP), hypertension (R-CHOP 2.5% and CHOP 0.5%) and atrial fibrillation (R-CHOP 2.5% and CHOP 0.5%).

Infusion-Related Reactions: Grade 3 and 4 infusion-related reactions (defined as starting during or within 1 day of an infusion with Rituxirel) occurred in approximately 9% of patients at the time of the 1st cycle of R-CHOP. The incidence of grade 3 and 4 infusion-related reactions decreased to <1% by the 8th cycle of R-CHOP. The signs and symptoms were consistent with those observed during monotherapy, and included fever, chills, hypotension, hypertension, tachycardia, dyspnoea, bronchospasm, nausea, vomiting, pain and features of tumour lysis syndrome. Additional reactions reported in isolated cases at the time of R-CHOP therapy were myocardial infarction, atrial fibrillation and pulmonary oedema.

Infections: 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. Febrile neutropenia (ie, no report of concomitant documented infection) was reported only during the treatment period, in 20.8% in the R-CHOP group and 15.3% in the CHOP group. The overall incidence of grade 2 to 4 infections was 45.5% in the R-CHOP group and 42.3% in the CHOP group with no difference in the incidence of systemic bacterial and fungal infections. Grade 2 to 4 fungal infections were more frequent in the R-CHOP group (4.5% vs 2.6% in the CHOP group); this difference was due to a higher incidence of localised Candida infections during the treatment period. The incidence of grade 2 to 4 herpes zoster, including ophthalmic herpes zoster, was higher in the R-CHOP group (4.5%) than in the CHOP group (1.5%), with 7 of a total of 9 cases in the R-CHOP group occurring during the treatment phase.

Haematologic Events: After each treatment cycle, grade 3 and 4 leucopenia (88% vs 79%) and neutropenia (97% vs 88%) occurred more frequently in the R-CHOP group than in the CHOP group. There was no evidence that neutropenia was more prolonged in the R-CHOP group. No difference between the 2 treatment arms was observed with respect to grade 3 and 4 anaemia (19% in the CHOP group vs 14% in the R-CHOP group) and thrombocytopenia (16% in the CHOP group vs 15% in the R-CHOP group). The time to recovery from all haematological abnormalities was comparable in the 2 treatment groups.

Cardiac Events: The incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias eg, tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a Rituxirel infusion or were associated with predisposing conditions eg, fever, infection, acute myocardial infarction or preexisting respiratory and cardiovascular disease. 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.

Neurologic Events: During the treatment period, 4 patients (2%) in the R-CHOP group, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the 1st treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, 3 patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.

Rheumatoid Arthritis (RA): The clinical efficacy of Rituxirel, given together with methotrexate (MTX) was studied in 3 double-blind controlled clinical trials (1 phase III, 2 phase II trials) in patients with rheumatoid arthritis. More than 1000 patients received at least 1 treatment course and were followed for periods ranging from 6 months to over 3 years; nearly 600 patients received ≥2 courses of treatment during the follow-up period.

Patients received Rituxirel 2 x 1000 mg separated by an interval of 2 weeks; in addition to MTX (10-25 mg/week). Rituxirel infusions were administered after an IV infusion of methylprednisolone 100 mg; patients also received treatment with oral prednisone for 15 days.

The most frequent adverse reactions considered due to receipt of Rituxirel 2 x 1000 mg in phase II and III studies were acute infusion reactions. Infusion reactions occurred in 15% of patients following the 1st infusion of Rituxirel and 5% in placebo patients. Infusion reactions decreased to 2% following the 2nd infusion in both Rituxirel and placebo groups.

Events having an incidence of <5% were urticaria, rhinitis, throat irritation, hot flush, asthenia. In gastrointestinal disorders, dyspepsia and upper abdominal pain. In metabolism and nutritional disorders, hypercholesterolemia, muscle spasms, osteoarthritis and migraine.

In addition to the events tabulated previously, medically significant events reported uncommonly in the Rituxirel-treated population and considered potential reactions to treatment include the following: General Disorders: Generalized oedema.

Respiratory Disorders: Bronchospasm, wheezing, laryngeal oedema.

Skin and Subcutaneous Disorders: Angioneurotic oedema, generalized pruritus.

Immune System Disorders: Anaphylaxis, anaphylactoid reaction.

Multiple Courses: The limited clinical trial data on multiple courses of treatment of RA patients seem to be associated with a similar adverse event profile to that observed following 1st exposure. However, worsening of infusion or allergic reactions and failure for B-cell depletion following Rituxirel cannot be excluded in human anti-chimeric antibody (HACA)-positive patients after repeated exposure to Rituxirel on the basis of available data. The incidence of acute infusion reactions following subsequent treatment courses was generally lower than the incidence following the 1st infusion of Rituxirel.

Acute Infusion Reactions: Symptoms suggesting an acute infusion reaction (pruritis, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 79/540 (15%) patients following their 1st exposure to Rituxirel. In a study comparing the effect of glucocorticoid regimen, these events were observed in 5/149 (3%) of patients following their 1st Rituxirel placebo infusion and 42/192 (22%) of patients receiving their 1st infusion of Rituxirel 1000 mg. Premedication with glucocorticoid IV significantly reduced the incidence and severity of these events. Of the patients who received Rituxirel 1000 mg without premedication with glucocorticoids, 18/65 (28%) experienced an acute infusion reaction, compared with 24/127 (19%) in patients given glucocorticoid IV premedication, respectively.

Infections: The rate of infection was approximately 0.9 per patient/year in the Rituxirel-treated patients. The infections consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of clinically significant infections, some of which were fatal was 0.05 per patient/year in Rituxirel-treated patients.

Malignancies: The clinical data, particularly the number of repeated courses, are too limited to assess the potential incidence of malignancies following exposure to Rituxirel, although present data do not seem to suggest any increased risk. Long-term safety evaluations are ongoing.

Cardiovascular: Cardiac events were observed in 11% patients in clinical studies with Rituxirel. In placebo-controlled studies, serious cardiac events were reported equally in Rituxirel- and placebo-treated patients (2%).

Post-Marketing Experience: As part of the continuing post-marketing surveillance of Rituxirel safety, the following rare serious adverse reactions have been observed.

In the blood and lymphatic system, the disorders reported were late neutropenia, pancytopenia, aplastic anaemia, transient increase in immunoglobulin M (IgM) levels. Severe cardiac events, heart failure and myocardial infection in cardiovascular system. Hearing loss in ear disorders, vision loss in eye disorders and multi-organ failure in general disorders. Infusion related reactions, anaphylaxis and tumour lysis syndrome, cytokine release syndrome, serum sickness and hepatitis B reactivation among immune disorders. Cranial neuropathy, peripheral neuropathy, facial nerve palsy and loss of other senses were reported in nervous system disorders. Severe bullous skin reactions, vasculitis (predominately cutaneous), leucocytoclastic vasculitis and toxic epidermal necrolysis affecting skin and subcutaneous tissue. Bronchospasm, respiratory failure, pulmonary infiltrates and interstitial pneumonitis in the respiratory system and renal failure in the renal system.

Each 10 mL and 50 mL contains Rituximab (rDNA origin) 100 mg and 500 mg, respectively.

Rituxirel also contains the following excipients: Sodium citrate, polysorbate 80, sodium chloride and water for injection.