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4.1 Therapeutic indications
MabThera is indicated in adults for the following indications:
Non-Hodgkin’s lymphoma (NHL)
MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.
MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy. MabThera maintenance therapy is indicated for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without MabThera.
MabThera 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.
MabThera 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)
MabThera in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy.
See section 5.1 for further information.
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 (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.
MabThera 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.
4.2 Posology and method of administration
MabThera infusions should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available.
Posology
Non-Hodgkin’s lymphoma
Dosage adjustments during treatment
No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
Follicular non-Hodgkin's lymphoma
Combination therapy
The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular NHL lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles.
MabTthera should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.
Monotherapy/Maintenance therapy
Previously untreated follicular lymphoma
The recommended dose of MabThera 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.
Relapsed/refractory follicular lymphoma
The recommended dose of MabThera used as a maintenance treatment for patients with relapsed/refractory follicular NHL lymphoma who have responded to induction treatment with chemotherapy, with or without MabThera 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.
Monotherapy
Relapsed/refractory follicular lymphoma
The recommended dose of MabThera 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 MabThera monotherapy for patients who have responded to previous treatment with MabThera monotherapy for relapsed/refractory follicular NHLlymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).
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 intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of MabThera have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.
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 MabThera to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.
The recommended dosage of MabThera 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 MabThera infusion.
Rheumatoid arthritis
Patients treated with MabThera must be given the patient alert card with each infusion (see Annex IIIA – Labelling).
A course of MabThera consists of two 1000 mg intravenous infusions. The recommended dosage of MabThera 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.
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 sections 4.8 and 5.1).
Human anti chimeric antibodies (HACA) develop in some patients after the first course of MabThera (see section 5.1). 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.
PRheumatoid arthritis patients should receive treatment with 100 mg intravenous methylprednisolone to be completed 30 minutes prior to MabThera infusions to decrease the rateincidence and severity of acute infusion related 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.
Special populations
Paediatric use
The safety and efficacy of MabThera in children has not been established.
MabThera is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Elderly
No dose adjustment is required in elderly patients (aged >65 years).
Method of aAdministration
Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered before each infusion of MabThera.
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.
The prepared MabThera 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 (see section 4.4). 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 (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.
4.3 Contraindications
Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
Hypersensitivity to the active substance or to any of the excipients or to murine proteins.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state
Contraindications for use in rheumatoid arthritis
Hypersensitivity to the active substance or to any of the excipients or to murine proteins.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state
Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).
4.4 Special warnings and precautions for use
Progressive Multifocal multifocal Leukoencephalopathyleukoencephalopathy
All patients treated with MabThera for rheumatoid arthritis must be given the patient alert card with each infusion (see end of Annex IIIA - Labelling). The alert card contains important safety information for patients regarding potential increased risk of infections, including progressive multifocal leukoencephalopathy (PML).
Use of MabThera maybe associated with an increased risk of Progressive Multifocal Leukoencephalopathy (PML). 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, 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 MabThera 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 MabThera therapy may lead to similar stabilisation or improved outcome.
Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
Infusion reactions
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 only be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.
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 lLactate 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 (see section 4.2) 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 of all kinds have been observed in 77% of patients treated with MabThera (including cytokine release syndrome (see section 4.8) accompanied by hypotension and bronchospasm have been observed in 10 % of patients) see section 4.8treated with MabThera. These symptoms are usually reversible with interruption of MabThera 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 glucocorticooids, 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.
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.
Cardiac disorders
Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/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.
Haematological toxicities
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.
Regular full blood counts, including neutrophil and platelet counts, should be performed during MabThera therapy. 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 (cyclophosphamide, vincristine, and prednisone) chemotherapy, regular full blood counts should be performed according to usual medical practice.
Infections
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).
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 section 4.8).
Cases of hepatitis B reactivation have been reported in subjects receiving MabThera 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 suggest that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be considered for high risk patients before initiation of treatment with MabThera. Carriers of hepatitis B and patients with a history of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during and for several months (up to seven) following MabThera therapy.
Very rare cases of Progressive progressive Multifocal multifocal Leukoencephalopathy leukoencephalopathy (PML) have been reported during post-marketing use of MabThera in NHL and CLL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.
The safety of immunization with live viral vaccines, following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-live vaccinations. However with non-live vaccines response rates may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received MabThera 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. 69% 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 titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with MabThera
Rheumatoid arthritis
Methotrexate (MTX) naïve populations
The use of MabThera is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.
Infusion related reactions
MabThera is associated with infusion related reactions (IRR), which may be related to release of cytokines and/or other chemical mediators. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of these events and should be administered prior to MabThera treatment (see section 4.2 and section 4.8).
Most infusion events reported 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 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, intravenous 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 intravenous 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 (see section 5.1).
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 section 4.8).
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 section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. in hypogammaglobulinemia 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, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with MabThera.
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.
Very rare cases of fatal Pprogressive Mmultifocal Lleukoencephalopathy (PML) have been reported following use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and Vasculitis. These cases involved patients with multiple risk factors for PML, including the underlying disease and long-term immunosuppressive therapy or chemotherapy.
In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic chemotherapy, very rare cases of fatal hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera.
Immunization
Physicians should review the patient’s vaccination status and follow current immunization guidelines prior to MabThera therapy. Vaccination should be completed at least 4 weeks prior to first administration of MabThera.
The safety of immunization with live viral vaccines following MabThera therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on MabThera or whilst peripherally B cell depleted.
Patients treated with MabThera may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomized study, patients with RA treated with MabThera 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 MabThera as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the next course of MabThera.
In the overall experience of MabThera repeat treatment over one year, the proportions of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.
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 limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following MabThera (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with MabThera, however 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 section 4.8) a possible risk for the development of solid tumours cannot be excluded at this time, althoughthe 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.
4.5 Interaction with other medicinal products and other forms of interaction
Currently, there are limited data on possible drug interactions with MabThera.
In CLL patients, co-administration with MabThera did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.
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.
In a small cohort of patients with rheumatoid arthritis, 280 patients received subsequent therapy with other DMARDs of whom 185received 283 patients received subsequent therapy with a biologic DMARD following MabThera. In these patients the rate of clinically relevant infection while on MabThera only was 6.01 per 100 patient years compared to 4.97 per 100 patients years following treatment with the biologic DMARD.
4.8 Undesirable effects
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.
The safety profile of MabThera in patients with severe rheumatoid arthritis (RA) is summarized in the sections below. In clinical trials more than The clinical efficacy of MabThera, given together with methotrexate was studied in three double blind controlled clinical trials (one phase III two phase II trials) in patients with rheumatoid arthritis. More than 10003100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 35 years; nearly 600approximately 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 MabThera (see section 4.4)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 intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. ADRs, which occurred with at least a 2 % difference compared to the control arm 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 the Table belowEvents are listed in Table 2. Frequencies are defined as very common (≥1/10), and 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 2x1000 mg MabThera werein Phase II and III studies were acute infusion related reactions. 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. 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. In addition to adverse reactions seen in RA clinical trials for rituximab, progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness- like reaction have been reported during post marketing experience.
Table 2 Summary of aAdverse dDrug rReactions rReported in cClinical tTrials or dDuring pPostmarketing sSurveillance oOccurring in pPatients with rRheumatoid aArthritis receiving MabThera
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System Organ Class
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Very Common
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Common
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Uncommon
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Very rare
|
|
Infections and Infestations
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any infection, upper respiratory tract infection, urinary tract infections
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Bronchitis, sinusitis, gastroenteritis, tinea pedisurinary tract infections
|
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PML, reactivation of hepatitis B
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Blood and lymphatic system disorders
|
|
|
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Serum sickness-like reaction
|
|
Immune System Disorders
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*Infusion related reactions (hypertension, nausea, rash, pyrexia, pruritischills, rhinitis, urticaria, throat irritation, hot flush), hypertension, rash, pyrexia, pruritus, throat irritation and hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythema)
|
|
*Infusion related reactions (generalized oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalized pruritis, anaphylaxis, anaphylactoid reaction)
|
|
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General disorders and administration site conditions
|
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Metabolism and Nutritional Disorders
|
|
hypercholesterolemia
|
|
|
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Nervous System disorders
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headache
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pParaesthesia, migraine, dizziness, sciatica
|
|
|
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Skin and Subcutaneous Tissue Disorders
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|
alopecia
|
|
|
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Psychiatric Disorders
|
|
depression, anxiety
|
|
|
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Gastrointestinal Disorders
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Dyspepsia, diarrhoea, gastro-oesophageal reflux, mouth ulceration, upper abdominal pain
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|
|
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Musculo skeletal disorders
|
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arthralgia / musculoskeletal pain, osteoarthritis , bursitis
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|
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*Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. Infusion related reactions may occur as a result of hypersensitivity and/or to the mechanism of action.
The following terms have been reported as adverse events during clinical trials, however, were reported at a similar incidence in the MabThera-arms compared to control arms: lower respiratory tract infections/pneumonia, abdominal pain upper, muscle spasms and asthenia.
Multiple cCourses
The limited clinical trial data on mMultiple courses of treatment of RA patients seem to beare associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by infusion-related reactions (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.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.
Infusion-related reactions
The most frequent ADRs following receipt of MabThera in clinical studies were infusion-related reactions (IRRs) (refer to Table 2). Among the 3189 patients treated with MabThera, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to MabThera. The incidence of IRRs decline for all subsequent infusions. In clinical studies fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs. 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 (see section 4.2).
Symptoms suggesting an acute infusion reaction (e.g. pruritis, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 79/540 (15 %) patients following their 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 intravenous 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 intravenous glucocorticoid premedication, respectively.
Infections
The overall rate of infection was approximately 0.994 per 100 patient years in MabThera treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of clinically significant infections, that were serious or required IV antibiotic some of which were fatal, was approximately 40.05 per 100 patient years in MabThera treated patients. The rate of serious infections did not show any significant increase following multiple courses of MabThera. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the Mabthera arms compared to control arms.
Cases of pProgressive mMultifocal Lleukoencephalopathy with fatal outcome have been reported following use of MabThera for the treatment of autoimmune diseases. This includes Rheumatoid Arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis.
In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera (see Section 4.4).
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
Serious cardiac events were reported at a rate of 1.3 per 100 patient years in the MabThera treated patients compared to 1.3 per 100 patients years in placebo treated patients. The proportions of patients experiencing cardiac events (all or serious) did not increase over multiple courses.
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 %).
4.9 Overdose
There has been no experience of overdose in human clinical trials. However, single doses higher than 1000 mg have not been tested in controlled clinical trials. in patients with autoimmune disease. The highest dose tested to date is 5g in patients with chronic lymphocytic leukaemia. No additional safety signals were identified.
In the postmarketing setting five cases of rituximab 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.
5.1 Pharmacodynamic properties
Maintenance therapy
Previously untreated follicular lymphoma
In a prospective, open label, international, multi-center, 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 randomized to MabThera maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. MabThera maintenance treatment consisted of a single infusion of MabThera at 375 mg/m2 body surface area given every 2 months until disease progression or for a maximum period of two years.
After a median observation time of 25 months from randomization, maintenance therapy with MabThera resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to oberservation in patients with previously untreated follicular lymphoma (Table 4).
Significant benefit from maintenance treatment with MabThera 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) (Table 4).
Table 4 Maintenance phase: overview of efficacy results MabThera vs. observation (25 months median observation time)
|
|
Observation
N=513
|
Rituximab
N=505
|
Log-rank P value
|
Risk reduction
|
|
Primary Efficacy
|
|
|
|
|
|
|
PFS (median)
|
NR
|
NR
|
<0.0001
|
50%
|
|
Secondary Efficacy
|
|
|
|
|
|
|
EFS (median)
|
37.8 months
|
NR
|
< 0.0001
|
46%
|
|
|
OS (median)
|
NR
|
NR
|
0.7246
|
11%
|
|
|
TNLT (median)
|
NR
|
NR
|
0.0003
|
39%
|
|
|
TNCT (median)
|
NR
|
NR
|
0.0011
|
40%
|
|
|
ORR*
|
55.0%
|
74.0%
|
< 0.0001
|
[Odds ratio = 2.33]
|
|
|
Complete Response (CR/CRu) rate*
|
47.7%
|
66.8%
|
< 0.0001
|
[Odds ratio = 2.21]
|
|
|
|
|
|
|
|
*At end of maintenance/observation;
PFS: progression-free survival; EFS: event-free survival; OS: overall survival; TNLT: time to next anti-lymphoma treatment; TNCT: Time to next chemotherapy treatment; ORR: overall response rate: NR: Not Reached at time of clinical cut-off
MabThera 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 NHL lymphoma were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera 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 MabThera maintenance therapy (n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of MabThera 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 randomized 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 NHL lymphoma when compared to CHOP (see Table 45).
Table 45 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
|
naNa
|
|
CR2)
|
16 %
|
29 %
|
0.0005
|
naNa
|
|
PR2)
|
58 %
|
58 %
|
0.9449
|
naNa
|
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
Clinical Experience in rRheumatoid aArthritis
The efficacy and safety of MabThera in alleviating the symptoms and signs of rheumatoid arthritis in patients with an inadequate response to TNF-inhibitiors was demonstrated in three a pivotal randomized, controlled, double-blind, multicenter studiesstudy (Study 1).
Study 1 was a double blind comparative study which includedevaluated 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to the criteria of the American College of Rheumatology (ACR). MabThera was administered as two IV infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of MabThera or placebo in combination with MTX. All patients received concomitant 60 mg oral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion.Eligible patients had active rheumatoid arthritis for at least 6 months, diagnosed according to the criteria of the American College of Rheumatology (ACR), with swollen joint count (SJC) (8 (66 joint count)), and tender joint count (TJC) (8 (68 joint count)) and elevated CRP or ESR. The primary endpoint was the percentproportion of patients who achieved an ACR20 response at week 24. Patients received two 1000 mg intravenous infusions of MabThera, each following an intravenous infusion of 100 mg methylprednisone and separated by an interval of 15 days. All patients received concomitant oral methotrexate (10-25 mg/week) and 60 mg oral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. Patients were followed beyond week 24 for long term endpoints, including radiographic assessment at 56 weeks and at 104 weeks. During this time, 81 % of patients, from the original placebo group received rituximab between weeks 24 and 56, under an open label extension study protocol.
Studies of rituximab in patients with early arthritis (patients without prior methotrexate treatment and patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) have met their primary endpoints. MabThera is not indicated for these patients, since the safety data about long-term rituximab treatment are insufficient, in particular concerning the risk of development of malignancies and PML.
Study 2 was a randomized, double-blind, double-dummy, controlled, 3 x 3 multifactorial study which compared two different dose levels of rituximab given with or without one of two peri infusional corticosteroid regimens in combination with weekly methotrexate in patients with active rheumatoid arthritis which had not responded to treatment with 1 to 5 other DMARDs.
Study 3 was a double-blind, double-dummy, controlled study evaluating rituximab monotherapy, and rituximab in combination with either cyclophosphamide or methotrexate in patients with active rheumatoid arthritis which had not responded to one or more prior DMARDs
The comparator group in all three studies was weekly methotrexate (10-25mg weekly).
Disease activity outcomes
In all three studies, rituximabMabThera 2 x 1000 mgin combination with methotrexate significantly increased the proportion of patients achieving at least a 20 % improvement in ACR score compared with patients treated with methotrexate alone (Table 89). Across all development studies tThe treatment effectbenefit was similar in patients independent of rheumatoid factor status, age, gender, body surface area, race, number of prior treatments or disease status.
Clinically and statistically significant improvement was also noted on all individual components of the ACR response (tender and swollen joint counts, patient and physician global assessment, disability index scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL).
Table 89 Clinical response outcomes Cross-Study Comparison of ACR Responses at week 24primary endpoint in study 1Primary Endpoint timing (ITT population)
|
|
ACR Response
Outcome†
|
Placebo+MTX
|
Rituximab+MTX
(2 x 1000 mg)
|
|
Study 1
|
|
N= 201
|
N= 298
|
|
|
ACR20
|
36 (18%)
|
153 (51%)***1
|
|
|
ACR50
|
11 (5%)
|
80 (27%)1***
|
|
|
ACR70
|
3 (1%)
|
37 (12%)***1
|
|
|
EULAR Response (Good/Moderate)
|
44 (22%)
|
193 (65%)***
|
|
|
Mean Change in DAS
|
-0.34
|
-1.83***
|
|
Study 2
|
|
N= 143
|
N= 185
|
|
|
ACR20
|
45 (31%)
|
96 (52%)2
|
|
|
ACR50
|
19 (13%)
|
61 (33%)2
|
|
|
ACR70
|
6 (4%)
|
28 (15%)2
|
|
Study 3
|
|
N= 40
|
N= 40
|
|
|
ACR20
|
15 (38%)
|
28 (70%)3
|
|
|
ACR50
|
5 (13%)
|
17 (43%)3
|
|
|
ACR70
|
2 (5%)
|
9 (23%)3
|
† Outcome at 24 weeks
Significant difference from placebo + MTX at the primary timepoint: ***p ≤ 0.0001
1 p £ 0.0001; 2 p £ 0.001; 3 p <0.05
MTX – Methotrexate
In study 3, the ACR20 response in patients Patients treated with rituximabMabThera +in combination with methotrexate alone was 65 % compared with 38 % on methotrexate alone (p=0.025).
Rituximab treated patients had a significantly greater reduction in disease activity score (DAS28) than patients treated with methotrexate alone (Table 89). Similarly, a (Mean change in DAS28 from baseline -1.9 vs. -0.4, p<0.0001, respectively). A good to moderate European League Against Rheumatism (EULAR) response was achieved by significantly more rituximabMabThera treated patients treated with MabThera and methotrexate compared to patients treated with methotrexate alone (Table 89).
Radiographic response
Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.
In Study 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor therapies, receiving MabThera in combination with methotrexate structural joint damage was assessed radiographically and expressed as change in modified total Sharp score and its components, the erosion score and joint space narrowing score. Patients originally receiving rituximab/MTX demonstrated significantly less radiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of the patients originally receiving methotrexate alone, 81 % received rituximab either as rescue between weeks 16-24 or in the extension trial, before week 56. A higher proportion of patients receiving the original rituximabMabThera/MTX treatment also had no erosive progression over 56 weeks (Table 910).
Table 910 Radiographic outcomes at 1 year (mITT population)mean changes over 56 weeks in Study 1
|
|
Placebo+MTX
|
Rituximab +MTX
2 × 1000 mg
|
|
Study 1
|
(n = 184)
|
(n = 273)
|
|
Mean Change from Baseline:
|
|
|
|
Modified Total Sharp score
|
2.31
|
1.00*
p=0.0046
|
|
Erosion Score
|
1.32
|
0.59*
p=0.0114
|
|
Joint Space narrowing score
|
0.99
|
0.41**
p=0.0006
|
|
Proportion of patients with no radiographic change
|
46%
|
53%
|
|
Proportion of patients with no erosiveerosive progression over 56 weekschange
|
52%
|
61%*
p=0.0494
|
150 patients originally randomized to placebo + MTX in Study 1 received at least one course of RTX + MTX by one year
* p <0 05, ** p < 0.001, *** p < 0.0001
Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years in study 1 demonstrated significantly reduced progression of structural joint damage in patients receiving MabThera in combination with methotrexate compared to methotrexate alone as well as a significantly higher proportion of patients with no progression of joint damage over the 2 year period.
Physical fFunction and qQuality of life outcomes
Significant reductions in disability index (HAQ-DI), and fatigue (FACIT-Fatigue) scores (Table 10), and improvement in both the physical and mental health domains of the SF-36 were observed in patients treated with rituximabMabThera compared to patients treated with methotrexate alone. (SF-36 Physical 5.8 vs. 0.9, SF-36 Mental 4.7 vs. 1.3, respectively, Study 1).The proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in HAQ-DI (defined as an individual total score decrease of >0.22) was also higher than among patients receiving methotrexate alone (Table 11).
Significant improvement in health related quality of life was also demonstrated with significant improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. Further, a significantly higher proportion of patients achieved MCIDs for these scores (Table 11).
Table 1011 Disease activityPhysical Function and Quality of Life outcomes at week 24 in Sstudy 1
|
Week 24 response:
Change from baseline
|
Placebo+MTX1
N= 201
mean (SD)
|
Rituximab+MTX1
N= 298
mean (SD) switch
|
p-value
|
|
EULAR Good/moderate
|
22%
|
65%
|
|
|
HAQ2
|
-0.1 (0.5)
|
-0.4 (0.6)
|
<0.0001
|
|
FACIT-F3
|
-0.5 (9.8)
|
-9.1 (11.3)
|
<0.0001
|
1 MTX, 2 Health assessment questionnaire (HAQ),3 Functional assessment of chronic illness therapy (FACIT-F)
|
Outcome†
|
Placebo+MTX
|
Rituximab+MTX
(2 x 1000 mg)
|
|
Mean change in HAQ-DI
|
n=201
0.1
|
n=298
-0.4***
|
|
% HAQ-DI MCID
|
20%
|
51%
|
|
Mean change in FACIT-T
|
-0.5
|
-9.1***
|
|
Mean Change in SF-36 PHS
|
n=197
0.9
|
n=294
5.8***
|
|
% SF-36 PHS MCID
|
13%
|
48%***
|
|
Mean Change in SF-36 MHS
|
1.3
|
4.7**
|
|
% SF-36 MHS MCID
|
20%
|
38%*
|
† Outcome at 24 weeks
Significant difference from placebo at the primary time point: * p < 0.05, **p < 0.001 ***p ≤ 0.0001
MCID HAQ-DI ≥0.22, MCID SF-36 PHS >5.42, MCID SF-36 MHS >6.33
At week 24, in all three studies, the proportion of rituximab treated patients showing a clinically relevant improvement in HAQ-DI (defined as an individual total score decrease of >0.25) was higher than among patients receiving methotrexate alone.
Efficacy in autoantibody (RF and or anti-CCP) seropositive patients
Patients seropositive to Rheumatoid Factor (RF) and/or anti- Cyclic Citrullinated Peptide (anti-CCP) who were treated with MabThera in combination with methotrexate showed an enhanced response compared to patients negative to both.
Efficacy outcomes in MabThera treated patients were analysed based on autoantibody status prior to commencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP at baseline had a significantly increased probability of achieving ACR20 and 50 responses compared to seronegative patients (p=0.0312 and p=0.0096) (Table 1112). These findings were replicated at Week 48, where autoantibody seropositivity also significantly increased the probability of achieving ACR70. At week 48 seropositive patients were 2-3 times more likely to achieve ACR responses compared to seronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESR compared to seronegative patients (Figure 1).
Table 1112 Summary of efficacy by baseline autoantibody status
|
|
Week 24
|
Week 48
|
|
|
Seropositive
(n=514)
|
Seronegative
(n=106)
|
Seropositive
(n=506)
|
Seronegative
(n=101)
|
|
ACR20 (%)
|
62.3*
|
50.9
|
71. 1*
|
51.5
|
|
ACR50 (%)
|
32.7*
|
19.8
|
44.9**
|
22.8
|
|
ACR70 (%)
|
12.1
|
5.7
|
20.9*
|
6.9
|
|
EULAR Response (%)
|
74.8*
|
62.9
|
84.3*
|
72.3
|
|
Mean change DAS28-ESR
|
-1.97**
|
-1.50
|
-2.48***
|
-1.72
|
Significance levels were defined as * p<0.05 **p<0.001, ***p<0.0001.
Figure 1: Change from baseline of DAS28-ESR by baseline autoantibody status
Long-term efficacy with multiple course therapy
Treatment with MabThera in combination with methotrexate over multiple courses resulted in sustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESR and EULAR responses which was evident in all patient populations studied (Figure 2). Sustained improvement in physical function as indicated by the HAQ-DI score and the proportion of patients achieving MCID for HAQ-DI were observed.
Figure 2: ACR responses for 4 treatment courses (24 weeks after each course (within pPatient, within visit) in patients with an inadequate response to TNF-inhibitors (n=146)
Laboratory evaluationsClinical laboratory finding
A total of 96392/10393095 (9.21312.7 %) patients with rheumatoid arthritis tested positive for HACA in clinical studies following therapy with MabThera. The emergence of HACA was not associated with clinical deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. The presence of HACA may be associated with 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.
In 675 patients in clinical studies, the following shifts in anti-nuclear antibody (ANA) status were observed before and after rituximab: 26 % ANA negative to positive and 32 % ANA positive to negative. There was no evidence of new onset autoimmune disease.
In rheumatoid factor (RF) positive patients, marked decreases were observed in rheumatoid factor concentrations following treatment with rituximab in all three studies (range 45-64 %).
Hyperuricemia (grade 3/4) occurred in 143/950 (15 %) patients, with the majority post-infusion on days 1 and/or 15. It was not associated with any clinical symptoms, and none of these patients developed evidence of renal disease.
Plasma total immunoglobulin concentrations, total lymphocytes counts, and white cells generally remained within normal limits following MabThera treatment, with the exception of a transient drop in white cells counts over the first four weeks following therapy. Titers of Ig G antigen specific antibody to mumps, rubella, varicella, tetanus toxoid, influenza and streptococcus pneumococci remained stable over 24 weeks following exposure to MabThera in rheumatoid arthritis patients.
Multiple course therapy
Following completion of the 24-week double blind comparative study period, patients were permitted to enroll into an open-label long term follow up study. Patients received subsequent courses of MabThera as needed according to the treating clinician’s assessment of disease activity and irrespective of the peripheral B lymphocyte count. The time interval between courses was variable, with the majority of patients receiving further therapy 6-12 months after the previous course. Some patients required even less frequent retreatment. The response to further therapy was at least the same magnitude as that following the initial treatment course, as evidenced by the change from baseline DAS28. Mean change in DAS28 from original baseline: first course -2.18, second course -2.75.
5.2 Pharmacokinetic properties
Rheumatoid arthritis
Following two intravenous infusions of rituximab 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 lL/day (range, 0.091 to 0.67 lL/day), and mean steady-state distribution volume was 4.6 lL (range, 1.7 to 7.51 lL). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 lL/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. Following the intravenous administration of 500 and 1000 mg doses of rituximab on two occasions, two weeks apart, mean Cmax values were 183 mg/mL (range, 81.8 to 279 mg/mL) and 370 mg/mL (212 to 637 mg/mL), and mean half-lives were 17.9 days (range, 12.3 to 31.3 days) and 19.7 days (range, 12.3 to 34.6 days), respectively. No pharmacokinetic data are available in patients with hepatic or renal impairment. No pharmacokinetic data are available for patients receiving multiple courses of therapy.
The pharmacokinetics of rituximab were assessed following two 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 mg/mlL for 2 x 500 mg dose and ranged from 298 to 341 mg/mlL for 2 x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 mg/mlL for the 2 ´ 500 mg dose and ranged from 355 to 404 mg/mlL 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 mg/mlL for 2 x 500 mg dose and 317 to 370 mg/mlL for 2 x 1000 mg dose. Cmax following second infusion, was 207 mg/mlL for the 2 x 500 mg dose and ranged from 377 to 386 mg/mlL 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 mg/mlL and a mean terminal half-life of 19.2 days.
|
