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Drug Details

MABTHERA Solution for Infusion

Drug Class Description
Antineoplastic Agents
Generic Name
Rituximab
Presentation
Concentrate for solution for infusion. Clear, colourless liquid.
Description
MabThera 100 mg (10 mg/ml) concentrate for solution for infusion MabThera 500 mg (10 mg/ml) concentrate for solution for infusion
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 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 MabThera is indicated for first-line treatment of patients with chronic lymphocytic leukaemia (CLL) in combination with 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 (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.
Adult Dosage
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 is: 375 mg/m² body surface area per cycle, for up to 8 cycles.

Mabthera should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.

Monotherapy/Maintenance

The recommended dose of MabThera used as a maintenance treatment for patients with relapsed/refractory follicular NHL who have responded to induction treatment with chemotherapy, with or without MabThera is: 375 mg/m² body surface area once every 3 months until disease progression or for a maximum period of two years.

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/m²body 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 NHL, the recommended dose is: 375 mg/m² body surface area, administered as an intravenous infusion once weekly for four weeks.

Diffuse large B cell non-Hodgkin's lymphoma

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 is 375 mg/m² body surface area administered on day 1 of the first treatment cycle followed by 500 mg/m²body 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

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.

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.

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 intravenous 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.

Specail populations

Paediatric use

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 Administration

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. 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 usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.
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 and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to any of the excipients or to murine proteins.

Active, severe infections.

Contraindications for use in rheumatoid arthritis

Hypersensitivity to the active substance or to any of the excipients or to murine proteins.

Active, severe infections.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease.
Special Precautions
Progressive Multifocal Leukoencephalopathy

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

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.

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated Lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.

Infusion related adverse reactions including cytokine release syndrome 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, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of 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 (cyclophosphamide, vincristine, and prednisone) chemotherapy, regular full blood counts should be performed according to usual medical practice.

Serious infections, including fatalities, can occur during therapy with MabThera. MabThera should not be administered to patients with an active and/or severe infection (eg. tuberculosis, sepsis and opportunistic infections).

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.

Very rare cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminant hepatitis with fatal outcome. 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 Leukoencephalopathy (PML) have been reported during post-marketing use of MabThera in NHL and CLL. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

The safety of immunisation 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-randomised 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 titre). For CLL patients similar results are assumable considering similarities between both diseases but this has not been investigated in clinical trials

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with MabThera.

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 intravenous glucocorticoid significantly reduced the incidence and severity of these events.

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, 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.

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.

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 ischaemic 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.MabThera should not be administered to patients with an active and/or severe infection (eg. tuberculosis, sepsis and opportunistic infections) 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.

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 Progressive Multifocal Leukoencephalopathy (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 hepatitis B reactivation have been reported (see non-Hodgkin's lymphoma).

Immunisation

Physicians should review the patient's vaccination status and follow current immunisation guidelines prior to MabThera therapy. Vaccination should be completed at least 4 weeks prior to first administration of MabThera.

The safety of immunisation 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 randomised 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 titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs

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. 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 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.
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.

In a cohort of patients with rheumatoid arthritis, 280 patients received subsequent therapy with other DMARDs, of whom 185 received biologic DMARD following MabThera. In these patients the rate of clinically relevant infection while on MabThera was 6.99 per 100 patient years compared to 5.49 per 100 patients years following treatment with the biologic DMARD.

Adverse Drug Reactions

Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

The overall safety profile of MabThera in nonHodgkin's lymphoma and chronic lymphocytic leukaemia is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving MabThera were infusion-related reactions which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 3055 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trial in patients with CLL.

The most frequent reported or observed serious adverse drug reactions were:

• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome).

• Infections

• Cardiovascular events

Other serious ADRs reported include hepatitis B reactivation and PML

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in the tables below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10) and uncommon ( 1/1,000 to < 1/100). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “unknown”.

Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy

System Organ Class	Very Common	Common	Uncommon	Unknown
Infections and infestations	bacterial infections , viral infections , ⁺ bronchitis	sepsis, ⁺ pneumonia, ⁺ febrile infection, ⁺ herpes zoster, ⁺ respiratory tract infection, fungal infections, infections of unknown aetiology, ⁺ acute bronchitis, ⁺ sinusitis		serious viral infection¹ , hepatitis B reactivation¹
Blood and lymphatic system disorders	neutropenia, leucopenia, ⁺ febrile neutropenia	anaemia, thrombocytopenia, ⁺ pancytopenia	coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy	Late neutropenia² , transient increase in serum IgM levels²
Immune system disorders	infusion related reactions, angioedema	hypersensitivity		Tumour lysis syndrome³ , cytokine release syndrome³ , serum sickness, anaphylaxis
Metabolism and nutrition disorders		hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia
Psychiatric disorders			depression, nervousness,
Nervous system disorders		paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety	Dysgeusia	cranial neuropathy, peripheral neuropathyfacial nerve palsy⁴ , loss of other senses⁴
Eye disorders		lacrimation disorder, conjunctivitis		severe vision loss⁴
Ear and labyrinth disorders		tinnitus, ear pain		hearing loss⁴
Cardiac disorders		⁺ myocardial infarction^{3 and 5} , arrhythmia, ⁺ atrial fibrillation, tachycardia, ⁺ cardiac disorder	⁺ left ventricular failure, ⁺ supraventricular tachycardia, ⁺ ventricular tachycardia, ⁺ angina, ⁺ myocardial ischaemia, bradycardia,	heart failure^{3 and 5} , severe cardiac events ^{3 and 5}
Vascular disorders		hypertension, orthostatic hypotension, hypotension		vasculitis (predominately cutaneous), leukocytoclastic vasculitis
Respiratory, thoracic and mediastinal disorders		bronchospasm³ , respiratory disease, chest pain, dyspnoea, increased cough, rhinitis	asthma, bronchiolitis obliterans, lung disorder, hypoxia	respiratory failure³ , pulmonary infiltrates, interstitial pneumonitis
Gastrointestinal disorders	nausea	vomiting , diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation	abdominal enlargement	gastro-intestinal perforation⁶
Skin and subcutaneous tissue disorders	pruritus, rash, ⁺ alopecia	urticaria, sweating, night sweats, ⁺ skin disorder		severe bullous skin reactions, toxic epidermal necrolysis⁶
Musculoskeletal, connective tissue and bone disorders		hypertonia, myalgia, arthralgia, back pain, neck pain, pain
Renal and urinary disorders				renal failure³
General disorders and administration site conditions	fever , chills, asthenia, headache	tumour pain, flushing, malaise, cold syndrome, ⁺ fatigue, ⁺ shivering,⁺ multi-organ failure³	pain at the infusion site
Investigations	decreased IgG levels
For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe ( grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported 1 see also section infection below 2 see also section haematologic adverse reactions below 3 see also section infusion-related reactions below. Rarely fatal cases reported 4 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 5 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions6 includes fatal cases

The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the MabThera-arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Infusion-related reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in about 10 % of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation and pulmonary oedema. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1 % of patients by the eighth cycle of MabThera (-containing) treatment.

Infections

MabThera induces B-cell depletion in about 70-80 % of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster was reported at a higher incidence in the MabThera-containing arm of randomised studies. Severe infections were reported in about 4 % of patients. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of hepatitis B reactivation, have been reported, the majority of which were in subjects receiving MabThera in combination with cytotoxic chemotherapy. Progression of Kaposi's sarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic Adverse Reactions

In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2 %, anaemia in 1.1 % and thrombocytopenia in 1.7 % of the patients. During MabThera maintenance treatment for up to 2 years, leucopenia (5 % vs 2 %, grade 3/4) and neutropenia (10 % vs 4 %, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1, grade 3/4 %) and was not different between treatment arms. In studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88 % vs CHOP 79 %, R-FC 23 % vs FC 12 %), neutropenia (R-CVP 24 % vs CVP 14 %; R-CHOP 97 % vs. CHOP 88 %, R-FC 30 % vs FC 19 %), pancytopenia (R-FC 3 % vs FC 1 %) were reported higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone and the neutropenia was not prolonged in the MabThera group. There were no differences reported for the incidence of thrombocytopenia or anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs FC 71%).

In studies of MabThera in patients with Waldenstrom's macroglobulinaemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

Cardiovascular reactions

Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8 % of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3 % of patients treated with MabThera compared to <1 % on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9 %) as compared to the CHOP group (3 patients, 1.5 %). All of these arrhythmias either occurred in the context of a 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. In the CLL first-line study, the overall incidence of grade 3 or 4 cardiac disorders was low (4 % R-FC, 3 % FC).

Neurologic events

During the treatment period, four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5 %) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In the CLL first-line study, the overall incidence of grade 3 or 4 nervous system disorders was low (4 % R-FC, 4 % FC).

Gastrointestinal Disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non Hodgkin's lymphoma. In the majority of these cases, MabThera was administered with chemotherapy.

IgG levels

In the clinical trial evaluating MabThera maintenance treatment, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment 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 in the MabThera group. 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).

Patient subpopulations (MabThera monotherapy)

Elderly patients ( 65 years):

The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to younger patients (<65 years).

Bulky disease

There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these two groups.

Re-treatment

The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).

Experience from rheumatoid arthritis

The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

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 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 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 below. Frequencies are defined as very common (1/10) and common (1/100 to <1/10). 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 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. The safety information collected during post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for MabThera.

Table 2 Summary of Adverse Drug Reactions Reported in Clinical Trials or During Postmarketing Surveillance Occurring in Patients with Rheumatoid Arthritis receiving MabThera

System Organ Class	Very Common	Common	Uncommon
Infections and Infestations	any infection, upper respiratory tract infection	urinary tract infections
Immune System Disorders	*Infusion related reactions (nausea, chills, rhinitis, urticaria hot flush) hypertension, rash, pyrexia, pruritus, throat irritation and hypotension		*Infusion related reactions (generalised oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalised pruritus, anaphylaxis, anaphylactoid reaction)
General disorders and administration site conditions
Metabolism and Nutritional Disorders		hypercholesterolaemia
Nervous System disorders		Paraesthesia, migraine
Gastrointestinal Disorders		dyspepsia
Musculo skeletal disorders		arthralgia / musculoskeletal pain, osteoarthritis
*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 Courses

The limited clinical trial data on multiple courses of treatment of RA patients seem to be associated with a similar ADR 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.

Infusion-related reactions

Symptoms suggesting an acute infusion reaction (e.g.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 intravenous glucocorticoid significantly reduced the incidence and severity of these events. Of the patients who received 1000 mg rituximab without premeditation with glucocorticoids, 18/65 (28 %) experienced an acute infusion reaction, compared with 24/127 (19 %) in patients given intravenous glucocorticoid premeditation, 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.

Cases of Progressive Multifocal Leukoencephalopathy 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. All the reported cases had multiple risk factors for PML, including either the underlying disease and or long-term immunosuppressive therapy or chemotherapy.

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 %).