Limited experience with doses higher than the approved dose of intravenous Мабтера formulation is available from clinical trials in humans. The highest intravenous dose of Мабтера tested in humans to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional safety signals were identified.
Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.
In the postmarketing setting five cases of Мабтера overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.
Contraindications for use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia
Active, severe infections.
Patients in a severely immunocompromised state.
Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis
Active, severe infections.
Patients in a severely immunocompromised state.
No incompatibilities between Мабтера and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia
Summary of the safety profile
The overall safety profile of Мабтера in non-Hodgkin's lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with Мабтера monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.
The most frequently observed adverse drug reactions (ADRs) in patients receiving Мабтера were IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of Мабтера.
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trials in patients with CLL.
The most frequent reported or observed serious adverse drug reactions were:
-
-
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Other serious ADRs reported include hepatitis B reactivation and PML.
Tabulated list of adverse reactions
The frequencies of ADRs reported with Мабтера alone or in combination with chemotherapy are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not knownâ€.
Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with Мабтера monotherapy/maintenance or in combination with chemotherapy
| System Organ Class | Very Common | Common | Uncommon | Rare | Very Rare | Not known |
| Infections and infestations | bacterial infections, viral infections, +bronchitis | sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 | serious viral infection2 Pneumocystis jirovecii | PML | ||
| Blood and lymphatic system disorders | neutropenia, leucopenia, +febrile neutropenia, +thrombo-cytopenia | anaemia, +pancytopenia, +granulocyto-penia | coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphaden-opathy | transient increase in serum IgM levels3 | late neutropenia3 | |
| Immune system disorders | infusion related reactions4, angioedema | hypersensitivity | anaphylaxis | tumour lysis syndrome, cytokine release syndrome4, serum sickness | infusion-related acute reversible thrombocyto-penia4 | |
| Metabolism and nutrition disorders | hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia | |||||
| Psychiatric disorders | depression, nervousness, | |||||
| Nervous system disorders | paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety | Dysgeusia | peripheral neuropathy, facial nerve palsy5 | cranial neuropathy, loss of other senses5 | ||
| Eye disorders | lacrimation disorder, conjunctivitis | severe vision loss5 | ||||
| Ear and labyrinth disorders | tinnitus, ear pain | hearing loss5 | ||||
| Cardiac disorders | +myocardial infarction4 and 6, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder | +left ventricular failure, +supra-ventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia | severe cardiac disorders 4 and 6 | heart failure4 and 6 | ||
| Vascular disorders | hypertension, orthostatic hypotension, hypotension | vasculitis (predominately cutaneous), leukocytoclastic vasculitis | ||||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm4, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis | asthma, bronchiolitis obliterans, lung disorder, hypoxia | interstitial lung disease7 | respiratory failure4, | lung infiltration, | |
| Gastrointestinal disorders | nausea | vomiting , diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation | abdominal enlargement | gastro-intestinal perforation7 | ||
| Skin and subcutaneous tissue disorders | pruritus, rash, +alopecia | urticaria, sweating, night sweats, +skin disorder | severe bullous skin reactions, Stevens-Johnson syndrome toxic epidermal necrolysis (Lyell's syndrome) 7 | |||
| Musculoskeletal, connective tissue and bone disorders | hypertonia, myalgia, arthralgia, back pain, neck pain, pain | |||||
| Renal and urinary disorders | renal failure4 | |||||
| General disorders and administration site conditions | fever , chills, asthenia, headache | tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure4 | infusion site pain | |||
| Investigations | decreased IgG levels | |||||
| For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (> grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported 1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below 3 see also section haematologic adverse reactions below 4 see also section infusion related reactions below. Rarely fatal cases reported 5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of Мабтера therapy 6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 7 includes fatal cases | ||||||
The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the Мабтера arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of Мабтера (containing) treatment.
Description of selected adverse reactions
Infections
Мабтера induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.
Localized candida infections as well as Herpes zoster were reported at a higher incidence in the Мабтера-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with Мабтера monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during Мабтера maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with Мабтера treatment. The majority of patients had received Мабтера in combination with chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving Мабтера in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi's sarcoma has been observed in Мабтера-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Haematologic adverse reactions
In clinical trials with Мабтера monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7 % of the patients. During Мабтера maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4 %, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with Мабтера in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% 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 Мабтера 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 up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with Мабтера plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of Мабтера were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.
In studies of Мабтера in patients with Waldenstrom's macroglobulinaemia, 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.
Cardiovascular adverse reactions
Cardiovascular reactions during clinical trials with Мабтера monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with Мабтера and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3% of patients treated with Мабтера compared to <1% on observation. In studies evaluating Мабтера in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as 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 Мабтера infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing 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. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).
Respiratory system
Cases of interstitial lung disease, some with fatal outcome have been reported.
Neurologic disorders
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included 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.
Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving Мабтера for treatment of non-Hodgkin lymphoma. In the majority of these cases, Мабтера was administered with chemotherapy.
IgG levels
In the clinical trial evaluating Мабтера maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the Мабтера groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the Мабтера group. The proportion of patients with IgG levels below the LLN was about 60% in the Мабтера group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).
A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed in paediatric patients treated with Мабтера, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.
Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Patient subpopulations - Мабтера monotherapy
Elderly patients (> 65 years):
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to younger patients (<65 years).
Bulky disease
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these two groups.
Re-treatment
The percentage of patients reporting ADRs upon re-treatment with further courses of Мабтера was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).
Patient subpopulations - Мабтера combination therapy
Elderly patients (> 65 years)
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL.
Experience from rheumatoid arthritis
Summary of the safety profile
The overall safety profile of Мабтера in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.
The safety profile of Мабтера in patients with moderate to severe rheumatoid arthritis (RA) is summarized in the sections below. In clinical trials more than 3100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2400 patients received two or more courses of treatment with over 1000 having received 5 or more courses. The safety information collected during post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for Мабтера.
Patients received 2 x 1000 mg of Мабтера separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). Мабтера infusions were administered after an intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.
Tabulated list of adverse reactions
Adverse reactions are listed in Table 2. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most frequent adverse reactions considered due to receipt of Мабтера were IRRs. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for Мабтера, progressive multifocal leukoencephalopathy (PML) and serum sickness-like reaction have been reported during post marketing experience.
Table 2 Summary of adverse drug reactions reported in clinical trials or during postmarketing surveillance occurring in patients with rheumatoid arthritis receiving Мабтера
| System Organ Class | Very Common | Common | Uncommon | Rare | Very rare |
| Infections and Infestations | upper respiratory tract infection, urinary tract infections | Bronchitis, sinusitis, gastroenteritis, tinea pedis | PML, reactivation of hepatitis B | ||
| Blood and lymphatic system disorders | neutropenia1 | late neutropenia2 | Serum sickness-like reaction | ||
| Cardiac disorders | Angina pectoris, atrial fibrillation, heart failure, myocardial infarction | Atrial flutter | |||
| Immune system disorders | 3Infusion related reactions (hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat irritation, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythema) | 3Infusion related reactions (generalized oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalized pruritus, anaphylaxis, anaphylactoid reaction) | |||
| General disorders and administration site conditions | |||||
| Metabolism and nutritional disorders |
| hypercholesterolemia | |||
| Nervous system disorders | headache | paraesthesia, migraine, dizziness, sciatica | |||
| Skin and subcutaneous tissue disorders |
| alopecia | Toxic Epidermal Necrolysis (Lyell's syndrome), Stevens-Johnson syndrome5 | ||
| Psychiatric disorders |
| depression, anxiety | |||
| Gastrointestinal disorders |
| Dyspepsia, diarrhoea, gastro-oesophageal reflux, mouth ulceration, upper abdominal pain | |||
| Musculo skeletal disorders | arthralgia / musculoskeletal pain, osteoarthritis, bursitis | ||||
| Investigations | decreased IgM levels4 | decreased IgG levels4 | |||
| 1 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 2 Frequency category derived from post-marketing data. 3 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a result of hypersensitivity and/or to the mechanism of action. 4 Includes observations collected as part of routine laboratory monitoring. 5 Includes fatal cases | |||||
Multiple courses
Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first Мабтера exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.
Infusion-related reactions
The most frequent ADRs following receipt of Мабтера in clinical studies were IRRs (refer to Table 2). Among the 3189 patients treated with Мабтера, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to Мабтера. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs. Severe IRRs with fatal outcome have been reported in the post-marketing setting.
In a trial designed to evaluate the safety of a more rapid Мабтера infusion in patients with rheumatoid arthritis, patients with moderat
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.
Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 6 months of birth and did not compromise the reaction to immunisation.
Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule. No long-term animal studies have been performed to establish the carcinogenic potential of rituximab.
Specific studies to determine the effects of rituximab on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed.
Мабтера is indicated in adults for the following indications:
Non-Hodgkin's lymphoma (NHL)
Мабтера is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.
Мабтера maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Мабтера monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.
Мабтера is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.
Chronic lymphocytic leukaemia (CLL)
Мабтера in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including Мабтера or patients refractory to previous Мабтера plus chemotherapy.
Rheumatoid arthritis
Мабтера in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.
Мабтера has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Мабтера, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA).
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all B cell non-Hodgkin's lymphomas.
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, does not compete for antibody binding.
The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.
Peripheral B cell counts declined below normal following completion of the first dose of Мабтера. In patients treated for haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg Мабтера separated by a 14 day interval. Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether Мабтера was administered as monotherapy or in combination with methotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of Мабтера. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most patients up to the 6 month timepoint. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by month 12, increasing to 87% of patients by month 18.
Clinical experience in Non-Hodgkin's lymphoma and in chronic lymphocytic leukaemia
Follicular lymphoma
Monotherapy
Initial treatment, weekly for 4 doses
In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of Мабтера as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95 % 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 histological subtypes as compared to IWF A subtype (58 % vs. 12 %), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53 % vs. 38 %), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50 % vs. 22 %). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78 % versus 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 Мабтера. A statistically significant correlation was noted between response rates and bone marrow involvement. 40 % 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 stepwise 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 trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 of Мабтера as intravenous infusion weekly for eight doses. The ORR was 57 % (95% Confidence interval (CI); 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 trials, 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 Мабтера as intravenous infusion weekly for four doses. The ORR was 36 % (CI95 % 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-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of Мабтера, were re-treated with 375 mg/m2 of Мабтера as intravenous infusion weekly for four doses. Three of the patients had received two courses of Мабтера before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38 % (CI95 % 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 favourably with the TTP achieved after the prior course of Мабтера (12.4 months).
Initial treatment, in combination with chemotherapy
In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised 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 Мабтера 375 mg/m2 in combination with CVP (R-CVP). Мабтера was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow up of patients was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour 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 significant clinical difference (p=0.029, log-rank test stratified by centre): 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 randomised trials using Мабтера in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have 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 4.
Table 4 Summary of key results from four phase III randomised studies evaluating the benefit of Мабтера with different chemotherapy regimens in follicular lymphoma
| Study | Treatment, N | Median FU, months | ORR, % | CR, % | Median TTF/PFS/ EFS mo | OS rates, % |
| M39021 | CVP, 159 R-CVP, 162 | 53 | 57 81 | 10 41 | Median TTP: 14.7 33.6 P<0.0001 | 53-months 71.1 80.9 p=0.029 |
| GLSG'00 | CHOP, 205 R-CHOP, 223 | 18 | 90 96 | 17 20 | Median TTF: 2.6 years Not reached p < 0.001 | 18-months 90 95 p = 0.016 |
| OSHO-39 | MCP, 96 R-MCP, 105 | 47 | 75 92 | 25 50 | Median PFS: 28.8 Not reached p < 0.0001 | 48-months 74 87 p = 0.0096 |
| FL2000 | CHVP-IFN, 183 R-CHVP-IFN, 175 | 42 | 85 94 | 49 76 | Median EFS: 36 Not reached p < 0.0001 | 42-months 84 91 p = 0.029 |
EFS - Event Free Survival
TTP - Time to progression or death
PFS - Progression-Free Survival
TTF - Time to Treatment Failure
OS rates - survival rates at the time of the analyses
Maintenance therapy
Previously untreated follicular lymphoma
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), R-CVP (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 randomised to Мабтера maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. Мабтера maintenance treatment consisted of a single infusion of Мабтера at 375 mg/m2 body surface area given every 2 months until disease progression or for a maximum period of two years.
The pre-specified primary analysis was conducted at a median observation time of 25 months from randomization, maintenance therapy with Мабтера resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 5).
Significant benefit from maintenance treatment with Мабтера 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) in the primary analysis (Table 5).
Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed the long-term benefit of Мабтера maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 5).
Table 5 Overview of efficacy results for Мабтера maintenance vs. observation at the protocol-defined primary analysis and after 9 years median follow-up (final analysis)
| Primary analysis (median FU: 25 months) | Final analysis (median FU: 9.0 years) | |||
| Observation N=513 | Мабтера N=505 | Observation N=513 | Мабтера N=505 | |
| Primary efficacy |
|
|
|
|
| Progression-free survival (median) | NR | NR | 4.06 years | 10.49 years |
| log-rank p value | <0.0001 | <0.0001 | ||
| hazard ratio (95% CI) risk reduction | 0.50 (0.39, 0.64) 50% | 0.61 (0.52, 0.73) 39% | ||
| Secondary efficacy |
|
|
|
|
| Overall survival (median) | NR | NR | NR | NR |
| log-rank p value | 0.7246 | 0.7948 | ||
| hazard ratio (95% CI) risk reduction | 0.89 (0.45, 1.74) 11% | 1.04 (0.77, 1.40) -6% | ||
| Event-free survival (median) | 38 months | NR | 4.04 years | 9.25 years |
| log-rank p value | <0.0001 | <0.0001 | ||
| hazard ratio (95% CI) risk reduction | 0.54 (0.43, 0.69) 46% | 0.64 (0.54, 0.76) 36% | ||
| TNLT (median) | NR | NR | 6.11 years | NR |
| log-rank p value | 0.0003 | <0.0001 | ||
| hazard ratio (95% CI) risk reduction | 0.61 (0.46, 0.80) 39% | 0.66 (0.55, 0.78) 34% | ||
| TNCT (median) | NR | NR | 9.32 years | NR |
| log-rank p value | 0.0011 | 0.0004 | ||
| hazard ratio (95% CI) risk reduction | 0.60 (0.44, 0.82) 40% | 0.71 (0.59, 0.86) 39% | ||
| Overall response rate* | 55% | 74% | 61% | 79% |
| chi-squared test p value | <0.0001 | <0.0001 | ||
| odds ratio (95% CI) | 2.33 (1.73, 3.15) | 2.43 (1.84, 3.22) | ||
| Complete response (CR/CRu) rate* | 48% | 67% | 53% | 67% |
| chi-squared test p value | <0.0001 | <0.0001 | ||
| odds ratio (95% CI) | 2.21 (1.65, 2.94) | 2.34 (1.80, 3.03) | ||
* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.
FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to next anti lymphoma treatment.
Мабтера maintenance treatment provided consistent benefit in all predefined 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,CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced effect in elderly patients (> 70 years of age), however sample sizes were small.
Relapsed/Refractory follicular lymphoma
In a prospective, open label, international, multi-centre, phase III trial, 465 patients with relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or Мабтера 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 randomised in a second step to Мабтера maintenance therapy (n=167) or observation (n=167). Мабтера maintenance treatment consisted of a single infusion of Мабтера at 375 mg/m2 body surface area given every 3 months until disease progression or for a maximum period of two years.
The final efficacy analysis included all patients randomised to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 6).
Table 6 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)
|
| CHOP | R-CHOP | p-value | Risk Reduction1) |
| Primary efficacy |
|
|
|
|
| ORR2) | 74 % | 87 % | 0.0003 | Na |
| CR2) | 16 % | 29 % | 0.0005 | Na |
| PR2) | 58 % | 58 % | 0.9449 | Na |
1) Estimates were calculated by hazard ratios
2) Last tumour response as assessed by the investigator. The “primary†statistical test for “response†was the trend test of CR versus PR versus non-response (p < 0.0001)
Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response
For patients randomised to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with Мабтера led to a clinically relevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenance randomisation 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 Мабтера 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 Мабтера maintenance treatment when compared to observation (95 % CI; 45 %-72 %). Kaplan-Meier estimated progression-free rates at 12 months were 78 % in the Мабтера maintenance group vs. 57 % in the observation group. An analysis of overall survival confirmed the significant benefit of Мабтера maintenance over observation (p=0.0039 log-rank test). Мабтера maintenance treatment reduced the risk of death by 56 % (95 % CI; 22 %-75 %).
Table 7 Maintenance phase: overview of efficacy results Мабтера vs. observation (28 months median observation time)
| Efficacy Parameter | Kaplan-Meier Estimate of Median Time to Event (Months) | Risk Reduction | ||
| Observation (N = 167) | Мабтера (N=167) | Log-Rank p value | ||
| Progression-free survival (PFS) | 14.3 | 42.2 | < 0.0001 | 61 % |
| Overall survival | NR | NR | 0.0039 | 56 % |
| Time to new lymphoma treatment | 20.1 | 38.8 | < 0.0001 | 50 % |
| Disease-free survivala | 16.5 | 53.7 | 0.0003 | 67 % |
| Subgroup analysis |
|
|
|
|
| PFS CHOP R-CHOP CR PR OS CHOP R-CHOP |
11.6 22.1 14.3 14.3 NR NR |
37.5 51.9 52.8 37.8 NR NR |
< 0.0001 0.0071 0.0008 < 0.0001 0.0348 0.0482 |
71 % 46 % 64 % 54 % 55 % 56 % |
NR: not reached; a: only applicable to patients achieving a CR
The benefit of Мабтера maintenance treatment was confirmed in all subgroups analysed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (table 7). Мабтера 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). Although subgroups were small, Мабтера maintenance treatment provided a significant benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.
Diffuse large B cell non-Hodgkin's lymphoma
In a randomised, 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 Мабтера 375 mg/m2 plus CHOP (R-CHOP). Мабтера was administered on the first day of the treatment cycle.
The final efficacy analysis included all randomised 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 disease characteristics and disease status. The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in 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, β2 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.
Clinical laboratory findings
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 356 patients evaluated for HACA, 1.1 % (4 patients) were positive.
Chronic lymphocytic leukaemia
In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or Мабтера in combination with FC (R-FC). Мабтера was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 8a and Table 8b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 9) were analysed for efficacy.
In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, log-rank test) (Table 8a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 8b).
Table 8a First-line treatment of chronic lymphocytic leukaemia
Overview of efficacy results for Мабтера plus FC vs. FC alone - 48.1 months median observation time
| Efficacy Parameter | Kaplan-Meier Estimate of Median Time to Event (Months) | Risk Reduction | ||
| FC (N = 409) | R-FC (N=408) | Log-Rank p value | ||
Non-Hodgkin's lymphoma
Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of Мабтера as a single agent or in combination with CHOP therapy (applied Мабтера doses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1), specific clearance (CL2) likely contributed by B cells or tumour 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 Мабтера was 22 days (range, 6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability in CL2 of Мабтера in data from 161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. However, a large component of inter-individual variability remained for CL2 after correction for CD19-positive cell counts and tumour 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 and WHO performance status had no effect on the pharmacokinetics of Мабтера. This analysis suggests that dose adjustment of Мабтера with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.
Мабтера, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4 doses to 203 patients with NHL naive to Мабтера, yielded a mean Cmax following the fourth infusion of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of patients 3 - 6 months after completion of last treatment.
Upon administration of Мабтера at a dose of 375 mg/m2 as an intravenous 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 Мабтера when administered as 6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with Мабтера alone.
Chronic lymphocytic leukaemia
Мабтера was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 µg/mL (range, 97 - 764 µg/mL) after the fifth 500 mg/ m2 infusion and the mean terminal half-life was 32 days (range, 14 - 62 days).
Rheumatoid arthritis
Following two intravenous infusions of Мабтера at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to 7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.
The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first infusion ranged from 157 to 171 μg/mL for 2 x 500 mg dose and ranged from 298 to 341 μg/mL for 2 x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 μg/mL for the 2 × 500 mg dose and ranged from 355 to 404 μg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 × 1000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first infusion for both doses.
The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 170 to 175 μg/mL for 2 x 500 mg dose and 317 to 370 μg/mL for 2 x 1000 mg dose. Cmax following second infusion, was 207 μg/mL for the 2 x 500 mg dose and ranged from 377 to 386 μg/mL for the 2 x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. PK parameters for rituximab were comparable over the two treatment courses.
The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum concentration of 369 µg/mL and a mean terminal half-life of 19.2 days.
Granulomatosis with polyangiitis and microscopic polyangiitis
Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received 375 mg/m2 Мабтера once weekly for four doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these patients appear similar to what has been observed in rheumatoid arthritis patients.
In order to improve traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Excipients: This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial. To be taken into consideration by patients on a controlled sodium diet.
Progressive multifocal leukoencephalopathy
All patients treated with Мабтера for rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including progressive multifocal leukoencephalopathy (PML).
Very rare cases of fatal PML have been reported following use of Мабтера. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.
If a patient develops PML, the dosing of Мабтера must be permanently discontinued.
Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of Мабтера therapy may lead to similar stabilisation or improved outcome.
Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia
Infusion related reactions
Мабтера is associated with infusion-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.
This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the route of administration of Мабтера and can be observed with both formulations.
Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of the Мабтера intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first Мабтера intravenous infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms.
Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately 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.
Patients with a high tumour burden or with a high number (>25 x 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, should 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 >25 x 109/L.
These symptoms are usually reversible with interruption of Мабтера infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of Мабтера. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Since hypotension may occur during Мабтера administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the Мабтера infusion.
Cardiac disorders
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with Мабтера. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.
Haematological toxicities
Although Мабтера is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. Мабтера has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.
Regular full blood counts, including neutrophil and platelet counts, should be performed during Мабтера therapy.
Infections
Serious infections, including fatalities, can occur during therapy with Мабтера. Мабтера should not be administered to patients with an active, severe infection.
Physicians should exercise caution when considering the use of Мабтера in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection.
Cases of hepatitis B reactivation have been reported in subjects receiving Мабтера including fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that Мабтера treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Мабтера. At minimum this should include 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 Мабтера. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of Мабтера in NHL and CLL. The majority of patients had received Мабтера in combination with chemotherapy or as part of a hematopoietic stem cell transplant.
Immunisations
The safety of immunisation with live viral vaccines, following Мабтера therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with Мабтера may receive non-live vaccinations. However with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received Мабтера 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) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.
Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with Мабтера.
Skin reactions
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported. In case of such an event, with a suspected relationship to Мабтера, treatment should be permanently discontinued.
Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis
Methotrexate (MTX) naïve populations with rheumatoid arthritis
The use of Мабтера is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.
Infusion related reactions
Мабтера is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered before each infusion of Мабтера. In rheumatoid arthritis premedication with glucocorticoids should also be administered before each infusion of Мабтера in order to reduce the frequency and severity of IRRs.
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses. The reactions reported were usually reversible with a reduction in rate, or interruption, of Мабтера infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue Мабтера. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.
Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of Мабтера.
There are no data on the safety of Мабтера in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with Мабтера, the occurrence of pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, and those who experienced prior cardiopulmonary adverse reactions, the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with Мабтера and patients closely monitored during administration. Since hypotension may occur during Мабтера infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the Мабтера infusion.
IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to those seen for rheumatoid arthritis patients in clinical trials .
Cardiac disorders
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with Мабтера. Therefore patients with a history of cardiac disease should be monitored closely (see Infusion related reactions, above).
Infections
Based on the mechanism of action of Мабтера and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following Мабтера therapy. Serious infections, including fatalities, can occur during therapy with Мабтера. Мабтера should not be administered to patients with an active, severe infection or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of Мабтера in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobulinaemia. It is recommended that immunoglobulin levels are determined prior to initiating treatment with Мабтера.
Patients reporting signs and symptoms of infection following Мабтера therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of Мабтера treatment, patients should be re-evaluated for any potential risk for infections.
Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of Мабтера for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.
Hepatitis B Infections
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving Мабтера.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Мабтера. At minimum this should include 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 Мабтера. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Late neutropenia
Measure blood neutrophils prior to each course of Мабтера, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection.
Skin reactions
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported. In case of such an event with a suspected relationship to Мабтера, treatment should be permanently discontinued.
Immunisation
Physicians should review the patient's vaccination status and follow current immunisation guidelines prior to Мабтера therapy. Vaccination should be completed at least 4 weeks prior to first administration of Мабтера.
The safety of immunisation with live viral vaccines following Мабтера therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on Мабтера or whilst peripherally B cell depleted.
Patients treated with Мабтера may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with Мабтера and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after Мабтера as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving Мабтера therapy, these should be completed at least 4 weeks prior to commencing the next course of Мабтера.
In the overall experience of Мабтера repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.
Concomitant/sequential use of other DMARDs in rheumatoid arthritis
The concomitant use of Мабтера and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.
There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following Мабтера. The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with Мабтера, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following Мабтера therapy.
Malignancy
Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with Мабтера in rheumatoid arthritis patients the present data do not seem to suggest any increased risk of malignancy. However, the possible risk for the development of solid tumours cannot be excluded at this time.
No studies on the effects of Мабтера on the ability to drive and use machines have been performed, although the pharmacological activity and adverse reactions reported to date suggest that Мабтера would have no or negligible influence on the ability to drive and use machines.
Мабтера should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available.
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of Мабтера.
In patients with non-Hodgkin's lymphoma and CLL, premedication with glucocorticoids should be considered if Мабтера is not given in combination with glucocorticoid-containing chemotherapy.
In patients with rheumatoid arthritis, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to Мабтера infusions to decrease the incidence and severity of infusion related reactions (IRRs).
In patients with granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Мабтера (the last dose of methylprednisolone may be given on the same day as the first infusion of Мабтера). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after Мабтера treatment.
Posology
It is important to check the medicinal product labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) is being given to the patient, as prescribed.
Non-Hodgkin's lymphoma
Follicular non-Hodgkin's lymphoma
Combination therapy
The recommended dose of Мабтера in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles.
Мабтера should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.
Maintenance therapy
- Previously untreated follicular lymphoma
The recommended dose of Мабтера used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (12 infusions in total).
- Relapsed/refractory follicular lymphoma
The recommended dose of Мабтера used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (8 infusions in total).
Monotherapy
- Relapsed/refractory follicular lymphoma
The recommended dose of Мабтера monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.
For retreatment with Мабтера monotherapy for patients who have responded to previous treatment with Мабтера monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.
Diffuse large B cell non-Hodgkin's lymphoma
Мабтера should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of Мабтера have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin's lymphoma.
Dose adjustments during treatment
No dose reductions of Мабтера are recommended. When Мабтера is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
Chronic lymphocytic leukaemia
Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours 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 intravenous shortly before infusion with Мабтера to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.
The recommended dosage of Мабтера in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Мабтера infusion.
Rheumatoid arthritis
Patients treated with Мабтера must be given the patient alert card with each infusion.
A course of Мабтера consists of two 1000 mg intravenous infusions. The recommended dosage of Мабтера is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.
The need for further courses should be evaluated 24 weeks following the previous course. Retreatment should be given at that time if residual disease activity remains, otherwise retreatment should be delayed until disease activity returns.
Available data suggest that clinical response is usually achieved within 16 - 24 weeks of an initial treatment course. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.
Granulomatosis with polyangiitis and microscopic polyangiitis
Patients treated with Мабтера must be given the patient alert card with each infusion.
The recommended dosage of Мабтера for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).
Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following Мабтера treatment, as appropriate.
Special populations
Paediatric population
The safety and efficacy of Мабтера in children below 18 years has not been established. No data are available.
Elderly
No dose adjustment is required in elderly patients (aged >65 years).
Method of administration
The prepared Мабтера solution should be administered as an intravenous infusion through a dedicated line. It should not be administered as an intravenous push or bolus.
Patients should be closely monitored for the onset of cytokine release syndrome. Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin's lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.
) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.First infusion
The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.
Subsequent infusions
All indications
Subsequent doses of Мабтера can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.
Rheumatoid arthritis only
Alternative subsequent, faster, infusion schedule
If patients did not experience a serious infusion related reaction with their first or subsequent infusions of a dose of 1000 mg Мабтера administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions.
Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion.
Мабтера is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Aseptically withdraw the necessary amount of Мабтера, and dilute to a calculated concentration of 1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
