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Drug details for : MABTHERA Solution for Infusion
| Drug class description : | Antineoplastic Agents |
| Generic Name : | Rituximab |
| Drug description : | Concentrate for solution for infusion. Clear, colourless liquid. |
| Presentation : | MabThera 100 mg concentrate for solution for infusion - Single-use vial containing rituximab 100 mg/10 ml. MabThera 500 mg concentrate for solution for infusion - Single-use vial containing rituximab 500 mg/50 ml. Single-use vial containing rituximab 500 mg/50 ml Each ml of solution contains 10 mg of rituximab. Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures. |
| Indications : | Non-Hodgkin's Lymphoma MabThera 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. MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with CVP chemotherapy. MabThera maintenance therapy is indicated for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without MabThera. MabThera is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's Lymphoma in combination with CHOP chemotherapy. Rheumatoid Arthritis MabThera 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 including one or more tumour necrosis factor (TNF) inhibitor therapies. |
| Adult Dosage : | Method of Administration The prepared MabThera solution should be administered as an IV infusion through a dedicated line. Do not administer the prepared infusion solutions as an IV push or bolus. MabThera infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced physician. Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered before each infusion of MabThera. Premedication with glucocorticoids should also be considered (see posology). Patients should be closely monitored for the onset of cytokine release syndrome (See Special Precautions). 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. Mild or moderate infusion-related reactions (Adverse Reactions) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms. Posology non-Hodgkin's lymphoma Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing (CHOP or CVP) chemotherapy for treatment of non-Hodgkin's lymphoma. Follicular non-Hodgkin's Lymphoma The recommended dosage of MabThera used as a single agent for adult patients is 375 mg/m2 body surface area, administered as an IV infusion once weekly for four weeks. The recommended dosage of MabThera in combination with CVP chemotherapy is 375 mg/m2 body surface area for 8 cycles (21 days/cycle), administered on day 1 of each chemotherapy cycle after IV administration of the glucocorticoid component of CVP. Retreatment following relapse in non-Hodgkin's Lymphoma Patients who have responded to MabThera initially have been treated again with MabThera at a dose of 375 mg/m2 body surface area, administered as an IV infusion once weekly for four weeks. Maintenance treatment Patients who have responded to induction treatment may receive maintenance therapy with MabThera given at 375 mg/m2 body surface area once every 3 months until disease progression or for a maximum period of two years. Diffuse large B cell non-Hodgkin's Lymphoma MabThera 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 IV administration of the glucocorticoid component of CHOP. Safety and efficacy of MabThera have not been established in combination with other chemotherapies. First infusion The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent infusions Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr. Dosage adjustments during treatment No dose reductions of MabThera are recommended. When MabThera is given in combination with CHOP or CVP chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied. Rheumatoid Arthritis A course of MabThera consists of two 1000 mg IV infusions. The recommended dosage of MabThera is 1000 mg by IV infusion followed by a second 1000 mg IV infusion two weeks later. Disease activity should be regularly monitored. There are limited clinical data on the safety and efficacy of further courses of therapy with MabThera. In a small observational cohort, approximately 600 patients with evidence of continued disease activity received 2-5 repeated courses of treatment 6-12 months after the previous course. (See Adverse Reactions). Human anti chimeric antibodies (HACA) develop in some patients after the first course of MabThera. The presence of HACA may be associated with the worsening of infusion or allergic reactions after the second infusion of subsequent courses. Furthermore, in one case with HACA, failure to deplete B-cells after receipt of further treatment courses has been observed. Thus, the benefit/risk balance of therapy with MabThera should be carefully considered before administering subsequent courses of Mabthera. If a repeat course of treatment is considered it should not be given at an interval less than 16 weeks. Background therapy with glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during treatment with MabThera. Rheumatoid arthritis patients should receive treatment with 100 mg IV methylprednisolone 30 minutes prior to MabThera to decrease the rate and severity of acute infusion reactions (see method of administration). First infusion of each course The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Second infusion of each course Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr. |
| Child Dosage : | MabThera is not recommended for use in children due to a lack of data on safety and efficacy. |
| Elderly Dosage : | No dose adjustment is required in elderly patients (aged >65 years). |
| Contra Indications : | Contraindications for use in non-Hodgkin's lymphoma Hypersensitivity to the active substance or to any of the excipients of this product or to murine proteins. Contraindications for use in Rheumatoid Arthritis Hypersensitivity to the active substance or to any of the excipients of this product or to murine proteins. Active, severe infections (See Special Precautions). Severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease. |
| Special Precautions : | Non-Hogkin's lymphoma Patients with a high tumour burden or with a high number (25 x 109/l) of circulating malignant cells, who may be at higher risk of especially severe cytokine release syndrome, should only be treated with extreme caution and when other therapeutic alternatives have been exhausted. 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. Severe cytokine release syndrome is characterised by severe dyspnea, 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, hyperphosphaetemia, acute renal failure, elevated 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 (See Adult Dosage) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome. Infusion related adverse reactions including cytokine release syndrome (see Adverse Reactions) accompanied by hypotension and bronchospasm have been observed in 10 % of patients treated with MabThera. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, IV 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 IV 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 MabThera. 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. Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion. Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation heart failure or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. Although MabThera 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. MabThera 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. Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with MabThera. When MabThera is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice. Very rare cases of hepatitis B reactivation, including reports of fulminant hepatitis, have been reported in subjects receiving rituximab, although the majority of these subjects were also exposed to cytotoxic chemotherapy. The reports are confounded by both the underlying disease state and the cytotoxic chemotherapy. Patients with a history of hepatitis B infection should be carefully monitored for signs of active hepatitis B infection when rituximab is used in association with cytotoxic chemotherapy. Very rare cases of Progressive Multifocal Leucoencephalopathy have been reported during post-marketing use of MabThera/Rituxan in NHL (see Adverse Reactions). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Physicians treating patients with non-Hodgkin's Lymphoma should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated. The safety of immunization with any vaccine, particularly live viral vaccines, following MabThera therapy has not been studied. The ability to generate a primary or anamnestic humoral response to any vaccine has also not been studied. Rheumatoid Arthritis Infusion Reactions MabThera is associated with infusion reactions, which may be related to release of cytokines and/or other chemical mediators. Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events (see Adverse Reactions). Most infusion events reported were mild to moderate in severity. The proportion of affected patients decreases with subsequent infusions. The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, IV saline or bronchodilators, and glucocorticoids if required. 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. Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins, including MabThera, to patients. 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 MabThera. The presence of HACA may be associated with worsening infusion or allergic reactions after the second infusion of subsequent courses. In clinical studies 10/990 (1 %) patients with rheumatoid arthritis who received a first infusion of MabThera at any dose experienced a serious reaction during the infusion (see Adverse Reactions). There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with MabThera, 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, the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with MabThera and patients closely monitored during administration. Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the MabThera infusion. Infections Serious infections, including fatalities, can occur during therapy with MabThera (see Adverse Reactions).MabThera should not be administered to patients with an active and/or severe infection (eg. tuberculosis, sepsis and opportunistic infections, see Contraindications) or severely immunocompromised patients (eg. In hypogammaglobulinaemia or where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see Adverse Reactions). Patients reporting signs and symptoms of infection following MabThera therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of MabThera treatment, patients should be re-evaluated for any potential risk for infections. In patients with non-Hodgkin's lymphoma receiving rituximab in combination with cytotoxic chemotherapy, very rare cases of hepatitis B reactivation have been reported (see non-Hodgkin's Lymphoma). Immunization There are no data concerning the use of vaccines while patients are B cell depleted following MabThera therapy. Physicians should review the vaccination status of patients being considered for treatment with MabThera and follow local/national guidance for adult vaccination against infectious disease. Vaccination should be completed at least four weeks prior to first administration of MabThera. Live vaccines are not recommended in patients while B cell depleted. Concomitant/Sequential use of other DMARDs The concomitant use of MabThera and antirheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended. There are insufficient data from clinical trials to fully assess the safety of sequential use of other DMARDs (including TNF inhibitors) following therapy with MabThera (See Interactions). Patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following MabThera therapy. Malignancy Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with MabThera in rheumatoid arthritis patients (see Adverse Reactions) a possible risk for the development of solid tumours cannot be excluded at this time, although present data do not seem to suggest any increased risk. Spontaneous Reporting Cases of fatal Progressive Multifocal Leucoencephalopathy have been reported following off-label use of MabThera for the treatment of certain autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis. The patients with autoimmune diseases had a history of prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of MabThera. No cases of PML have been reported in patients with rheumatoid arthritis. PML has also been reported in patients with autoimmune disease not treated with MabThera. The reported cases had multiple risk factors for PML, including the underlying disease and long-term immunosuppressive therapy. Physicians treating patients with autoimmune diseases should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated. The efficacy and safety of MabThera for the treatment of autoimmune diseases other than rheumatoid arthritis has not been established. |
| Interactions : | Currently, there are limited data on possible drug interactions with MabThera. Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera in rheumatoid arthritis patients. Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. The tolerability of simultaneously or sequential combination of MabThera with chemotherapy other than CHOP or CVP, or agents which are liable to cause depletion of normal B cells is not well defined. In a small cohort of patients with rheumatoid arthritis, 110 patients received subsequent therapy with other DMARDs (including biologicals). Patients received subsequent DMARDs 4-6 months following therapy with MabThera and generally while peripherally B cell depleted. The rate of clinically relevant infections was 7.8 per 100 patient years. Pregnancy There are no adequate data from the use of MabThera in pregnant women. As IgG is known to pass the placental barrier, rituximab may cause B cell depletion in the fetus. For these reasons MabThera should not be given to a pregnant woman unless the potential benefit outweighs the potential risk. Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and for 12 months following MabThera therapy. Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of embryotoxicity in utero. New born offspring of maternal animals exposed to MabThera were noted to have depleted B cell populations during the post natal phase. B cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. Lactation Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment. |
| Adverse Reactions : | Non-Hodgkin's lymphoma Follicular non-Hodgkin's lymphoma Monotherapy The following data are based on 356 patients treated in single-arm studies of MabThera administered as single agent. Most patients received MabThera 375 mg/m2 weekly for 4 doses. These include 39 patients with bulky disease (lesions 10 cm) and 58 patients who received more than one course of MabThera (60 re-treatments). Thirty-seven patients received 375 mg/m2 for eight doses and 25 patients received doses other than 375 mg/m2 for four doses and up to 500 mg/m2 single dose in the Phase I setting. The following adverse events were also reported (< 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 first infusion, usually during the first one to two hours. These events mainly comprised 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 pre-existing cardiac conditions such as angina pectoris or congestive heart failure. The incidence of infusion-related symptoms decreases substantially with subsequent infusions (See Special Precautions). Infections MabThera induced B cell depletion in 70 % to 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 MabThera 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 MabThera 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 patients (0.6 %) experienced grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) during a MabThera infusion and one 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 % versus 92.0 % for any adverse event and 16.0 % versus 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 % versus 15.4 %). The incidence of any adverse event was similar in these two groups (92.3 % in bulky disease versus 89.2 % in non-bulky disease). Re-treatment The percentage of patients reporting any adverse event and grade 3 and 4 adverse events upon re-treatment (N=60) with further courses of MabThera was similar to the percentage of patients reporting any adverse event and grade 3 and 4 adverse events upon initial exposure (N=203) (95.0 % versus 89.7 % for any adverse event and 13.3 % versus 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 MabThera monotherapy for treatment of diffuse large B cell lymphoma. In combination with CVP chemotherapy The following data are based on 321 patients from a randomised phase III clinical trial comparing MabThera plus CVP (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 MabThera 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 four-scale National Cancer Institute (NCI) Common Toxicity Criteria: - 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 one day of an infusion with MabThera) occurred in 9 % of all patients who received R-CVP. These results are consistent with those observed during monotherapy (See Special Precautions and 4.8, Undesirable effects, monotherapy), and included rigors, fatigue, dyspnoea, dyspepsia, nausea, rash NOS, 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 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 two 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 non-Hodgkin's Lymphoma were randomised in a first phase to induction treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or MabThera plus CHOP (R-CHOP). Patients who responded to induction treatment with CHOP or R-CHOP were randomised in a second phase to receive no further treatment (observation) or MabThera maintenance treatment. MabThera maintenance treatment consisted of a single infusion of MabThera at 375 mg/m2 body surface area administered every 3 months for a maximum period of 2 years or until disease progression. 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 one day of a rituximab infusion) occurred in < 1% of patients treated with MabThera maintenance. Infections The proportion of patients with grade 1 to 4 infections was 25 % in the observation group and 45 % in the MabThera group with grade 3-4 infections in 3 % of patients on observation and 11 % receiving MabThera maintenance treatment. Grade 3 to 4 infections reported in 1 % of patients in the MabThera 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 %, MabThera 10 %), viruses (observation 7 %, MabThera 11 %) and fungi (observation 2 %, MabThera 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 vs 29 % of patients in the MabThera arm, and neutropenia was reported in 12 % of patients on observation and in 23 % of patients on MabThera. There was a higher incidence of grade 3-4 neutropenia (observation 4 %, MabThera 10 %) and leucopenia (observation 2 %, MabThera 5 %) in the MabThera arm compared to the observation arm. The incidence of grade 3 to 4 thrombocytopenia (observation 1 %, MabThera < 1 %) was low. Cardiac disorders The incidence of grade 3 to 4 cardiac disorders was comparable between the two treatment groups (4 % in observation, 5 % in MabThera). Cardiac events were reported as serious adverse event in < 1 % of patients on observation and in 3 % of patients on MabThera: atrial fibrillation (1 %), myocardial infarction (1 %), left ventricular failure (< 1%), myocardial ischemia (< 1%). 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 MabThera groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during MabThera treatment. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera 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 Infusion-related reactions Grade 3 and 4 infusion-related reactions (defined as starting during or within one day of an infusion with MabThera) occurred in approximately 9 % of patients at the time of the first cycle of R-CHOP. The incidence of grade 3 and 4 infusion-related reactions decreased to less than 1 % by the eighth cycle of R-CHOP. The signs and symptoms were consistent with those observed during monotherapy (See Special Precautions and 4.8, Undesirable effects, 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 (i.e. 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 two 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 two treatment groups. Cardiac events 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 MabThera 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. Neurologic events During the treatment period, four patients (2 %) in the R-CHOP group, 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. Rheumatoid Arthritis The clinical efficacy of MabThera, given together with methotrexate (MTX) was studied in three double blind controlled clinical trials (one phase III two phase II trials) in patients with rheumatoid arthritis. More than 1000 patients received at least one treatment course and were followed for periods ranging from 6 months to over 3 years; nearly 600 patients received two or more courses of treatment during the follow up period. Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). MabThera infusions were administered after an IV infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. Reactions, which were reported by at least 1 % of patients and more frequently by patients who had received at least one infusion of MabThera than among patients that had received placebo in the phase III trial and the combined population included in phase II studies, are listed in Table 5. The most frequent adverse reactions considered due to receipt of 2x1000 mg MabThera in Phase II and III studies were acute infusion reactions. Infusion reactions occurred in 15 % patients following the first infusion of rituximab and 5 % in placebo patients. Infusion reactions decreased to 2 % following the second infusion in both rituximab and placebo groups. Medically significant events reported uncommonly in the rituximab treated population and considered potential reactions to treatment include the following: General Disorders: Generaliseded oedema Respiratory Disorders: Bronchospasm, wheezing, laryngeal oedema Skin and Subcutaneous Disorders: Angioneurotic oedema, generaliseded 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 first exposure. However, worsening of infusion or allergic reactions and failure to B cell deplete following rituximab cannot be excluded in HACA positive patients after repeated exposure to rituximab on the basis of available data. The incidence of acute infusion reactions following subsequent treatment courses was generally lower than the incidence following the first infusion of MabThera. Acute Infusion reactions Symptoms suggesting an acute infusion reaction (pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 79/540 (15 %) patients following their first exposure to MabThera; In a study comparing the effect of glucocorticoid regimen, these events were observed in 5/149 (3 %) of patients following their first rituximab placebo infusion and 42/192 (22 %) of patients receiving their first infusion of 1000 mg rituximab. Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events. Of the patients who received 1000 mg rituximab without premedication with glucocorticoids, 18/65 (28 %) experienced an acute infusion reaction, compared with 24/127 (19 %) in patients given IV glucocorticoid premedication, respectively. Infections The rate of infection was approximately 0.9 per patient year in MabThera treated patients. The infections consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of clinically significant infection, some of which were fatal, was 0.05 per patient year in MabThera 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 rituximab, 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 MabThera. In placebo controlled studies, serious cardiac events were reported equally in MabThera and placebo treated patients (2%). Post-marketing experience As part of the continuing post-marketing surveillance of MabThera safety, the following serious adverse reactions have been observed: non-Hodgkin's Lymphoma Below are serious adverse reactions observed during post-marketing surveillance Infections and infestations Very rare (< 1/10,000): Serious viral infection1 Blood and lymphatic system disorders Rare ( 1/10,000, < 1/1000): Late neutropenia2 Very rare (< 1/10,000): Pancytopenia Aplastic anaemia Transient increase in serum IgM levels3 Cardiovascular system Rare ( 1/10,000, < 1/1000): *Severe cardiac events4 Very rare (< 1/10,000): *Heart failure4 *Myocardial infarction4 Ear and labyrinth disorders Very rare (< 1/10,000): † Hearing loss Eye disorders Very rare (< 1/10,000): † Severe vision loss General disorders and administration site conditions Very rare (< 1/10,000): *Multi-organ failure Immune system disorders Uncommon ( 1/1000, < 1/100): Infusion related reactions Rare ( 1/10,000, < 1/1000): Anaphylaxis Very rare (< 1/10,000): *Tumour lysis syndrome *Cytokine release syndrome Serum sickness Hepatitis B reactivation5 Nervous system disorders Very rare (< 1/10,000): Cranial neuropathy Peripheral neuropathy † Facial nerve palsy † Loss of other senses Renal and urinary disorders Very rare (< 1/10,000): *Renal failure Respiratory, thoracic and mediastinal disorders Rare ( 1/10,000, < 1/1000): *Bronchospasm Very rare (< 1/10,000): *Respiratory failure Pulmonary infiltrates Interstitial pneumonitis Gastrointestinal disorders Very rare (< 1/10,000): Gastro-intestinal perforation6 Skin and subcutaneous tissue disorders Very rare (< 1/10,000): Severe bullous skin reactions Toxic epidermal necrolysis7 Vascular disorders Very rare (< 1/10,000): Vasculitis (predominately cutaneous) Leucocytoclastic vasculitis *Associated with infusion-related reactions. Rarely fatal cases reported † Signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 1 Other serious viral infections, either new, reactivation or exacerbation some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a 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 leucoencephalopathy (PML)) and Hepatitis C virus. 2 Neutropenia that has occurred more than four weeks after the last infusion of MabThera. 3 In post-marketing studies of rituximab 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. 4 Observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 5 Very rare cases of hepatitis B reactivation, have been reported, the majority of which were in subjects receiving rituximab in combination with cytotoxic chemotherapy. 6 Gastro-intestinal perforation in some cases leading to death has been observed in patients receiving rituximab for treatment of Non Hodgkin Lymphoma. In the majority of these cases, rituximab was administered with chemotherapy. 7 Including fatal cases |
| Manufacturer : | Roche |
| Drug Availability : | (POM) |
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